WorldWideScience

Sample records for antiretroviral drug resistance

  1. Public health implications of antiretroviral therapy and HIV drug resistance.

    Science.gov (United States)

    Wainberg, M A; Friedland, G

    1998-06-24

    Widespread use of antiretroviral agents and increasing occurrence of human immunodeficiency virus (HIV) strains resistant to these drugs have given rise to a number of important issues. Some of these concerns are distinct from the obvious question of the relationship between drug resistance and treatment failure and have potentially widespread public health implications. The relevant issues include but are not limited to the following: (1) frequency with which drug-resistant virus may be transmitted via sexual, intravenous, or mother-to-child routes; (2) ability of drug-resistant variants to be transmitted, a question that relates, in part, to the relative fitness of such strains; (3) effectiveness of antiviral therapy in diminishing viral burden in both blood and genital secretions, and whether this may be compromised in persons harboring resistant virus; and (4) importance of patient adherence to antiviral therapy and its relationship to sustained reduction in viral load to minimize the appearance in and transmission of drug-resistant virus from both blood and genital secretions. Thus, prevention of both development of HIV drug resistance as well as transmission of drug-resistant variants is a central issue of public health importance. Unless this topic is appropriately addressed, the likelihood is that drug-resistant variants of HIV, if able to successfully replicate, will sustain the epidemic and limit the effectiveness of antiviral therapy. PMID:9643862

  2. Antiretroviral drugs.

    Science.gov (United States)

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one. PMID:20471318

  3. Antiretroviral drugs.

    Science.gov (United States)

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one.

  4. Estimating prevalence of accumulated HIV-1 drug resistance in a cohort of patients on antiretroviral therapy

    DEFF Research Database (Denmark)

    Bannister, Wendy P; Cozzi-Lepri, Alessandro; Kjær, Jesper;

    2011-01-01

    Estimating the prevalence of accumulated HIV drug resistance in patients receiving antiretroviral therapy (ART) is difficult due to lack of resistance testing at all occasions of virological failure and in patients with undetectable viral load. A method to estimate this for 6498 EuroSIDA patients...

  5. Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala

    NARCIS (Netherlands)

    N. Ndembi; R.L. Hamers; K.C.E. Sigaloff; F. Lyagoba; B. Magambo; B. Nanteza; C. Watera; P. Kaleebu; T.F. Rinke de Wit

    2011-01-01

    To assess the emergence of transmitted HIV-1 drug resistance (TDR) in Kampala, Uganda, 10 years after the scale-up of antiretroviral treatment (ART) and to compare with a previous survey among antenatal clinic attendees in 2007 (reporting 0% TDR). A cross-sectional survey was conducted among newly H

  6. Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

    Directory of Open Access Journals (Sweden)

    Susana Monge

    Full Text Available BACKGROUND: The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR defined by the 2009 update of the WHO SDRM list. METHODS: We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". RESULTS: 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9 vs. 3.6% (2.9-4.3 by the WHO list] and PIs [0.8% (0.4-1.1 vs. 1.7% (1.2-2.2], while it was higher for NNRTIs [4.6% (3.8-5.3 vs. 3.7% (3.0-4.7]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02. CONCLUSIONS: Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

  7. HIV-1 drug resistance among antiretroviral treatment-naïve Ethiopian patients

    Directory of Open Access Journals (Sweden)

    A Mulu

    2012-11-01

    Full Text Available Background: In many African countries, access to antiretroviral treatment (ART has been significantly scaled up over the last five years. Nevertheless, data on drug resistance mutation are scarce. The objective of the current study was to determine the predominant subtypes of HIV-1 as well as to identify baseline mutations with potential drug resistance among ART-naïve patients from Ethiopia. Methods: Genotypic drug resistance on the entire protease and partial reverse transcriptase (codons 1–335 regions of the pol gene was determined by an in-house protocol in 160 ART-naïve patients. Genotypic drug resistance was defined as the presence of one or more resistance-related mutations, as specified by the consensus of the Stanford University HIV drug resistance database (HIVDB available at http://hivdb.stanford.edu/ and the 2011 International AIDS Society (IAS mutation list (http://www.iasusa.org/resistance-mutations/. Results: A predominance of HIV-1 subtype C (98.7% was observed. According to the IAS mutation list, antiretroviral drug resistance mutations were detected in 20 patients (13%. However, the level of drug resistance is 5.2% (8/155 when the most conservative method, HIVDB algorithms were applied. In both algorithms, none had major PI mutation and mutation-conferring resistance to NRTI and NNRTI were not overlapping. Conclusions: There is strong evidence for clade homogeneity in Ethiopia and low influx of other subtypes to the country. The level of transmitted drug resistance exceeds that of WHO estimates and indicates that many HIV-infected individuals on ART are practicing risk-related behaviours. The results also show that HIV drug resistance testing should be installed in resource limited settings.

  8. Antiretroviral drug resistance mutations in naïve and experienced patients in Shiraz, Iran, 2014.

    Science.gov (United States)

    Naziri, Hamed; Baesi, Kazem; Moradi, Abdolvahab; Aghasadeghi, Mohammad R; Tabarraei, Alijan; McFarland, Willi; Davarpanah, Mohamad Ali

    2016-09-01

    Resistance to antiretroviral agents is a significant concern in the clinical management of HIV-infected individuals, particularly in areas of the world where treatment options are limited. In this study, we aimed to identify HIV drug-resistance-associated mutations in 40 drug-naïve patients and 62 patients under antiretroviral therapy (ART) referred to the Shiraz HIV/AIDS Research Center - the first such data available for the south of Iran. HIV reverse transcriptase and protease genes were amplified and sequenced to determine subtypes and antiretroviral- resistance-associated mutations (RAMs). Subtype CRF35-AD recombinant was the most prevalent in all patients (98 of 102, 96 %), followed by subtype A1, and subtype B (one each, 2 %). Among the 40 ART-naïve patients, two mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance (two with Y115F and T215I) and three associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (two with G190S and Y181C, four with V179T) were found. Among ART-experienced patients, four mutations associated with resistance to NRTI, four with NNRTI, and five with protease inhibitors (PI) were found. Twenty patients with high levels of resistance were already on second-line therapy. We document for the first time in this region of Iran high levels of ART resistance to multiple drugs. Our findings call for more vigilant systematic ART resistance surveillance, increased resistance testing, careful management of patients with existing regimens, and strong advocacy for expansion of available drugs in Iran. PMID:27368990

  9. Emergence of HIV-1 drug resistance mutations among antiretroviral-naïve HIV-1-infected patients after rapid scaling up of antiretroviral therapy in Thailand

    Directory of Open Access Journals (Sweden)

    Sungkanuparph Somnuek

    2012-03-01

    Full Text Available Abstract Background After rapid scaling up of antiretroviral therapy in HIV-1-infected patients, the data of primary HIV-1 drug resistance in Thailand is still limited. This study aims to determine the prevalence and associated factors of primary HIV-1 drug resistance in Thailand. Methods A prospective observational study was conducted among antiretroviral-naïve HIV-1-infected Thai patients from 2007 to 2010. HIV-1 subtypes and mutations were assayed by sequencing a region of HIV-1 pol gene. Surveillance drug resistance mutations recommended by the World Health Organization for surveillance of transmitted HIV-1 drug resistance in 2009 were used in all analyses. Primary HIV-1 drug resistance was defined as the presence of one or more surveillance drug resistance mutations. Results Of 466 patients with a mean age of 38.8 years, 58.6% were males. Risks of HIV-1 infection included heterosexual (77.7%, homosexual (16.7%, and intravenous drug use (5.6%. Median (IQR CD4 cell count and HIV-1 RNA were 176 (42-317 cells/mm3 and 68,600 (19,515-220,330 copies/mL, respectively. HIV-1 subtypes were CRF01_AE (86.9%, B (8.6 and other recombinants (4.5%. The prevalence of primary HIV-1 drug resistance was 4.9%; most of these (73.9% had surveillance drug resistance mutations to only one class of antiretroviral drugs. The prevalence of patients with NRTI, NNRTI, and PI surveillance drug resistance mutations was 1.9%, 2.8% and 1.7%, respectively. From logistic regression analysis, there was no factor significantly associated with primary HIV-1 drug resistance. There was a trend toward higher prevalence in females [odds ratio 2.18; 95% confidence interval 0.896-5.304; p = 0.086]. Conclusions There is a significant emergence of primary HIV-1 drug resistance in Thailand after rapid scaling up of antiretroviral therapy. Although HIV-1 genotyping prior to antiretroviral therapy initiation is not routinely recommended in Thailand, our results raise concerns about the

  10. Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection.

    Science.gov (United States)

    Menéndez-Arias, Luis; Alvarez, Mar

    2014-02-01

    One to two million people worldwide are infected with the human immunodeficiency virus type 2 (HIV-2), with highest prevalences in West African countries, but also present in Western Europe, Asia and North America. Compared to HIV-1, HIV-2 infection undergoes a longer asymptomatic phase and progresses to AIDS more slowly. In addition, HIV-2 shows lower transmission rates, probably due to its lower viremia in infected individuals. There is limited experience in the treatment of HIV-2 infection and several antiretroviral drugs used to fight HIV-1 are not effective against HIV-2. Effective drugs against HIV-2 include nucleoside analogue reverse transcriptase (RT) inhibitors (e.g. zidovudine, tenofovir, lamivudine, emtricitabine, abacavir, stavudine and didanosine), protease inhibitors (saquinavir, lopinavir and darunavir), and integrase inhibitors (raltegravir, elvitegravir and dolutegravir). Maraviroc, a CCR5 antagonist blocking coreceptor binding during HIV entry, is active in vitro against CCR5-tropic HIV-2 but more studies are needed to validate its use in therapeutic treatments against HIV-2 infection. HIV-2 strains are naturally resistant to a few antiretroviral drugs developed to suppress HIV-1 propagation such as nonnucleoside RT inhibitors, several protease inhibitors and the fusion inhibitor enfuvirtide. Resistance selection in HIV-2 appears to be faster than in HIV-1. In this scenario, the development of novel drugs specific for HIV-2 is an important priority. In this review, we discuss current anti-HIV-2 therapies and mutational pathways leading to drug resistance. PMID:24345729

  11. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel

    OpenAIRE

    Hirsch, M S; Günthard, H F; Schapiro, J. M.; Brun-Vézinet, F.; Clotet, B; Hammer, S M; Johnson, V A; Kuritzkes, D.R.; Mellors, J W; Pillay, D; Yeni, P G; Jacobsen, D M; Richman, D. D.

    2008-01-01

    Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug...

  12. Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba.

    Science.gov (United States)

    Pérez, Lissette; Kourí, Vivian; Alemán, Yoan; Abrahantes, Yeisel; Correa, Consuelo; Aragonés, Carlos; Martínez, Orlando; Pérez, Jorge; Fonseca, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Dekeersmaeker, Nathalie; Imbrechts, Stijn; Beheydt, Gertjan; Vinken, Lore; Soto, Yudira; Álvarez, Alina; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2013-06-01

    In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007-2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%-4.8%) in 2003 versus 12.5% (CI 7.2%-14.5%) in 2007-2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%-17.0%) in 2007-2011 versus 3.8% (CI 0.9%-4.7%) in 2003 (OR 3.9, CI 1.5-17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the

  13. Drug-resistant tuberculosis among HIV-infected patients starting antiretroviral therapy in Durban, South Africa.

    Directory of Open Access Journals (Sweden)

    Jeffrey K Hom

    Full Text Available OBJECTIVE: To estimate the prevalence of drug-resistant tuberculosis (TB and describe the resistance patterns in patients commencing antiretroviral therapy (ART in an HIV clinic in Durban, South Africa. DESIGN: Cross-sectional cohort study. METHODS: Consecutive HIV-infected adults (≥ 18y/o initiating HIV care were enrolled from May 2007-May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium. Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed. RESULTS: 1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42-150/µl. 267 subjects (26% reported a prior history of TB and 210 (20% were receiving TB treatment at enrollment; 191 (18% subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0-12.4. Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9-30.5 compared to 5.2% (95% CI 2.1-8.9 among those with no prior TB. 5.1% (95% CI 2.4-9.5 had rifampin or rifampin plus INH resistance. CONCLUSIONS: The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.

  14. Short Communication: Transmitted HIV Drug Resistance in Antiretroviral-Naive Pregnant Women in North Central Nigeria

    Science.gov (United States)

    Sagay, Atiene S.; Chaplin, Beth; Chebu, Philippe; Musa, Jonah; Okpokwu, Jonathan; Hamel, Donald J.; Pam, Ishaya C.; Agbaji, Oche; Samuels, Jay; Meloni, Seema; Sankale, Jean-Louis; Okonkwo, Prosper; Kanki, Phyllis

    2014-01-01

    Abstract The World Health Organization (WHO) recommends periodic surveillance of transmitted drug resistance (TDR) in communities in which antiretroviral therapy (ART) has been scaled-up for greater than 3 years. We conducted a survey of TDR mutations among newly detected HIV-infected antiretroviral (ARV)-naive pregnant women. From May 2010 to March 2012, 38 ARV-naive pregnant women were recruited in three hospitals in Jos, Plateau state, north central Nigeria. Eligible subjects were recruited using a modified version of the binomial sequential sampling technique recommended by WHO. HIV-1 genotyping was performed and HIV-1 drug resistance mutations were characterized according to the WHO 2009 surveillance drug resistance mutation (SDRM) list. HIV subtypes were determined by phylogenetic analysis. The women's median age was 25.5 years; the median CD4+ cell count was 317 cells/μl and the median viral load of 16 was 261 copies/ml. Of the 38 samples tested, 34 (89%) were successfully genotyped. The SDRM rate was <5% for all ART drug classes, with 1/34 (2.9%) for NRTIs/NNRTIs and none for protease inhibitors 0/31 (0%). The specific SDRMs detected were M41L for nucleoside reverse transcriptase inhibitors (NRTIs) and G190A for nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIV-1 subtypes detected were CRF02_AG (38.2%), G′ (41.2%), G (14.7%), CRF06-CPX (2.9%), and a unique AG recombinant form (2.9%). The single ARV-native pregnant woman with SDRMs was infected with HIV-1 subtype G′. Access to ART has been available in the Jos area for over 8 years. The prevalence of TDR lower than 5% suggests proper ART administration, although continued surveillance is warranted. PMID:24164431

  15. Transmitted antiretroviral drug resistance mutations in newly diagnosed HIV-1 positive patients in Turkey

    Directory of Open Access Journals (Sweden)

    Murat Sayan

    2014-11-01

    Full Text Available Introduction: The objective of this study was to determine the transmitted drug resistance mutations (TDRMs in newly diagnosed HIV-1 positive patients in Turkey. Materials and Methods: The study was carried out between 2009 and 2014 and antiretroviral naïve 774 HIV-1 infected patients from 19 Infectious Diseases and Clinical Microbiology Departments in Turkey were included; gender: 664 (86% male, median age: 37 (range; 1–77, median CD4+T-cell: 360 (range; 1–1320 count/mm3, median HIV-RNA load: 2.10+E6 (range; 4.2+E2–7.41+E8 IU/mL. HIV-1 drug resistance mutations were detected by population based sequencing of the reverse transcriptase (codon 41–238 and protease (codon 1–99 domains of pol gene of HIV-1, and analyzed according to the criteria by the World Health Organization 2009 list of surveillance drug resistance mutations [1]. Results: The patients had TDRMs to NRTIs (K65R, M184V, NNRTIs (K101E, K103N/S, G190A/E/S, Y181I/C, Y188H/L and PIs (M46L, I54V, L76V, V82L/T, N83D, I84V, L90M. The prevalence of overall TDRMs was 6.7% (52/774. Resistance mutations were found to be 0.7% (6/774, 4.1% (32/774 and 2.1% (17/774 to NRTIs, NNRTIs and PIs drug groups, respectively. Three patients had NRTIs+NNRTs resistance mutations (M184V+K103N as multi-class drug resistance. However, thymidine analogue resistance mutations (TAMs determined two distinct genotypic profiles in the HIV-1 reverse transcriptase: TAM1: M41L, L210W and T215Y, and TAM2: D67N, K70R, K219E/Q, and T215F. The prevalence of TAM1 and TAM2 were 7.7% (60/774 and 4.3% (34/774, respectively. Conclusions: The TDRMs prevalence of antiretroviral naïve HIV-1 infected patients may be suggested current situation of Turkey. These long-term and large-scale results show that the resistance testing must be an integral part of the management of HIV infection in Turkey.

  16. Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study

    DEFF Research Database (Denmark)

    Cozzi-Lepri, Alessandro; Phillips, Andrew N; Clotet, Bonaventura;

    2008-01-01

    OBJECTIVE(S): To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. DESIGN: Virological failure was defined as experiencing two consecutive viral loads of more than 400 cop...

  17. HIV-1 Drug Resistance Mutations Are Present in Six Percent of Persons Initiating Antiretroviral Therapy in Lusaka, Zambia

    NARCIS (Netherlands)

    R.L. Hamers; M. Siwale; C.L. Wallis; M. Labib; R. van Hasselt; W.S. Stevens; R. Schuurman; A.M.J. Wensing; M. van Vugt; T.F. Rinke de Wit

    2010-01-01

    Objective: To assess the mutational patterns and factors associated with baseline drug-resistant HIV-1 present at initiation of first-line antiretroviral therapy (ART) at 3 sites in Lusaka, Zambia, in 2007-2008. Methods: Population sequencing of the HIV-1 pol gene was performed in the PharmAccess Af

  18. Evolution of drug resistance in HIV-infected patients remaining on a virologically failing combination antiretroviral therapy regimen

    DEFF Research Database (Denmark)

    Cozzi-Lepri, Alessandro; Phillips, Andrew N; Ruiz, Lidia;

    2007-01-01

    OBJECTIVE: To estimate the extent of drug resistance accumulation in patients kept on a virologically failing regimen and its determinants in the clinical setting. DESIGN: The study focused on 110 patients of EuroSIDA on an unchanged regimen who had two genotypic tests performed at two time points...... (t0 and t1) when viral load was > 400 copies/ml. METHODS: Accumulation of resistance between t0 and t1 was measured using genotypic susceptibility scores (GSS) obtained by counting the total number of active drugs (according to the Rega system v6.4.1) among all licensed antiretrovirals as of 1...... January 2006. Patients were grouped according to the number of active drugs in the failing regimen at t0 (GSS_f-t0). RESULTS: At t0, patients had been on the failing combination antiretroviral therapy (cART) for a median of 11 months (range, 6-50 months). Even patients with extensive resistance...

  19. Surveillance of transmitted HIV drug resistance in antiretroviral-naive patients aged less than 25 years, in Bangkok, Thailand.

    Science.gov (United States)

    Sungkanuparph, Somnuek; Pasomsub, Ekawat; Chantratita, Wasun

    2014-01-01

    Emergence of transmitted HIV drug resistance (TDR) is a concern after global scale-up of antiretroviral therapy (ART). World Health Organization had developed threshold survey method for surveillance of TDR in resource-limited countries. ART in Thailand has been scaling up for >10 years. To evaluate the current TDR in Thailand, a cross-sectional study was conducted among antiretroviral-naive HIV-infected patients aged Thailand after a decade of rapid scale-up of ART. Interventions to prevent TDR at the population level are essentially needed in Thailand. Surveillance for TDR in Thailand has to be regularly performed.

  20. Use of cohort data to estimate national prevalence of transmitted drug resistance to antiretroviral drugs in Spain (2007-2012).

    Science.gov (United States)

    Monge, S; Díez, M; Alvarez, M; Guillot, V; Iribarren, J A; Palacios, R; Delgado, R; Jaén, A; Blanco, J R; Domingo, P; Portilla, J; Pérez Elías, M J; Garcia, F

    2015-01-01

    Prevalence of transmitted drug resistance (pTDR) to antiretroviral drugs in Spain (2007-2012) was estimated using the CoRIS cohort, adjusting its territorial distribution and transmission route to the reference population from the Spanish Information System on New human immunodeficiency virus diagnoses. A total of 2702 patients from ten autonomous communities and with naive FASTA sequence within 6 months of human immunodeficiency virus diagnosis were selected. Weighted pTDR, estimated using the inverse probability of selection in the sample by autonomous communities and transmission group, was 8.12% (95% CI 6.44-9.80), not significantly different from unweighted pTDR. We illustrate how proportional weighting can maximize representativeness of cohort-based data, and its value to monitor pTDR at country level. PMID:25636937

  1. Increasing HIV-1 pretreatment drug resistance among antiretroviral-naïve adults initiating treatment between 2006 and 2014 in Nairobi, Kenya.

    Science.gov (United States)

    Chung, Michael H; Silverman, Rachel; Beck, Ingrid A; Yatich, Nelly; Dross, Sandra; McKernan-Mullin, Jennifer; Bii, Stephen; Tapia, Kenneth; Stern, Joshua; Chohan, Bhavna; Sakr, Samah R; Kiarie, James N; Frenkel, Lisa M

    2016-06-19

    Antiretroviral-naïve adults initiating antiretroviral therapy in Nairobi, Kenya were tested for HIV-1 drug resistance at codons K103N, Y181C, G190A, M184V, and K65R using an oligonucleotide ligation assay. Prevalence of pretreatment drug resistance increased from 3.89% in 2006 to 10.93% in 2014 (P nonnucleoside reverse transcriptase inhibitor mutation. Resistance to tenofovir (K65R) was found in 2014 but not in 2006. PMID:27058353

  2. Small-Molecule Inhibition of HIV pre-mRNA Splicing as a Novel Antiretroviral Therapy to Overcome Drug Resistance

    OpenAIRE

    Nadia Bakkour; Yea-Lih Lin; Sophie Maire; Lilia Ayadi; Florence Mahuteau-Betzer; Chi Hung Nguyen; Clément Mettling; Pierre Portales; David Grierson; Benoit Chabot; Philippe Jeanteur; Christiane Branlant; Pierre Corbeau; Jamal Tazi

    2007-01-01

    Author Summary Over the two decades highly active antiretroviral therapy (HAART) for the treatment of HIV infection has led to a significant decline in morbidity and mortality rates among HIV-infected individuals. HAART uses a combination of molecules that target the virus itself. However, naturally occurring and extensive genetic variation found in the virus allow the emergence of drug-resistant viruses, which rapidly render individuals untreatable. An alternative approach for effective anti...

  3. Mechanistic insights into the role of secondary mutations of HIV-1 reverse transcriptase in the acquisition of antiretroviral drug resistance

    OpenAIRE

    Betancor Quintana, Gilberto José

    2013-01-01

    Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17-12-2013 The human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS). Highly active antiretroviral therapy (HAART) has resulted in substantial improvements of the health of HIV-infected patients. However, the emergence of drug-resistant viral strains is still one of the major factors hampering effective resp...

  4. Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment

    DEFF Research Database (Denmark)

    Phillips, Andrew N; Cambiano, Valentina; Miners, Alec;

    2014-01-01

    BACKGROUND: With continued roll-out of antiretroviral therapy (ART) in resource-limited settings, evidence is emerging of increasing levels of transmitted drug-resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial......-effectiveness threshold. Results from our model will help inform WHO recommendations on monitoring of HIV drug resistance in people starting ART. FUNDING: WHO (with funds provided by the Bill & Melinda Gates Foundation), CHAIN (European Commission)....

  5. Small-molecule inhibition of HIV pre-mRNA splicing as a novel antiretroviral therapy to overcome drug resistance.

    Directory of Open Access Journals (Sweden)

    Nadia Bakkour

    2007-10-01

    Full Text Available The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16 that interferes with exonic splicing enhancer activity of the SR protein splicing factor SF2/ASF suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles. IDC16 inhibits replication of macrophage- and T cell-tropic laboratory strains, clinical isolates, and strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Importantly, drug treatment of primary blood cells did not alter splicing profiles of endogenous genes involved in cell cycle transition and apoptosis. Thus, human splicing factors represent novel and promising drug targets for the development of antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.

  6. Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia

    DEFF Research Database (Denmark)

    Abdissa, Alemseged; Yilma, Daniel; Fonager, Jannik;

    2014-01-01

    BACKGROUND: The ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub......-Saharan Africa is sparse. METHODS: HIV viral load (VL) and resistance mutations pre-ART and after 6 months were determined in a prospective cohort study of ART-naïve HIV patients initiating first-line therapy in Jimma, Ethiopia. VL measurements were done at baseline and after 3 and 6 months. Genotypic HIV drug...... was observed among 14 (5.3%) participants out of 265 patients. Twelve samples were genotyped and six had HIV drug resistance (HIVDR) mutations at baseline. Among virological failures, 9/11 (81.8%) harbored one or more HIVDR mutations at 6 months. The most frequent mutations were K103N and M184VI. CONCLUSIONS...

  7. The use of dried blood spot specimens for HIV-1 drug resistance genotyping in young children initiating antiretroviral therapy

    Science.gov (United States)

    Salimo, Anna T.; Ledwaba, Johanna; Coovadia, Ashraf; Abrams, Elaine J.; Technau, Karl-Günter; Kuhn, Louise; Morris, Lynn; Hunt, Gillian M.

    2015-01-01

    Paired plasma and dried blood spots (DBS) from 232 South African HIV-infected children initiating antiretroviral therapy (ART) were genotyped for drug resistance mutations, most of who had prior exposure to ART for prevention-of-mother-to-child-transmission. Non-nucleoside reverse transcriptase inhibitor mutations were most commonly detected in both specimen types, particularly Y181C/I and K103N/S. Resistance interpretation concordance was achieved in 97% of pairs with 7 children having mutations detected in DBS only. These results validate the preferential use of DBS specimens for HIVDR genotyping in this patient group. PMID:26192603

  8. HIV Drug Resistance-Associated Mutations in Antiretroviral Naïve HIV-1-Infected Latin American Children

    Directory of Open Access Journals (Sweden)

    Luis E. Soto-Ramirez

    2010-01-01

    Full Text Available Our goal was to describe the presence of HIV drug resistance among HIV-1-infected, antiretroviral (ARV naïve children and adolescents in Latin America and to examine resistance in these children in relation to drug exposure in the mother. Genotyping was performed on plasma samples obtained at baseline from HIV-1-infected participants in a prospective cohort study in Brazil, Argentina, and Mexico (NISDI Pediatric Study. Of 713 HIV-infected children enrolled, 69 were ARV naïve and eligible for the analysis. At enrollment, mean age was 7.3 years; 81.2% were infected with HIV perinatally. Drug resistance mutations (DRMs were detected in 6 (8.7%; 95% confidence interval 3.1–18.2% ARV-naïve subjects; none of the mothers of these 6 received ARVs during their pregnancies and none of the children received ARV prophylaxis. Reverse transcriptase mutations K70R and K70E were detected in 3 and 2 subjects, respectively; protease mutation I50 V was detected in 1 subject. Three of the 6 children with DRMs initiated ARV therapy during followup, with a good response in 2. The overall rate of primary drug resistance in this pediatric HIV-infected population was low, and no subjects had more than 1 DRM. Mutations associated with resistance to nucleoside reverse transcriptase inhibitors were the most prevalent.

  9. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study

    DEFF Research Database (Denmark)

    Wittkop, Linda; Günthard, Huldrych F; de Wolf, Frank;

    2011-01-01

    The effect of transmitted drug resistance (TDR) on first-line combination antiretroviral therapy (cART) for HIV-1 needs further study to inform choice of optimum drug regimens. We investigated the effect of TDR on outcome in the first year of cART within a large European collaboration....

  10. Genetic Diversity and Drug Resistance Among Antiretroviral Treatment-Failed Individuals from 2010 to 2012 in Honghe, China.

    Science.gov (United States)

    Yang, Cuixian; Yang, Shaomin; Li, Jianjian; Yang, Bihui; Liu, Jiafa; Li, Huiqin; Bian, Zhongqi

    2015-08-01

    The most common antiretroviral treatment (ART) received by individuals infected with HIV-1 in China is the combination therapy, comprised of nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). To assess the prevalence of HIV-1 drug resistance and subtypes in Honghe of Yunnan, China, patient plasmas from ART-failed individuals were collected from January 2010 to December 2012. Genotyping was conducted using an in-house assay on patient plasmas. A total of 254 pol sequences were obtained. The prevalence of drug resistance was 47.2% in ART-failed individuals. Of these drug-resistant individuals, 51.7% harbored HIV strains dually resistant to NRTIs and NNRTIs or protease inhibitors (PIs) (34.2% for NNRTIs and 14.2% for NRTIs). Mutations such as M184V, A62V, T69Ins, K103N, Y181C, and G190A were common among the ART-failed individuals. The frequencies of M184V, A62V, and K103N were 20.5%, 11.0%, and 23.6%, respectively. The most common subtypes in Honghe were CRF08_BC (68.50%) and CRF07_BC (12.20%). The subtypes were almost consistent in different time points for one individual. When receiving ART for 6-12 months, the frequency of HIV-1 drug-resistant variants ranked first. This study shows that the high prevalence of HIV drug resistance observed among the ART-failed individuals should be of increasing concern (monitoring of resistance mutations) in ART regions and facilitate developing novel strategies for prevention and control of HIV infection in China. PMID:25919896

  11. Transmitted antiretroviral drug resistance in treatment naïve HIV-infected persons in London in 2011 to 2013

    Directory of Open Access Journals (Sweden)

    Katie McFaul

    2014-11-01

    Full Text Available Introduction: Previously published UK data on HIV transmitted drug resistance (TDR shows that it ranges between 3 and 9.4% [1,2]. However, there are no recent data from populations where HIV transmission rates are increasing. The aim of this study was to assess the prevalence of TDR in untreated HIV-infected individuals attending three HIV specialist clinics under the HIV Directorate, Chelsea and Westminster Hospital and based throughout London – the Kobler Clinic, 56 Dean Street and West London Centre for Sexual Health. Methods: We included all patients with a HIV diagnosis, no history of antiretroviral therapy (ART intake, attending one of the three clinics (Kobler (K, 56 Dean Street (DS and West London (WL, between 2011 and 2013 who started antiretrovirals. Reverse transcriptase (RT and protease region sequencing was performed using Vircotype virtual phenotype resistance analysis. Drug resistance mutations were identified according to Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu/. Results: Among 1705 HIV-1-infected patients enrolled in the study, 1252 were males (919 were MSM, 107 were females and 346 had no gender recorded. Ethnicity was 51.1% white British/Irish/other, 6.1% African, 2.1% Caribbean, 2.8% Asian, 1.3% Indian/Pakistani/Bangladeshi, 4.2%, other, 3.2% not stated, and 29.2% unknown. 547 were from K (84.3% males, 48.3% MSM, 826 were from DS (84.3% males, 71.9% MSM, and 109 from WL (87.2% males, 56.0% MSM, 223 from other sites not specified. 77.5% (1321 of 1705 of patients had baseline viral resistance testing performed. Prevalence of primary resistance in those with a baseline viral resistance test was 13.5% overall: 19.3% in K, 14.9% in DS, and 14.7% in WL. The most common mutations detected were: NRTI: 184V, 215F, 41L; NNRTI 103N, 179D, 90I; PI 90M, 46I, and 82A. Among patients who tested with TDR, 79.1% had one single mutation, 18.7% and 2.2% exhibited dual or triple class-resistant viruses

  12. Drug resistance among newly-diagnosed HIV-infected children in the era of more efficacious antiretroviral prophylaxis

    Science.gov (United States)

    Kuhn, Louise; Hunt, Gillian; Technau, Karl-Günter; Coovadia, Ashraf; Ledwaba, Johanna; Pickerill, Sam; Penazzato, Martina; Bertagnolio, Silvia; Mellins, Claude A.; Black, Vivian; Morris, Lynn; Abrams, Elaine J.

    2015-01-01

    Background In the era of more efficacious prevention of mother-to-child transmission (PMTCT) regimens, documenting the profile of drug resistance in HIV-infected infants and young children is critical to our efforts to improve care and treatment for children. Methods HIV drug resistance mutations in plasma virus were ascertained using population sequencing among 230 newly-diagnosed HIV-infected children under 2 years of age recruited in Johannesburg, South Africa, during 2011. By this time, more effective PMTCT regimens, including combination antiretroviral therapy (cART) for pregnant women, were being implemented. Results Two-thirds (67.4%) of HIV-infected children had been exposed to some form of maternal (89%) and/or infant (97%) PMTCT. Among PMTCT-exposed, 56.8% had non-nucleoside reverse transcriptase inhibitor (NNRTI), 14.8% nucleoside reverse transcriptase inhibitor (NRTI), and 1.3% protease inhibitor (PI) mutations. NNRTI mutations were strongly related to younger age. The remaining third (32.6%) had no reported or recorded PMTCT exposures but resistance to NNRTI was detected in 24.0%, NRTI in 10.7% and PI in 1.3%. Conclusion The new PMTCT strategies dramatically reduce the number of children who acquire infection but among those who do become infected, NNRTI resistance prevalence is high. In this South African setting with high PMTCT coverage, almost a quarter of children with no reported or recorded PMTCT also have drug resistance mutations. PMTCT history is an inadequate means of ruling out pre-treatment drug resistance. Our results support the use of PI-based first-line regimens in HIV-infected infants and young children regardless of PMTCT history. PMID:24785949

  13. Emergence of minor drug-resistant HIV-1 variants after triple antiretroviral prophylaxis for prevention of vertical HIV-1 transmission.

    Directory of Open Access Journals (Sweden)

    Andrea Hauser

    Full Text Available BACKGROUND: WHO-guidelines for prevention of mother-to-child transmission of HIV-1 in resource-limited settings recommend complex maternal antiretroviral prophylaxis comprising antenatal zidovudine (AZT, nevirapine single-dose (NVP-SD at labor onset and AZT/lamivudine (3TC during labor and one week postpartum. Data on resistance development selected by this regimen is not available. We therefore analyzed the emergence of minor drug-resistant HIV-1 variants in Tanzanian women following complex prophylaxis. METHOD: 1395 pregnant women were tested for HIV-1 at Kyela District Hospital, Tanzania. 87/202 HIV-positive women started complex prophylaxis. Blood samples were collected before start of prophylaxis, at birth and 1-2, 4-6 and 12-16 weeks postpartum. Allele-specific real-time PCR assays specific for HIV-1 subtypes A, C and D were developed and applied on samples of mothers and their vertically infected infants to quantify key resistance mutations of AZT (K70R/T215Y/T215F, NVP (K103N/Y181C and 3TC (M184V at detection limits of <1%. RESULTS: 50/87 HIV-infected women having started complex prophylaxis were eligible for the study. All women took AZT with a median duration of 53 days (IQR 39-64; all women ingested NVP-SD, 86% took 3TC. HIV-1 resistance mutations were detected in 20/50 (40% women, of which 70% displayed minority species. Variants with AZT-resistance mutations were found in 11/50 (22%, NVP-resistant variants in 9/50 (18% and 3TC-resistant variants in 4/50 women (8%. Three women harbored resistant HIV-1 against more than one drug. 49/50 infants, including the seven vertically HIV-infected were breastfed, 3/7 infants exhibited drug-resistant virus. CONCLUSION: Complex prophylaxis resulted in lower levels of NVP-selected resistance as compared to NVP-SD, but AZT-resistant HIV-1 emerged in a substantial proportion of women. Starting AZT in pregnancy week 14 instead of 28 as recommended by the current WHO-guidelines may further increase

  14. Transmitted drug resistant HIV-1 and association with virologic and CD4 cell count response to combination antiretroviral therapy in the EuroSIDA Study

    DEFF Research Database (Denmark)

    Bannister, Wendy P; Cozzi-Lepri, Alessandro; Clotet, Bonaventura;

    2008-01-01

    OBJECTIVES: To investigate prevalence of transmitted drug-resistant human immunodeficiency virus (TDR) and factors associated with TDR and to compare virological and CD4 count response to combination antiretroviral therapy. METHODS: In this study, 525 mostly chronically infected EuroSIDA patients...

  15. Virological outcome and patterns of HIV-1 drug resistance in patients with 36 months’ antiretroviral therapy experience in Cameroon

    Directory of Open Access Journals (Sweden)

    Avelin F Aghokeng

    2013-01-01

    Full Text Available Introduction: The current expansion of antiretroviral treatment (ART in the developing world without routine virological monitoring still raises concerns on the outcome of the strategy in terms of virological success and drug resistance burden. We assessed the virological outcome and drug resistance mutations in patients with 36 months’ ART experience, and monitored according to the WHO public health approach in Cameroon. Methods: We consecutively recruited between 2008 and 2009 patients attending a national reference clinic in Yaoundé – Cameroon, for their routine medical visits at month 36±2. Observance data and treatment histories were extracted from medical records. Blood samples were collected for viral load (VL testing and genotyping of drug resistance when HIV-1 RNA≥1000 copies/ml. Results: Overall, 376 HIV-1 infected adults were recruited during the study period. All, but four who received PMTCT, were ART-naïve at treatment initiation, and 371/376 (98.7% started on a first-line regimen that included 3TC +d4T/AZT+NVP/EFV. Sixty-six (17.6% patients experienced virological failure (VL≥1000 copies/ml and 53 carried a resistant virus, thus representing 81.5% (53/65 of the patients who failed. Forty-two out of 53 were resistant to nucleoside and non-nucleoside reverse-transcriptase inhibitors (NRTIs+NNRTIs, one to protease inhibitors (PI and NNRTIs, two to NRTIs only and eight to NNRTIs only. Among patients with NRTI resistance, 18/44 (40.9% carried Thymidine Analog Mutations (TAMs, and 13/44 (29.5% accumulated at least three NRTI resistance mutations. Observed NNRTI resistance mutations affected drugs of the regimen, essentially nevirapine and efavirenz, but several patients (10/51, 19.6% accumulated mutations that may have compromised etravirine use. Conclusions: We observed a moderate level of virological failure after 36 months of treatment, but a high proportion of patients who failed developed drug resistance. Although we

  16. Pharmacokinetics and drug-drug interactions of antiretrovirals: an update.

    Science.gov (United States)

    Dickinson, Laura; Khoo, Saye; Back, David

    2010-01-01

    Current antiretroviral treatment has allowed HIV infection to become a chronic manageable condition with many HIV patients living longer. However, available antiretrovirals are not without limitations, for example the development of resistance and adverse effects. Consequently, new drugs in existing and novel classes are urgently required to provide viable treatment options to patients with few remaining choices. Darunavir, etravirine, maraviroc and raltegravir have been recently approved for treatment-experienced patients and other agents such as rilpivirine, vicriviroc and elvitegravir are currently under phase III study. Clinical studies are necessary to optimise potential treatment combinations and to manage drug-drug interactions to help avoid toxicity or therapy failure. This review aims to summarise the pharmacokinetics and key drug-drug interaction studies for newly available antiretrovirals and those in development. Further information regarding drug-drug interactions of well established antiretrovirals and those recently approved are readily available online at sites such as http://www.hiv-druginteractions.org, http://www.clinicaloptions.com/hiv, http://hivinsite.ucsf.edu. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

  17. First-line antiretroviral treatment outcome in a patient presenting an HIV-1/2 multiclass drug resistant infection

    Directory of Open Access Journals (Sweden)

    E Castro

    2012-11-01

    Full Text Available Background: With the expansion of HIV-2 epidemic beyond African countries, co-infection with HIV-1 becomes a global challenge. We have recently identified an HIV-1/2 dual infection with both viruses bearing multiclass drug resistance in an untreated patient [1]. We now present the patient's combined antiretroviral treatment (cART outcome after 6 months follow-up. Patient and Methods: Clinical samples were obtained upon informed consent from a 23-year-old man living in Guinea-Bissau until March 2011 when he moved to Switzerland. As previously reported [1], HIV-1/2 co-infection was confirmed by HIV-1 PCR (21.000 copies/ml and total HIV-1/2 viremia (4.351 nU/ml by product-enhanced reverse transcriptase (PERT assay. The patient denied previous HIV testing or exposure to antiretroviral drugs. Dual infection consisted of HIV-1 CRF02_AG bearing resistance mutations M184V/V90I and HIV-2 clade A, harboring K65R/D67N mutations as amplified from proviral-DNA. Baseline CD4 + T-cell count was 408 cell/mm3. We initiated cART in accordance to drug resistance mutations (see below. Treatment compliance was assessed with an electronic pillbox device and drug-plasma concentrations. Clinical and laboratory follow up were done at weeks 2, 4, 9, 12 and 24. Results: cART was initiated with tenofovir/emtricitabine (TDF/FTC, boosted-darunavir (DRV/r and raltegravir(RAL. Treatment compliance was fluctuant during the first 3 months after which it remained stable with an average monthly intake of 92%. Antiretroviral drug-plasma concentrations were traced at percentile 25th. HIV-1 viremia became undetectable at week 12. Additionally, HIV-2 viremia was retrospectively assessed by real-time RT-PCR at two independent laboratories showing undetectable values across the study period including baseline. Thus, baseline viremia, as assessed by the PERT test for particle-associated reverse transcriptase activity was due to HIV-1 alone. CD4 + T-cell count was 559 cell/mm3 at

  18. Transmitted antiretroviral drug resistance in New York State, 2006-2008: results from a new surveillance system.

    Directory of Open Access Journals (Sweden)

    Adam C Readhead

    Full Text Available BACKGROUND: HIV transmitted drug resistance (TDR is a public health concern because it has the potential to compromise antiretroviral therapy (ART at the population level. In New York State, high prevalence of TDR in a local cohort and a multiclass resistant case cluster led to the development and implementation of a statewide resistance surveillance system. METHODOLOGY: We conducted a cross-sectional analysis of the 13,109 cases of HIV infection that were newly diagnosed and reported in New York State between 2006 and 2008, including 4,155 with HIV genotypes drawn within 3 months of initial diagnosis and electronically reported to the new resistance surveillance system. We assessed compliance with DHHS recommendations for genotypic resistance testing and estimated TDR among new HIV diagnoses. PRINCIPAL FINDINGS: Of 13,109 new HIV diagnoses, 9,785 (75% had laboratory evidence of utilization of HIV-related medical care, and 4,155 (43% had a genotype performed within 3 months of initial diagnosis. Of these, 11.2% (95% confidence interval [CI], 10.2%-12.1% had any evidence of TDR. The proportion with mutations associated with any antiretroviral agent in the NNRTI, NRTI or PI class was 6.3% (5.5%-7.0%, 4.3% (3.6%-4.9% and 2.9% (2.4%-3.4%, respectively. Multiclass resistance was observed in <1%. TDR did not increase significantly over time (p for trend = 0.204. Men who have sex with men were not more likely to have TDR than persons with heterosexual risk factor (OR 1.0 (0.77-1.30. TDR to EFV+TDF+FTC and LPV/r+TDF+FTC regimens was 7.1% (6.3%-7.9% and 1.4% (1.0%-1.8%, respectively. CONCLUSIONS/SIGNIFICANCE: TDR appears to be evenly distributed and stable among new HIV diagnoses in New York State; multiclass TDR is rare. Less than half of new diagnoses initiating care received a genotype per DHHS guidelines.

  19. HIV Drug Resistance Surveillance in Honduras after a Decade of Widespread Antiretroviral Therapy

    OpenAIRE

    Santiago Avila-Ríos; Claudia García-Morales; Daniela Tapia-Trejo; Rita I Meza; Nuñez, Sandra M.; Leda Parham; Norma A Flores; Diana Valladares; Pineda, Luisa M.; Dixiana Flores; Roxana Motiño; Víctor Umanzor; Candy Carbajal; Wendy Murillo; Ivette Lorenzana

    2015-01-01

    Introduction We assessed HIV drug resistance (DR) in individuals failing ART (acquired DR, ADR) and in ART-naïve individuals (pre-ART DR, PDR) in Honduras, after 10 years of widespread availability of ART. Methods 365 HIV-infected, ART-naïve, and 381 ART-experienced Honduran individuals were enrolled in 5 reference centres in Tegucigalpa, San Pedro Sula, La Ceiba, and Choluteca between April 2013 and April 2015. Plasma HIV protease-RT sequences were obtained. HIVDR was assessed using the WHO ...

  20. HIV-1 Transmitted Drug Resistance Mutations in Newly Diagnosed Antiretroviral-Naive Patients in Turkey.

    Science.gov (United States)

    Sayan, Murat; Sargin, Fatma; Inan, Dilara; Sevgi, Dilek Y; Celikbas, Aysel K; Yasar, Kadriye; Kaptan, Figen; Kutlu, Selda; Fisgin, Nuriye T; Inci, Ayse; Ceran, Nurgul; Karaoglan, Ilkay; Cagatay, Atahan; Celen, Mustafa K; Koruk, Suda T; Ceylan, Bahadir; Yildirmak, Taner; Akalın, Halis; Korten, Volkan; Willke, Ayse

    2016-01-01

    HIV-1 replication is rapid and highly error-prone. Transmission of a drug-resistant HIV-1 strain is possible and occurs within the HIV-1-infected population. In this study, we aimed to determine the prevalence of transmitted drug resistance mutations (TDRMs) in 1,306 newly diagnosed untreated HIV-1-infected patients from 21 cities across six regions of Turkey between 2010 and 2015. TDRMs were identified according to the criteria provided by the World Health Organization's 2009 list of surveillance drug resistance mutations. The HIV-1 TDRM prevalence was 10.1% (133/1,306) in Turkey. Primary drug resistance mutations (K65R, M184V) and thymidine analogue-associated mutations (TAMs) were evaluated together as nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations. NRTI TDRMs were found in 8.1% (107/1,306) of patients. However, TAMs were divided into three categories and M41L, L210W, and T215Y mutations were found for TAM1 in 97 (7.4%) patients, D67N, K70R, K219E/Q/N/R, T215F, and T215C/D/S mutations were detected for TAM2 in 52 (3.9%) patients, and M41L + K219N and M41L + T215C/D/S mutations were detected for the TAM1 + TAM2 profile in 22 (1.7%) patients, respectively. Nonnucleoside reverse transcriptase inhibitor-associated TDRMs were detected in 3.3% (44/1,306) of patients (L100I, K101E/P, K103N/S, V179F, Y188H/L/M, Y181I/C, and G190A/E/S) and TDRMs to protease inhibitors were detected in 2.3% (30/1,306) of patients (M46L, I50V, I54V, Q58E, L76V, V82A/C/L/T, N83D, I84V, and L90M). In conclusion, long-term and large-scale monitoring of regional levels of HIV-1 TDRMs informs treatment guidelines and provides feedback on the success of HIV-1 prevention and treatment efforts. PMID:26414663

  1. HIV-1 antiretroviral drug resistance in recently infected patients in Abidjan, Côte d'Ivoire: A 4-year survey, 2002-2006.

    Science.gov (United States)

    Toni, Thomas d'Aquin; Masquelier, Bernard; Minga, Albert; Anglaret, Xavier; Danel, Christine; Coulibaly, Ali; Chenal, Henri; Dabis, François; Salamon, Roger; Fleury, Hervé J

    2007-09-01

    We performed HIV-1 drug resistance genotypic analysis of viral isolates from 100 antiretroviral (ARV)-naive, recently HIV-1-infected (between 2002 and 2006) individuals from Abidjan (Côte d'Ivoire). The overall prevalence of HIV-1 variants with resistance mutations to reverse transcriptase, protease, or fusion inhibitors was 6%. The majority of isolates were CRF02_AG. Compared with a previous study carried out by our group in 2001-2002 in a similar population in Abidjan, our findings confirm the circulation and transmission of HIV-1 carrying key ARV drug resistance mutation.

  2. Taking Current Antiretroviral Drugs

    Science.gov (United States)

    ... INHIBITORS INTEGRASE INHIBITORS 1. NUCLEOSIDE AND NUCLEOTIDE ANALOG REVERSE TRANSCRIPTASE INHIBITORS (NUKES) DRUG DAILY PILLS (ADULTS) HOW TO TAKE & ... Don't combine with d4T. 2. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS** (NNRTIs or NON-NUKES) DRUG DAILY PILLS (Adults)* ...

  3. HIV Drug Resistance Surveillance in Honduras after a Decade of Widespread Antiretroviral Therapy.

    Directory of Open Access Journals (Sweden)

    Santiago Avila-Ríos

    Full Text Available We assessed HIV drug resistance (DR in individuals failing ART (acquired DR, ADR and in ART-naïve individuals (pre-ART DR, PDR in Honduras, after 10 years of widespread availability of ART.365 HIV-infected, ART-naïve, and 381 ART-experienced Honduran individuals were enrolled in 5 reference centres in Tegucigalpa, San Pedro Sula, La Ceiba, and Choluteca between April 2013 and April 2015. Plasma HIV protease-RT sequences were obtained. HIVDR was assessed using the WHO HIVDR mutation list and the Stanford algorithm. Recently infected (RI individuals were identified using a multi-assay algorithm.PDR to any ARV drug was 11.5% (95% CI 8.4-15.2%. NNRTI PDR prevalence (8.2% was higher than NRTI (2.2% and PI (1.9%, p500 vs. <350 CD4+ T cells/μL. PDR in recently infected individuals was 13.6%, showing no significant difference with PDR in individuals with longstanding infection (10.7%. The most prevalent PDR mutations were M46IL (1.4%, T215 revertants (0.5%, and K103NS (5.5%. The overall ADR prevalence in individuals with <48 months on ART was 87.8% and for the ≥48 months on ART group 81.3%. ADR to three drug families increased in individuals with longer time on ART (p = 0.0343. M184V and K103N were the most frequent ADR mutations. PDR mutation frequency correlated with ADR mutation frequency for PI and NNRTI (p<0.01, but not for NRTI. Clusters of viruses were observed suggesting transmission of HIVDR both from ART-experienced to ART-naïve individuals and between ART-naïve individuals.The global PDR prevalence in Honduras remains at the intermediate level, after 10 years of widespread availability of ART. Evidence of ADR influencing the presence of PDR was observed by phylogenetic analyses and ADR/PDR mutation frequency correlations.

  4. Response to Therapy in Antiretroviral Therapy–Naive Patients With Isolated Nonnucleoside Reverse Transcriptase Inhibitor–Associated Transmitted Drug Resistance

    Science.gov (United States)

    Fessel, W. Jeffrey; Rhee, Soo-Yon; Hurley, Leo B.; Klein, Daniel B.; Ioannidis, John P. A.; Silverberg, Michael J.; Shafer, Robert W.

    2016-01-01

    Background: Nonnucleoside reverse transcriptase inhibitor (NNRTI)–associated transmitted drug resistance (TDR) is the most common type of TDR. Few data guide the selection of antiretroviral therapy (ART) for patients with such resistance. Methods: We reviewed treatment outcomes in a cohort of HIV-1–infected patients with isolated NNRTI TDR who initiated ART between April 2002 and May 2014. In an as-treated analysis, virological failure (VF) was defined as not reaching undetectable virus levels within 24 weeks, virological rebound, or switching regimens during viremia. In an intention-to-treat analysis, failure was defined more broadly as VF, loss to follow-up, and switching during virological suppression. Results: Of 3245 patients, 131 (4.0%) had isolated NNRTI TDR; 122 received a standard regimen comprising 2 NRTIs plus a boosted protease inhibitor (bPI; n = 54), an integrase strand transfer inhibitor (INSTI; n = 52), or an NNRTI (n = 16). The median follow-up was 100 weeks. In the as-treated analysis, VF occurred in 15% (n = 8), 2% (n = 1), and 25% (n = 4) of patients in the bPI, INSTI, and NNRTI groups, respectively. In multivariate regression, there was a trend toward a lower risk of VF with INSTIs than with bPIs (hazard ratio: 0.14; 95% confidence interval: 0.02 to 1.1; P = 0.07). In intention-to-treat multivariate regression, INSTIs had a lower risk of failure than bPIs (hazard ratio: 0.38; 95% confidence interval: 0.18 to 0.82; P = 0.01). Conclusions: Patients with isolated NNRTI TDR experienced low VF rates with INSTIs and bPIs. INSTIs were noninferior to bPIs in an analysis of VF but superior to bPIs when frequency of switching and loss to follow-up were also considered. PMID:26855248

  5. Identification of Immunogenic Cytotoxic T Lymphocyte Epitopes Containing Drug Resistance Mutations in Antiretroviral Treatment-Naive HIV-Infected Individuals.

    Directory of Open Access Journals (Sweden)

    Juan Blanco-Heredia

    Full Text Available Therapeutic HIV vaccines may prove helpful to intensify antiretroviral treatment (ART efficacy and may be an integral part of future cure strategies.We examined IFN-gamma ELISpot responses to a panel of 218 HIV clade B consensus-based HIV protease-reverse transcriptase peptides, designed to mimic previously described and predicted cytotoxic T lymphocyte epitopes overlapping drug resistance (DR positions, that either included the consensus sequence or the DR variant sequence, in 49 ART-naïve HIV-infected individuals. Next generation sequencing was used to assess the presence of minority DR variants in circulating viral populations.Although a wide spectrum of differential magnitudes of response to DR vs. WT peptide pairs was observed, responses to DR peptides were frequent and strong in the study cohort. No difference between the median magnitudes of response to DR vs. WT peptides was observed. Interestingly, of the 22 peptides that were recognized by >15% of the participants, two-thirds (64% corresponded to DR peptides. When analysing responses per peptide pair per individual, responses to only WT (median 4 pairs/individual or DR (median 6 pairs/individual were more common than responses to both WT and DR (median 2 pairs/individual; p<0.001. While the presence of ELISpot responses to WT peptides was frequently associated with the presence of the corresponding peptide sequence in the patient's virus (mean 68% of cases, responses to DR peptides were generally not associated with the presence of DR mutations in the viral population, even at low frequencies (mean 1.4% of cases; p = 0.0002.Our data suggests that DR peptides are frequently immunogenic and raises the potential benefit of broadening the antigens included in a therapeutic vaccine approach to immunogenic epitopes containing common DR sequences. Further studies are needed to assess the quality of responses elicited by DR peptides.

  6. The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes

    NARCIS (Netherlands)

    Vijver, D.A. van de; Wensing, A.M.J.; Angarano, G.; Asjo, B.; Balotta, C.; Camacho, R.; Chaix, M.; Costagliola, D.; De Luca, A.; Derdelinckx, I.; Grossman, Z.; Hamouda, O.; Hatzakis, A.; Hemmer, R.; Hoepelman, A.I.M.; Horban, A.; Korn, K.; Kücherer, C.; Leitner, T.; Loveday, C.; MacRae, E.; Maljkovic, I.; Mendoza, C. de; Meyer, L.; Nielsen, C.; Op de Coul, E.L.M.; Omaasen, V.; Paraskevis, D.; Perrin, L.; Puchhammer-Stöckl, E.; Salminen, M.; Schmit, J.; Scheider, F.; Schuurman, R.; Soriano, V.; Stanczak, G.; Stanojevic, M.; Vandamme, A.; Laethem, K. van; Violin, M.; Wilde, K.; Yerly, S.; Zazzi, M.; Boucher, C.A.B.

    2006-01-01

    The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance s

  7. Prevention of mother-to-child HIV-1 transmission in Burkina Faso: evaluation of vertical transmission by PCR, molecular characterization of subtypes and determination of antiretroviral drugs resistance

    Science.gov (United States)

    Sagna, Tani; Bisseye, Cyrille; Compaore, Tegewende R.; Kagone, Therese S.; Djigma, Florencia W.; Ouermi, Djeneba; Pirkle, Catherine M.; Zeba, Moctar T. A.; Bazie, Valerie J. T.; Douamba, Zoenabo; Moret, Remy; Pietra, Virginio; Koama, Adjirita; Gnoula, Charlemagne; Sia, Joseph D.; Nikiema, Jean-Baptiste; Simpore, Jacques

    2015-01-01

    Background Vertical human immunodeficiency virus (HIV) transmission is a public health problem in Burkina Faso. The main objective of this study on the prevention of mother-to-child HIV-1 transmission was to determine the residual risk of HIV transmission in infants born to mothers receiving highly active antiretroviral therapy (HAART). Moreover, we detect HIV antiretroviral (ARV) drug resistance among mother–infant pairs and identify subtypes and circulating recombinant forms (CRF) in Burkina Faso. Design In this study, 3,215 samples of pregnant women were analyzed for HIV using rapid tests. Vertical transmission was estimated by polymerase chain reaction in 6-month-old infants born to women who tested HIV positive. HIV-1 resistance to ARV, subtypes, and CRFs was determined through ViroSeq kit using the ABI PRISM 3,130 sequencer. Results In this study, 12.26% (394/3,215) of the pregnant women were diagnosed HIV positive. There was 0.52% (2/388) overall vertical transmission of HIV, with rates of 1.75% (2/114) among mothers under prophylaxis and 0.00% (0/274) for those under HAART. Genetic mutations were also isolated that induce resistance to ARV such as M184V, Y115F, K103N, Y181C, V179E, and G190A. There were subtypes and CRF of HIV-1 present, the most common being: CRF06_CPX (58.8%), CRF02_AG (35.3%), and subtype G (5.9%). Conclusions ARV drugs reduce the residual rate of HIV vertical transmission. However, the virus has developed resistance to ARV, which could limit future therapeutic options when treatment is needed. Resistance to ARV therefore requires a permanent interaction between researchers, physicians, and pharmacists, to strengthen the network of monitoring and surveillance of drug resistance in Burkina Faso. PMID:25630709

  8. Prevention of mother-to-child HIV-1 transmission in Burkina Faso: evaluation of vertical transmission by PCR, molecular characterization of subtypes and determination of antiretroviral drugs resistance

    Directory of Open Access Journals (Sweden)

    Tani Sagna

    2015-01-01

    Full Text Available Background: Vertical human immunodeficiency virus (HIV transmission is a public health problem in Burkina Faso. The main objective of this study on the prevention of mother-to-child HIV-1 transmission was to determine the residual risk of HIV transmission in infants born to mothers receiving highly active antiretroviral therapy (HAART. Moreover, we detect HIV antiretroviral (ARV drug resistance among mother–infant pairs and identify subtypes and circulating recombinant forms (CRF in Burkina Faso. Design: In this study, 3,215 samples of pregnant women were analyzed for HIV using rapid tests. Vertical transmission was estimated by polymerase chain reaction in 6-month-old infants born to women who tested HIV positive. HIV-1 resistance to ARV, subtypes, and CRFs was determined through ViroSeq kit using the ABI PRISM 3,130 sequencer. Results: In this study, 12.26% (394/3,215 of the pregnant women were diagnosed HIV positive. There was 0.52% (2/388 overall vertical transmission of HIV, with rates of 1.75% (2/114 among mothers under prophylaxis and 0.00% (0/274 for those under HAART. Genetic mutations were also isolated that induce resistance to ARV such as M184V, Y115F, K103N, Y181C, V179E, and G190A. There were subtypes and CRF of HIV-1 present, the most common being: CRF06_CPX (58.8%, CRF02_AG (35.3%, and subtype G (5.9%. Conclusions: ARV drugs reduce the residual rate of HIV vertical transmission. However, the virus has developed resistance to ARV, which could limit future therapeutic options when treatment is needed. Resistance to ARV therefore requires a permanent interaction between researchers, physicians, and pharmacists, to strengthen the network of monitoring and surveillance of drug resistance in Burkina Faso.

  9. Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: Analysis of the HIV-2 Belgium and Luxembourg database

    Directory of Open Access Journals (Sweden)

    Delforge Marie-Luce

    2008-02-01

    Full Text Available Abstract Background Guidelines established for the treatment of HIV-1 infection and genotype interpretation do not apply for HIV-2. Data about antiretroviral (ARV drug efficacy and resistance mutations is scarce. Methods Clinical data about HIV-2 infected patients in Belgium and Luxembourg were collected and the effect of ARV therapy on plasma viral load and CD4 counts were analysed. Viral RNA encoding for protease (PR and reverse transcriptase (RT from ARV-naïve and treated patients were sequenced. Results Sixty-five HIV-2 infected patients were included in this cohort. Twenty patients were treated with 25 different ARV combinations in a total of 34 regimens and six months after the start of ARV therapy, only one third achieved viral load suppression. All of these successful regimens bar one contained protease inhibitors (PIs. Mean CD4 gains in the group of viral load suppressors and the group of patients treated with PI-containing regimens were respectively significantly higher than in the group of non-suppressors and the group of PI-sparing regimens. The most frequent mutations selected under therapy (compared to HIV-2 ROD were V71I, L90M and I89V within PR. Within RT, they were M184V, Q151M, V111I and K65R. All of these mutations, except K65R and M184V, were also found in variable proportions in ARV-naïve patients. Conclusion Despite a high rate of ARV treatment failure, better virological and immunological results were achieved with PI-containing regimens. The analysis of polymorphic positions and HIV-2 specific mutations selected during therapy showed for the first time that transmission of drug resistant viruses has occurred in Belgium and Luxembourg. The high heterogeneity in ARV combinations reflects a lack of guidelines for the treatment of HIV-2 infection.

  10. Stable and low prevalence of transmitted HIV type 1 drug resistance despite two decades of antiretroviral therapy in Hong Kong

    OpenAIRE

    Yam, WC; Wong, KH; Chan, WK; Chen, JHK; AlvarezBognar, FR; Chan, KCW

    2010-01-01

    Transmitted HIV resistance is of both clinical and public health importance. Baseline genotypic resistance testing was performed for HIV-1-infected treatment-naive patients who were newly diagnosed between 2003 and 2007 and attended the government HIV clinic in Hong Kong. International AIDS Society-USA mutation figures and the Stanford resistance interpretation algorithm were used to identify resistance mutations and drug susceptibility, respectively. The pattern and factors associated with r...

  11. Virological Response and Drug Resistance 1 and 2 Years Post-Partum in HIV-Infected Women Initiated on Life-Long Antiretroviral Therapy in Malawi.

    Science.gov (United States)

    Mancinelli, Sandro; Galluzzo, Clementina Maria; Andreotti, Mauro; Liotta, Giuseppe; Jere, Haswel; Sagno, Jean-Baptiste; Amici, Roberta; Pirillo, Maria Franca; Scarcella, Paola; Marazzi, Maria Cristina; Vella, Stefano; Palombi, Leonardo; Giuliano, Marina

    2016-08-01

    The objective of this study was to determine the virological response and the possible emergence of drug resistance at 1 and 2 years postpartum in HIV-positive pregnant women enrolled under the Option B approach and meeting the criteria for treatment. In the study, women with baseline CD4(+) HIV-RNA was measured at 12 and 24 months postpartum. Drug resistance mutations were assessed in those with HIV-RNA >50 copies/ml. Baseline resistance mutations were assessed in the entire cohort. A total of 107 women were studied. At baseline, resistance mutations were seen in 6.6% of the women. At 12 months, 26.7% of the women had >50 copies/ml and among them 12.9% had virological failure (HIV-RNA >1,000 copies/ml). At 24 months, detectable HIV-RNA was seen in 28.3% of the women and virological failure in 10.1% of the women. Resistance mutations (mainly non-nucleoside reverse transcriptase inhibitors mutations) were seen in 40% of the women with detectable HIV-RNA. Baseline mutations did not correlate with virological failure or the emergence of resistance at later time points. Virological failure 2 years postpartum and emergence of resistance were rare in this cohort of HIV-infected women. These findings are reassuring in the light of the new strategies for the prevention of mother-to-child HIV transmission, recommending life-long antiretroviral therapy administration. PMID:27067142

  12. HIV-1 drug resistance genotyping from antiretroviral therapy (ART naïve and first-line treatment failures in Djiboutian patients

    Directory of Open Access Journals (Sweden)

    Elmi Abar Aden

    2012-10-01

    Full Text Available Abstract In this study we report the prevalence of antiretroviral drug resistant HIV-1 genotypes of virus isolated from Djiboutian patients who failed first-line antiretroviral therapy (ART and from ART naïve patients. Patients and methods A total of 35 blood samples from 16 patients who showed first-line ART failure (>1000 viral genome copies/ml and 19 ART-naïve patients were collected in Djibouti from October 2009 to December 2009. Both the protease (PR and reverse transcriptase (RT genes were amplified and sequenced using National Agency for AIDS Research (ANRS protocols. The Stanford HIV database algorithm was used for interpretation of resistance data and genotyping. Results Among the 16 patients with first-line ART failure, nine (56.2% showed reverse transcriptase inhibitor-resistant HIV-1 strains: two (12.5% were resistant to nucleoside (NRTI, one (6.25% to non-nucleoside (NNRTI reverse transcriptase inhibitors, and six (37.5% to both. Analysis of the DNA sequencing data indicated that the most common mutations conferring drug resistance were M184V (38% for NRTI and K103N (25% for NNRTI. Only NRTI primary mutations K101Q, K103N and the PI minor mutation L10V were found in ART naïve individuals. No protease inhibitor resistant strains were detected. In our study, we found no detectable resistance in ∼ 44% of all patients who experienced therapeutic failure which was explained by low compliance, co-infection with tuberculosis and malnutrition. Genotyping revealed that 65.7% of samples were infected with subtype C, 20% with CRF02_AG, 8.5% with B, 2.9% with CRF02_AG/C and 2.9% with K/C. Conclusion The results of this first study about drug resistance mutations in first-line ART failures show the importance of performing drug resistance mutation test which guides the choice of a second-line regimen. This will improve the management of HIV-infected Djiboutian patients. Virtual slides The virtual slide(s for this article can be found

  13. Association between medication possession ratio, virologic failure and drug resistance in HIV-1 infected adults on antiretroviral therapy in Côte d’Ivoire

    Science.gov (United States)

    Messou, Eugène; Chaix, Marie-Laure; Gabillard, Delphine; Minga, Albert; Losina, Elena; Yapo, Vincent; Kouakou, Martial; Danel, Christine; Sloan, Caroline; Rouzioux, Christine; Freedberg, Kenneth A.; Anglaret, Xavier

    2011-01-01

    Background Adherence is a strong determinant of viral suppression with antiretroviral therapy (ART), but measuring it is challenging. Medication delivery can be measured accurately in settings with computerized prescription databases. We studied the association between Medication Possession Ratio (MPR), virologic suppression, and resistance to ART in Côte d’Ivoire. Methods We conducted a prospective cohort study of HIV-1 infected adults initiating ART in three clinics using computerized monitoring systems. Patients had viral load (VL) tests at month 6 (M6) and month 12 (M12) after ART initiation, and genotype tests if VL was detectable (≥300 copies/ml). MPR was defined as the number of daily doses of antiretroviral drug actually provided divided by the total number of follow-up days since ART initiation. Results Overall, 1,573 patients started ART with stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. At M6 and M12, 996 and 942 patients were in active follow-up; 20% (M6) and 25% (M12) of patients had detectable VL, including 7% (M6) and 11% (M12) with ≥1 resistance mutation. Among patients with MPR ≥95%, 80–94%, 65–79%, 50–64% and <50% at M12, the proportion with detectable VL [resistance] was 9% [4%], 17% [7%], 45% [24%], 67% [31%], and 85% [37%]. Among patients with ≥1 mutation at M12, 86% were resistant to lamivudine/emtricitabine and/or nevirapine/efavirenz but not to other drugs. Conclusion MPR was strongly associated with virologic outcomes. Half of those with detectable VL at M12 had no resistance mutations. MPR should be used at M6 to identify patients who might benefit from early interventions to reinforce adherence. PMID:21191309

  14. Cost-effectiveness of HIV drug resistance testing to inform switching to second line antiretroviral therapy in low income settings

    DEFF Research Database (Denmark)

    Phillips, Andrew; Cambiano, Valentina; Nakagawa, Fumiyo;

    2014-01-01

    BACKGROUND: To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations...... being identified. METHODS: An individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa...... outcomes were assessed over 2015-2025 in terms of viral suppression, first line failure, switching to second line regimen, death, HIV incidence, disability-adjusted-life-years averted and costs. Potential future low costs of resistance tests ($30) were used. RESULTS: The most effective strategy, in terms...

  15. Drug Resistance

    Science.gov (United States)

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  16. HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia

    Directory of Open Access Journals (Sweden)

    Awachana Jiamsakul

    2014-08-01

    Full Text Available Introduction: First-line antiretroviral therapy (ART failure often results from the development of resistance-associated mutations (RAMs. Three patterns, including thymidine analogue mutations (TAMs, 69 Insertion (69Ins and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs and may compromise treatment options for second-line ART. Methods: We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance – Monitoring study (TASER-M, and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥2 TAMs; or M184V+≥1 TAM. Virological suppression was defined as viral load (VL 2 years (OR=6.25, 95% CI [2.39–16.36], p<0.001. Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS for the second-line regimen was 2.00. Patients with ART adherence ≥95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43–35.81, p=0.001. Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome. Conclusions: Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy.

  17. High rates of virological failure and drug resistance in perinatally HIV-1-infected children and adolescents receiving lifelong antiretroviral therapy in routine clinics in Togo

    Directory of Open Access Journals (Sweden)

    Mounerou Salou

    2016-04-01

    Full Text Available Introduction: Antiretroviral treatment (ART has been scaled up over the last decade but compared to adults, children living with HIV are less likely to receive ART. Moreover, children and adolescents are more vulnerable than adults to virological failure (VF and emergence of drug resistance. In this study we determined virological outcome in perinatally HIV-1-infected children and adolescents receiving ART in Togo. Methods: HIV viral load (VL testing was consecutively proposed to all children and adolescents who were on ART for at least 12 months when attending HIV healthcare services for their routine follow-up visit (June to September 2014. Plasma HIV-1 VL was measured using the m2000 RealTime HIV-1 assay (Abbott Molecular, Des Plaines, IL, USA. Genotypic drug resistance was done for all samples with VL>1000 copies/ml. Results and discussion: Among 283 perinatally HIV-1-infected children and adolescents included, 167 (59% were adolescents and 116 (41% were children. The median duration on ART was 48 months (interquartile range: 28 to 68 months. For 228 (80.6%, the current ART combination consisted of two nucleoside reverse transcriptase inhibitors (NRTIs (zidovudine and lamivudine and one non-nucleoside reverse transcriptase inhibitor (NNRTI (nevirapine or efavirenz. Only 28 (9.9% were on a protease inhibitor (PI-based regimen. VL was below the detection limit (i.e. 40 copies/ml for 102 (36%, between 40 and 1000 copies/ml for 35 (12.4% and above 1000 copies/ml for 146 (51.6%. Genotypic drug-resistance testing was successful for 125/146 (85.6%; 110/125 (88.0% were resistant to both NRTIs and NNRTIs, 1/125 (0.8% to NRTIs only, 4/125 (3.2% to NNRTIs only and three harboured viruses resistant to reverse transcriptase and PIs. Overall, 86% (108/125 of children and adolescents experiencing VF and successfully genotyped, corresponding thus to at least 38% of the study population, had either no effective ART or had only a single effective drug in

  18. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes

    Science.gov (United States)

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A.; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T.; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M.

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007–2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5–10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID:27119150

  19. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes.

    Science.gov (United States)

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007-2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5-10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID:27119150

  20. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes.

    Science.gov (United States)

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007-2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5-10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV.

  1. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naive and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes.

    Directory of Open Access Journals (Sweden)

    Yaxelis Mendoza

    Full Text Available The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM and surveillance drug resistance mutations (SDRMs from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007-2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73% to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5-10% to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV.

  2. Population-based Surveillance of HIV Drug Resistance Emerging on Treatment and Associated Factors at Sentinel Antiretroviral Therapy Sites in Namibia

    Science.gov (United States)

    Hong, Steven Y.; Jonas, Anna; DeKlerk, Michael; Shiningavamwe, Andreas; Desta, Tiruneh; Badi, Alfons; Morris, Lynn; Hunt, Gillian M.; Ledwaba, Johanna; Sheehan, Heidi B.; Lau, Kiger; Trotter, Andrew; Tang, Alice M.; Wanke, Christine; Jordan, Michael R.

    2015-01-01

    Objective World Health Organization (WHO) prospective surveys of acquired HIV drug resistance (HIVDR) evaluate HIVDR emerging after the first year of antiretroviral therapy (ART) and associated factors. Methods Consecutive ART starters in 2009 were enrolled at three sentinel sites in Namibia. Genotyping was performed at start and after 12 months in patients with HIV viral load (VL) >1000 copies/mL. HIVDR outcomes were: HIVDR Prevention (VL ≤1000 copies/mL), Possible HIVDR (VL>1000 copies/mL without detectable HIVDR or loss to follow-up (LTFU) or ART stop), and HIVDR (VL>1000 copies/mL with detectable HIVDR). Adherence was assessed using medication possession ratio (MPR). Results Of 394 starters, at 12 months 80% were on first-line ART, 1% died, 4% transferred out, 1% stopped ART, <1% switched to second-line and 15% were LTFU. Among patients on first-line, 77% had VL testing. 94% achieved VL ≤1000 copies/mL. At baseline, 7% had HIVDR. After 12 months, among patients with VL testing, 5% had HIVDR. A majority of patients failing therapy had high level resistance to non-nucleoside reverse transcriptase inhibitors but none to protease inhibitors. All sites achieved WHO target of ≥70% HIVDR Prevention. Factors associated with not achieving HIVDR Prevention were: baseline resistance to non-nucleoside reverse transcriptase inhibitors (OR 3.0, p=0.023), WHO stage 3 or 4 at baseline (OR 2.0, p=0.012), and MPR<75% (OR 4.9, p=0.021). Conclusions Earlier ART initiation and removal of barriers to on-time drug pickups may help to prevent HIVDR. These data inform decisions at national and global levels on the effectiveness of first- and second-line regimens. PMID:25564107

  3. Treatment failure and drug resistance in HIV-positive patients on tenofovir-based first-line antiretroviral therapy in western Kenya

    Science.gov (United States)

    Brooks, Katherine; Diero, Lameck; DeLong, Allison; Balamane, Maya; Reitsma, Marissa; Kemboi, Emmanuel; Orido, Millicent; Emonyi, Wilfred; Coetzer, Mia; Hogan, Joseph; Kantor, Rami

    2016-01-01

    Introduction Tenofovir-based first-line antiretroviral therapy (ART) is recommended globally. To evaluate the impact of its incorporation into the World Health Organization (WHO) guidelines, we examined treatment failure and drug resistance among a cohort of patients on tenofovir-based first-line ART at the Academic Model Providing Access to Healthcare, a large HIV treatment programme in western Kenya. Methods We determined viral load (VL), drug resistance and their correlates in patients on ≥six months of tenofovir-based first-line ART. Based on enrolled patients’ characteristics, we described these measures in those with (prior ART group) and without (tenofovir-only group) prior non-tenofovir-based first-line ART using Wilcoxon rank sum and Fisher's exact tests. Results Among 333 participants (55% female; median age 41 years; median CD4 336 cells/µL), detectable (>40 copies/mL) VL was found in 18%, and VL>1000 copies/mL (WHO threshold) in 10%. Virologic failure at both thresholds was significantly higher in 217 participants in the tenofovir-only group compared with 116 in the prior ART group using both cut-offs (24% vs. 7% with VL>40 copies/mL; 15% vs. 1% with VL>1000 copies/mL). Failure in the tenofovir-only group was associated with lower CD4 values and advanced WHO stage. In 35 available genotypes from 51 participants in the tenofovir-only group with VL>40 copies/mL (69% subtype A), any resistance was found in 89% and dual-class resistance in 83%. Tenofovir signature mutation K65R occurred in 71% (17/24) of the patients infected with subtype A. Patients with K65R had significantly lower CD4 values, higher WHO stage and more resistance mutations. Conclusions In this Kenyan cohort, tenofovir-based first-line ART resulted in good (90%) virologic suppression including high suppression (99%) after switch from non-tenofovir-based ART. Lower virologic suppression (85%) and high observed resistance levels (89%) in the tenofovir-only group impact future treatment

  4. High-levels of acquired drug resistance in adult patients failing first-line antiretroviral therapy in a rural HIV treatment programme in KwaZulu-Natal, South Africa.

    Directory of Open Access Journals (Sweden)

    Justen Manasa

    Full Text Available To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa.Cross-sectional study nested within HIV treatment programme.Adult (≥ 18 years HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART regimen and with evidence of virological failure (one viral load >1000 copies/ml were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms.A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%; and stavudine, lamivudine and nevirapine (24%. Median duration of ART was 42 months (interquartile range (IQR 32-53 and median duration of antiretroviral failure was 27 months (IQR 17-40. One hundred and ninety one (86% had at least one drug resistance mutation. For 34 individuals (15%, the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR 5.70, 95% confidence interval (CI 2.60-12.49.There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved.

  5. HIV-1 Antiretroviral Drug Therapy

    OpenAIRE

    Arts, Eric J.; Hazuda, Daria J.

    2012-01-01

    The most significant advance in the medical management of HIV-1 infection has been the treatment of patients with antiviral drugs, which can suppress HIV-1 replication to undetectable levels. The discovery of HIV-1 as the causative agent of AIDS together with an ever-increasing understanding of the virus replication cycle have been instrumental in this effort by providing researchers with the knowledge and tools required to prosecute drug discovery efforts focused on targeted inhibition with ...

  6. Short Communication: Emerging Transmitted HIV Type 1 Drug Resistance Mutations Among Patients Prior to Start of First-Line Antiretroviral Therapy in Middle and Low Prevalence Sites in China

    OpenAIRE

    Wang, Xia; He, Cui; Xing, Hui; Liao, Lingjie; Xu, XiaoQin; He, Jianmei; Liu, Yong; Ling, Hua; Liang, Shu; Jenny H. Hsi; Ruan, Yuhua; Shao, Yiming

    2012-01-01

    It is known that transmitted drug resistance (TDR) will most likely emerge in regions where antiretroviral therapy (ART) has been widely available for years. However, after a decade of rapid scale-up of ART in China, there are few data regarding TDR among HIV-infected patients prior to initiating first-line ART in China. A prospective, observational cohort study was performed at sentinel sites in five provinces or municipalities. Study participants were recruited at the county- or city-level ...

  7. Virological failure and HIV-1 drug resistance mutations among naive and antiretroviral pre-treated patients entering the ESTHER program of Calmette Hospital in Cambodia.

    Directory of Open Access Journals (Sweden)

    Hubert Barennes

    Full Text Available INTRODUCTION: In resource limited settings, patients entering an antiretroviral therapy (ART program comprise ART naive and ART pre-treated patients who may show differential virological outcomes. METHODS: This retrospective study, conducted in 2010-2012 in the HIV clinic of Calmette Hospital located in Phnom Penh (Cambodia assessed virological failure (VF rates and patterns of drug resistance of naive and pre-treated patients. Naive and ART pre-treated patients were included when a Viral Load (VL was performed during the first year of ART for naive subjects or at the first consultation for pre-treated individuals. Patients showing Virological failure (VF (>1,000 copies/ml underwent HIV DR genotyping testing. Interpretation of drug resistance mutations was done according to 2013 version 23 ANRS algorithms. RESULTS: On a total of 209 patients, 164 (78.4% were naive and 45 (21.5% were ART pre-treated. Their median initial CD4 counts were 74 cells/mm3 (IQR: 30-194 and 279 cells/mm3 (IQR: 103-455 (p<0.001, respectively. Twenty seven patients (12.9% exhibited VF (95% CI: 8.6-18.2%, including 10 naive (10/164, 6.0% and 17 pre-treated (17/45, 37.8% patients (p<0.001. Among these viremic patients, twenty-two (81.4% were sequenced in reverse transcriptase and protease coding regions. Overall, 19 (86.3% harbored ≥1 drug resistance mutations (DRMs whereas 3 (all belonging to pre-treated patients harbored wild-types viruses. The most frequent DRMs were M184V (86.3%, K103N (45.5% and thymidine analog mutations (TAMs (40.9%. Two (13.3% pre-treated patients harbored viruses that showed a multi-nucleos(tide resistance including Q151M, K65R, E33A/D, E44A/D mutations. CONCLUSION: In Cambodia, VF rates were low for naive patients but the emergence of DRMs to NNRTI and 3TC occurred relatively quickly in this subgroup. In pre-treated patients, VF rates were much higher and TAMs were relatively common. HIV genotypic assays before ART initiation and for ART pre

  8. Care of Patients With HIV Infection: Antiretroviral Drug Regimens.

    Science.gov (United States)

    Bolduc, Philip; Roder, Navid; Colgate, Emily; Cheeseman, Sarah H

    2016-04-01

    The advent of combination antiretroviral drug regimens has transformed HIV infection from a fatal illness into a manageable chronic condition. All patients with HIV infection should be considered for antiretroviral therapy, regardless of CD4 count or HIV viral load, for individual benefit and to prevent HIV transmission. Antiretroviral drugs affect HIV in several ways: entry inhibitors block HIV entry into CD4 T cells; nucleotide and nucleoside reverse transcriptase inhibitors prevent reverse transcription from RNA to DNA via chain-terminating proteins; nonnucleoside reverse transcriptase inhibitors prevent reverse transcription through enzymatic inhibition; integrase strand transfer inhibitors block integration of viral DNA into cellular DNA; protease inhibitors block maturation and production of the virus. Current guidelines recommend six combination regimens for initial therapy. Five are based on tenofovir and emtricitabine; the other uses abacavir and lamivudine. Five include integrase strand transfer inhibitors. HIV specialists should assist with treating patients with complicated HIV infection, including patients with treatment-resistant HIV infection, coinfection with hepatitis B or C virus, pregnancy, childhood infections, severe opportunistic infections, complex drug interactions, significant drug toxicity, or comorbidities. Family physicians can treat most patients with HIV infection effectively by choosing appropriate treatment regimens, monitoring patients closely, and retaining patients in care. PMID:27092564

  9. The role of formulation on the pharmacokinetics of antiretroviral drugs

    NARCIS (Netherlands)

    Bastiaans, Diane E T; Cressey, Tim R; Vromans, Herman; Burger, David M

    2014-01-01

    INTRODUCTION: A multitude of antiretroviral drug formulations are now available for HIV-infected adults and children. These formulations include individual and co-formulated drugs, many of which are also supplied in generic versions. Many antiretroviral drugs have a low aqueous solubility and poor b

  10. Prevalence and evolution of low frequency HIV drug resistance mutations detected by ultra deep sequencing in patients experiencing first line antiretroviral therapy failure.

    Directory of Open Access Journals (Sweden)

    Marie-Anne Vandenhende

    Full Text Available OBJECTIVES: Clinical relevance of low-frequency HIV-1 variants carrying drug resistance associated mutations (DRMs is still unclear. We aimed to study the prevalence of low-frequency DRMs, detected by Ultra-Deep Sequencing (UDS before antiretroviral therapy (ART and at virological failure (VF, in HIV-1 infected patients experiencing VF on first-line ART. METHODS: Twenty-nine ART-naive patients followed up in the ANRS-CO3 Aquitaine Cohort, having initiated ART between 2000 and 2009 and experiencing VF (2 plasma viral loads (VL >500 copies/ml or one VL >1000 copies/ml were included. Reverse transcriptase and protease DRMs were identified using Sanger sequencing (SS and UDS at baseline (before ART initiation and VF. RESULTS: Additional low-frequency variants with PI-, NNRTI- and NRTI-DRMs were found by UDS at baseline and VF, significantly increasing the number of detected DRMs by 1.35 fold (p<0.0001 compared to SS. These low-frequency DRMs modified ARV susceptibility predictions to the prescribed treatment for 1 patient at baseline, in whom low-frequency DRM was found at high frequency at VF, and 6 patients at VF. DRMs found at VF were rarely detected as low-frequency DRMs prior to treatment. The rare low-frequency NNRTI- and NRTI-DRMs detected at baseline that correlated with the prescribed treatment were most often found at high-frequency at VF. CONCLUSION: Low frequency DRMs detected before ART initiation and at VF in patients experiencing VF on first-line ART can increase the overall burden of resistance to PI, NRTI and NNRTI.

  11. Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

    DEFF Research Database (Denmark)

    Baxter, J D; Dunn, D; White, E;

    2015-01-01

    on a modified 2009 World Health Organization definition to reflect newer resistance mutations. RESULTS: Baseline resistance testing was available in 1946 study participants. Higher rates of testing occurred in Europe (86.7%), the USA (81.3%) and Australia (89.9%) as compared with Asia (22.2%), South America (1...

  12. Identification of Immunogenic Cytotoxic T Lymphocyte Epitopes Containing Drug Resistance Mutations in Antiretroviral Treatment-Naïve HIV-Infected Individuals

    Science.gov (United States)

    Blanco-Heredia, Juan; Lecanda, Aarón; Valenzuela-Ponce, Humberto; Brander, Christian; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo

    2016-01-01

    Background Therapeutic HIV vaccines may prove helpful to intensify antiretroviral treatment (ART) efficacy and may be an integral part of future cure strategies. Methods We examined IFN-gamma ELISpot responses to a panel of 218 HIV clade B consensus-based HIV protease-reverse transcriptase peptides, designed to mimic previously described and predicted cytotoxic T lymphocyte epitopes overlapping drug resistance (DR) positions, that either included the consensus sequence or the DR variant sequence, in 49 ART-naïve HIV-infected individuals. Next generation sequencing was used to assess the presence of minority DR variants in circulating viral populations. Results Although a wide spectrum of differential magnitudes of response to DR vs. WT peptide pairs was observed, responses to DR peptides were frequent and strong in the study cohort. No difference between the median magnitudes of response to DR vs. WT peptides was observed. Interestingly, of the 22 peptides that were recognized by >15% of the participants, two-thirds (64%) corresponded to DR peptides. When analysing responses per peptide pair per individual, responses to only WT (median 4 pairs/individual) or DR (median 6 pairs/individual) were more common than responses to both WT and DR (median 2 pairs/individual; p<0.001). While the presence of ELISpot responses to WT peptides was frequently associated with the presence of the corresponding peptide sequence in the patient’s virus (mean 68% of cases), responses to DR peptides were generally not associated with the presence of DR mutations in the viral population, even at low frequencies (mean 1.4% of cases; p = 0.0002). Conclusions Our data suggests that DR peptides are frequently immunogenic and raises the potential benefit of broadening the antigens included in a therapeutic vaccine approach to immunogenic epitopes containing common DR sequences. Further studies are needed to assess the quality of responses elicited by DR peptides. PMID:26808823

  13. Pharmacological interactions between rifampicin and antiretroviral drugs: challenges and research priorities for resource-limited settings.

    Science.gov (United States)

    Semvua, Hadija H; Kibiki, Gibson S; Kisanga, Elton R; Boeree, Martin J; Burger, David M; Aarnoutse, Rob

    2015-02-01

    Coadministration of antituberculosis and antiretroviral therapy is often inevitable in high-burden countries where tuberculosis (TB) is the most common opportunistic infection associated with HIV/AIDS. Concurrent use of rifampicin and many antiretroviral drugs is complicated by pharmacokinetic drug-drug interactions. Rifampicin is a very potent enzyme inducer, which can result in subtherapeutic antiretroviral drug concentrations. In addition, TB drugs and antiretroviral drugs have additive (pharmacodynamic) interactions as reflected in overlapping adverse effect profiles. This review provides an overview of the pharmacological interactions between rifampicin-based TB treatment and antiretroviral drugs in adults living in resource-limited settings. Major progress has been made to evaluate the interactions between TB drugs and antiretroviral therapy; however, burning questions remain concerning nevirapine and efavirenz effectiveness during rifampicin-based TB treatment, treatment options for TB-HIV-coinfected patients with nonnucleoside reverse transcriptase inhibitor resistance or intolerance, and exact treatment or dosing schedules for vulnerable patients including children and pregnant women. The current research priorities can be addressed by maximizing the use of already existing data, creating new data by conducting clinical trials and prospective observational studies and to engage a lobby to make currently unavailable drugs available to those most in need. PMID:24943062

  14. Combination antiretroviral drugs in PLGA nanoparticle for HIV-1

    Directory of Open Access Journals (Sweden)

    Sharma Akhilesh

    2009-12-01

    Full Text Available Abstract Background Combination antiretroviral (AR therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the in vitro release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs. Methods Poly-(lactic-co-glycolic acid (PLGA nanoparticles (NPs containing ritonavir (RTV, lopinavir (LPV, and efavirenz (EFV were fabricated using multiple emulsion-solvent evaporation procedure. The nanoparticles were characterized by electron microscopy and zeta potential for size, shape, and charge. The intracellular concentration of AR drugs was determined over 28 days from NPs incubated with PBMCs. Macrophages were imaged by fluorescent microscopy and flow cytometry after incubation with fluorescent NPs. Finally, macrophage cytotoxicity was determined by MTT assay. Results Nanoparticle size averaged 262 ± 83.9 nm and zeta potential -11.4 ± 2.4. AR loading averaged 4% (w/v. Antiretroviral drug levels were determined in PBMCs after 100 μg of NP in 75 μL PBS was added to media. Intracellular peak AR levels from NPs (day 4 were RTV 2.5 ± 1.1; LPV 4.1 ± 2.0; and EFV 10.6 ± 2.7 μg and continued until day 28 (all AR ≥ 0.9 μg. Free drugs (25 μg of each drug in 25 μL ethanol added to PBMCs served as control were eliminated by 2 days. Fluorescence microscopy and flow cytometry demonstrated phagocytosis of NP into monocytes-derived macrophages (MDMs. Cellular MTT assay performed on MDMs demonstrated that NPs are not significantly cytotoxic. Conclusion These results demonstrated AR NPs could be fabricated containing three antiretroviral drugs (RTV, LPV, EFV. Sustained release of AR from PLGA NP show high drug levels in PBMCs until day 28 without cytotoxicity.

  15. HIV-1 subtypes and mutations associated to antiretroviral drug resistance in human isolates from Central Brazil Subtipos e mutações associadas à resistência aos anti-retrovirais em isolados de HIV-1 do Distrito Federal

    Directory of Open Access Journals (Sweden)

    Daniela Marreco Cerqueira

    2004-09-01

    Full Text Available The detection of polymorphisms associated to HIV-1 drug-resistance and genetic subtypes is important for the control and treatment of HIV-1 disease. Drug pressure selects resistant variants that carry mutations in the viral reverse transcriptase (RT and protease (PR genes. For a contribution to the public health authorities in planning the availability of therapeutic treatment, we therefore described the genetic variability, the prevalence of mutations associated to drug resistance and the antiretroviral resistance profile in HIV-1 isolates from infected individuals in Central Brazil. Nineteen HIV-1 RNA samples from a Public Health Laboratory of the Federal District were reversely transcribed and cDNAs were amplified by nested PCR. One fragment of 297 bp coding the entire protease gene, and another of 647 bp, corresponding to the partial RT gene (codons 19-234, were obtained. Automated sequencing and BLAST analysis revealed the presence of 17 B and 2 F1 HIV-1 subtypes. The amino acid sequences were analyzed for the presence of resistance-associated mutations. A total of 6 PR mutations, 2 major and 4 accessory, and 8 RT mutations related to drug resistance were found. Our data suggest a high prevalence of HIV-1 B subtype in the studied population of Federal District as well as the presence of genetically-resistant strains in individuals failing treatment.A detecção de polimorfismos do HIV-1 que estejam associados à resistência às drogas anti-retrovirais e aos subtipos genéticos é importante para o controle e tratamento da infecção pelo HIV-1. A pressão exercida pela terapia anti-retroviral seleciona variantes resistentes com mutações nos genes virais da transcriptase reversa (RT e da protease (PR. Assim, visando contribuir com as autoridades de saúde pública na perspectiva de planejar a disponibilidade de um tratamento terapêutico, nós descrevemos a variabilidade genética e a prevalência de mutações associadas à resist

  16. Alarming rates of virological failure and drug resistance in patients on long-term antiretroviral treatment in routine HIV clinics in Togo.

    Science.gov (United States)

    Konou, Abla A; Dagnra, Anoumou Y; Vidal, Nicole; Salou, Mounerou; Adam, Zakillatou; Singo-Tokofai, Assétina; Delaporte, Eric; Prince-David, Mireille; Peeters, Martine

    2015-11-28

    Information on efficacy of long-term antiretroviral treatment (ART) exposure in resource-limited countries is still scarce. In 767 patients attending routine HIV centers in Togo and receiving first-line ART for more than four years, 42% had viral load greater than 1000 copies/ml and either were on a completely ineffective ART regime or were with only a single drug active. The actual conditions to ensure lifelong ART in resource-limited countries can have dramatic long-term outcomes.

  17. HIV entry inhibitors: a new generation of antiretroviral drugs

    Institute of Scientific and Technical Information of China (English)

    Elias KRAMBOVITIS; Filippos PORICHIS; Demetrios A SPANDIDOS

    2005-01-01

    AIDS is presently treatable, and patients can have a good prognosis due to the success of highly active antiretroviral therapy (HAART), but it is still not curable or preventable. High toxicity of HAART, and the emergence of drug resistance add to the imperative to continue research into new strategies and interventions.Considerable progress in the understanding of HIV attachment and entry into host cells has suggested new possibilities for rationally designing agents that interfere with this process. The approval and introduction of the fusion inhibitor enfuvirtide (Fuzeon) for clinical use signals a new era in AIDS therapeutics. Here we review the crucial steps the virus uses to achieve cell entry, which merit attention as potential targets, and the compounds at pre-clinical and clinical development stages, reported to effectively inhibit cell entry.

  18. Comparison of 454 Ultra-Deep Sequencing and Allele-Specific Real-Time PCR with Regard to the Detection of Emerging Drug-Resistant Minor HIV-1 Variants after Antiretroviral Prophylaxis for Vertical Transmission.

    Directory of Open Access Journals (Sweden)

    Andrea Hauser

    Full Text Available Pregnant HIV-infected women were screened for the development of HIV-1 drug resistance after implementation of a triple-antiretroviral transmission prophylaxis as recommended by the WHO in 2006. The study offered the opportunity to compare amplicon-based 454 ultra-deep sequencing (UDS and allele-specific real-time PCR (ASPCR for the detection of drug-resistant minor variants in the HIV-1 reverse transcriptase (RT.Plasma samples from 34 Tanzanian women were previously analysed by ASPCR for key resistance mutations in the viral RT selected by AZT, 3TC, and NVP (K70R, K103N, Y181C, M184V, T215Y/F. In this study, the RT region of the same samples was investigated by amplicon-based UDS for resistance mutations using the 454 GS FLX System.Drug-resistant HIV-variants were identified in 69% (20/29 of women by UDS and in 45% (13/29 by ASPCR. The absolute number of resistance mutations identified by UDS was twice that identified by ASPCR (45 vs 24. By UDS 14 of 24 ASPCR-detected resistance mutations were identified at the same position. The overall concordance between UDS and ASPCR was 61.0% (25/41. The proportions of variants quantified by UDS were approximately 2-3 times lower than by ASPCR. Amplicon generation from samples with viral loads below 20,000 copies/ml failed more frequently by UDS compared to ASPCR (limit of detection = 650 copies/ml, resulting in missing or insufficient sequence coverage.Both methods can provide useful information about drug-resistant minor HIV-1 variants. ASPCR has a higher sensitivity than UDS, but is restricted to single resistance mutations. In contrast, UDS is limited by its requirement for high viral loads to achieve sufficient sequence coverage, but the sequence information reveals the complete resistance patterns within the genomic region analysed. Improvements to the UDS limit of detection are in progress, and UDS could then facilitate monitoring of drug-resistant minor variants in the HIV-1 quasispecies.

  19. Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives.

    Science.gov (United States)

    Tittle, Victoria; Bull, Lauren; Boffito, Marta; Nwokolo, Nneka

    2015-01-01

    More than 50 % of women living with HIV in low- and middle-income countries are of reproductive age, but there are limitations to the administration of oral contraception for HIV-infected women receiving antiretroviral therapy due to drug-drug interactions caused by metabolism via the cytochrome P450 isoenzymes and glucuronidation. However, with the development of newer antiretrovirals that use alternative metabolic pathways, options for contraception in HIV-positive women are increasing. This paper aims to review the literature on the pharmacokinetics and pharmacodynamics of oral hormonal contraceptives when given with antiretroviral agents, including those currently used in developed countries, older ones that might still be used in salvage regimens, or those used in resource-limited settings, as well as newer drugs. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), the usual backbone to most combined antiretroviral treatments (cARTs) are characterised by a low potential for drug-drug interactions with oral contraceptives. On the other hand non-NRTIs (NNRTIs) and protease inhibitors (PIs) may interact with oral contraceptives. Of the NNRTIs, efavirenz and nevirapine have been demonstrated to cause drug-drug interactions; however, etravirine and rilpivirine appear safe to use without dose adjustment. PIs boosted with ritonavir are not recommended to be used with oral contraceptives, with the exception of boosted atazanavir which should be used with doses of at least 35 µg of estrogen. Maraviroc, an entry inhibitor, is safe for co-administration with oral contraceptives, as are the integrase inhibitors (INIs) raltegravir and dolutegravir. However, the INI elvitegravir, which is given in combination with cobicistat, requires a dose of estrogen of at least 30 µg. Despite the growing evidence in this field, data are still lacking in terms of large cohort studies, randomised trials and correlations to real clinical outcomes, such as pregnancy rates, in women

  20. Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives.

    Science.gov (United States)

    Tittle, Victoria; Bull, Lauren; Boffito, Marta; Nwokolo, Nneka

    2015-01-01

    More than 50 % of women living with HIV in low- and middle-income countries are of reproductive age, but there are limitations to the administration of oral contraception for HIV-infected women receiving antiretroviral therapy due to drug-drug interactions caused by metabolism via the cytochrome P450 isoenzymes and glucuronidation. However, with the development of newer antiretrovirals that use alternative metabolic pathways, options for contraception in HIV-positive women are increasing. This paper aims to review the literature on the pharmacokinetics and pharmacodynamics of oral hormonal contraceptives when given with antiretroviral agents, including those currently used in developed countries, older ones that might still be used in salvage regimens, or those used in resource-limited settings, as well as newer drugs. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), the usual backbone to most combined antiretroviral treatments (cARTs) are characterised by a low potential for drug-drug interactions with oral contraceptives. On the other hand non-NRTIs (NNRTIs) and protease inhibitors (PIs) may interact with oral contraceptives. Of the NNRTIs, efavirenz and nevirapine have been demonstrated to cause drug-drug interactions; however, etravirine and rilpivirine appear safe to use without dose adjustment. PIs boosted with ritonavir are not recommended to be used with oral contraceptives, with the exception of boosted atazanavir which should be used with doses of at least 35 µg of estrogen. Maraviroc, an entry inhibitor, is safe for co-administration with oral contraceptives, as are the integrase inhibitors (INIs) raltegravir and dolutegravir. However, the INI elvitegravir, which is given in combination with cobicistat, requires a dose of estrogen of at least 30 µg. Despite the growing evidence in this field, data are still lacking in terms of large cohort studies, randomised trials and correlations to real clinical outcomes, such as pregnancy rates, in women

  1. Pharmacokinetics of para-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

    OpenAIRE

    de Kock, Lizanne; Sy, Sherwin K.B.; Rosenkranz, Bernd; Diacon, Andreas H; Prescott, Kim; Hernandez, Kenneth R.; Yu, Mingming; Derendorf, Hartmut; Donald, Peter R.

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, n...

  2. Study on pol gene polymorphism and drug resistance among antiretroviral treatment-naive patients in Tianjin%天津市HIV/AIDS病人未治疗人群pol基因多态性及耐药性分析

    Institute of Scientific and Technical Information of China (English)

    王欣; 于茂河; 柳忠泉; 郑敏娜; 程绍辉

    2012-01-01

    Objective To investigate background knowledge of drug-resistant mutation among antiretroviral treatment-naive patients in Tianjin, and compare the pol gene polymorphism among different genetic subtypes of HIV-1. Methods Seventy nine blood samples of antiretroviral treatment-naive patients were collected randomly in 2010. Nested PCR method was used to amplify pal genes sequences of HIV-1 after DNA was extracted. The nucleotide sequence of amplification products was determined, and the genetic subtype was identified by comparative analysis. Results Pnl gene fragments of HIV-1 were successfully amplified for 51 samples and 3 kinds of HIV-1 subtypes and recombinant gene were found. CRF01 _AE was major subtype, accounting for 49. 02% (25/51) of all positives. B was the second one, accounting for 41. 18% (21/51). Eight individuals were drug resistant, and the rate of drug resistance was 15. 67%(8/15). They had potential low-level resistance and low-level resistance respectively. The genotypes were K103R, V106I, V106IV.E138G, V179E and V179DINV. The pol gene polymorphism was different in different gene subtypes. Conclusions HIV-1 viruses with initial drug-resistant mutations were spreading in antimroviral treatment-naive patients in Tianjin. The surveillance of drug resistance and the control of local HIV transmission should be strengthened in the future.%目的 了解天津市艾滋病病毒(HIV)感染者/艾滋病(AIDS)病人(简称HV/AIDS病人)未治疗人群中,耐药基因的变异情况,比较不同基因亚型之间pol基因多态性耐药突变的分布差异.方法 收集2010年天津市HIV/AIDS病人未治疗人群的血液样本,提取样本DNA,用巢式聚合酶链式反应扩增病毒pol基因,并进行亚型及耐药基因型分析.结果 在79例样品中,扩增并得到有效pol基因序列的共有51例,共发现3种基因亚型.其中CRF01_AE为主要亚型,占49.02% (25/51);其次是B亚型,占41.18% (21/51).检出耐药者8例,占15.69%(8/51),

  3. Generic antiretroviral drugs and HIV care: An economic review.

    Science.gov (United States)

    Yazdanpanah, Y; Schwarzinger, M

    2016-03-01

    The cost of HIV care in European countries is high. Direct medical costs, in France, have been estimated at 500,000 Euros per patient's lifetime (20,000 Euros/year/patient). Overall, 73% of these costs are related to antiretroviral treatments. In the current financial crisis context, some European countries are beginning to make economic decisions on the drugs to be used. These approaches are likely to become more frequent. It is obviously essential to prescribe the most effective, appropriate, best tolerated, and easy-to-use antiretroviral treatments to patients. However, while taking the above into consideration, and if various treatment options or combinations are available, cost should also be considered in the treatment choice. One may thus reflect on the use of generic antiretroviral agents as they have just been launched in France. We aimed to review the cost and cost-effectiveness of generic antiretroviral drugs and to review treatment strategies other than generic drugs that could help reduce HIV-related costs. HIV clinicians should consider treatment costs to avoid any future coercive measures.

  4. Generic antiretroviral drugs and HIV care: An economic review.

    Science.gov (United States)

    Yazdanpanah, Y; Schwarzinger, M

    2016-03-01

    The cost of HIV care in European countries is high. Direct medical costs, in France, have been estimated at 500,000 Euros per patient's lifetime (20,000 Euros/year/patient). Overall, 73% of these costs are related to antiretroviral treatments. In the current financial crisis context, some European countries are beginning to make economic decisions on the drugs to be used. These approaches are likely to become more frequent. It is obviously essential to prescribe the most effective, appropriate, best tolerated, and easy-to-use antiretroviral treatments to patients. However, while taking the above into consideration, and if various treatment options or combinations are available, cost should also be considered in the treatment choice. One may thus reflect on the use of generic antiretroviral agents as they have just been launched in France. We aimed to review the cost and cost-effectiveness of generic antiretroviral drugs and to review treatment strategies other than generic drugs that could help reduce HIV-related costs. HIV clinicians should consider treatment costs to avoid any future coercive measures. PMID:26905394

  5. HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis.

    Directory of Open Access Journals (Sweden)

    Clement Zeh

    2011-03-01

    Full Text Available BACKGROUND: Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS, a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants. METHODS AND FINDINGS: All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR-positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75% infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable, for 30% (6/20 at 6 wk, 63% (14/22 positive at 14 wk, and 67% (16/24 at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100% and 7/15 (47% infected infants

  6. Transmission of HIV drug resistance in antiretroviral treatment-naive HIV-infected individuals%未治疗艾滋病患者中HIV耐药株的传播研究

    Institute of Scientific and Technical Information of China (English)

    李扬; 邢辉

    2016-01-01

    HIV病毒通过血液、性和母婴多种途径扩散传播,感染者数量持续增长,抗病毒药物的应用虽然大大抑制了病毒的复制,但药物使用过程中由于产生了耐药突变,使治疗效果降低。而且耐药株已传播至未接受抗病毒治疗的人群中,本文综述了近几年全球发现的耐药传播株在不同地域和高危人群中的分布和耐药株发生传播的影响因素。%Human immunodeficiency virus ( HIV) is commonly transmitted through blood transfu-sion, sexual contact and mother-to-child transmission. The number of patients with HIV infection has kept growing in the last three decades. Although the wide application of antiretroviral therapy ( ART) has effec-tively suppressed the replication of HIV, the emergence of drug resistant mutants compromises the efficacy of ART. What is worse is that there has been transmission of drug resistance strains in ART-naïve HIV-infected individuals. This review describes the distribution of transmitted drug resistance strains in different regions and high risk population as well as the factors associated with the transmission in recent years.

  7. HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition.

    Science.gov (United States)

    Kis, Olena; Sankaran-Walters, Sumathi; Hoque, M Tozammel; Walmsley, Sharon L; Dandekar, Satya; Bendayan, Reina

    2016-05-01

    This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV(+)) subjects, and HIV(+) subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of CYP3A4 and ABCC2/MRP2 in the HIV(+) ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV(+) naive group than in the control group and was partially restored to baseline levels in HIV(+) subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV(+) subjects on ART relative to HIV(+) ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV(+) subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV(+) subjects. This has clinical implications when using data from healthy volunteers to guide ART. PMID:26902756

  8. Class of Antiretroviral Drugs and the Risk of Myocardial Infarction

    DEFF Research Database (Denmark)

    Friis-Møller, Nina; Reiss, P; Sabin, CA;

    2007-01-01

    BACKGROUND: We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction. It is not clear whether this association differs according to the class of antiretroviral drugs. We conducted a study to investigate the association...... to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to nonnucleoside reverse......-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively. CONCLUSIONS: Increased exposure to protease inhibitors is associated with an increased risk...

  9. Study on integrase gene polymorphism and drug resistance among antiretroviral treatment-naive patients in Tianjin City%天津市HIV/AIDS未治疗人群整合酶基因多态性及耐药性分析

    Institute of Scientific and Technical Information of China (English)

    王欣; 董笑月; 于茂河; 柳忠泉; 周宁; 程绍辉

    2013-01-01

    目的 了解天津市HIV/AIDS未治疗人群整合酶基因的变异情况,比较不同基因亚型之间整合酶基因多态性及耐药突变的分布差异.方法 收集2010年天津市HIV/AIDS未治疗人群的血液样本50例,并提取DNA,用巢式聚合酶链式反应扩增病毒整合酶基因,并进行亚型及耐药基因型分析.结果 在50例样本中,扩增并得到有效整合酶基因序列的共有38例.共发现2种基因亚型,其中CRF01 _AE为主要亚型,占73.68%(28/38),其次是B亚型,占26.32% (10/38).检出1例针对埃替格韦存在低度耐药,占2.63% (1/38),其耐药相关突变位点为R263KR.不同基因亚型中,整合酶基因变异存在差异.结论 天津市不同HIV-1基因亚型中,整合酶基因多态性及耐药突变情况均存在一定差异,应深入研究整合酶基因序列特征,掌握基线数据,从而为更好地开展抗病毒治疗提供科学依据.%Objective To investigate background knowledge of drug-resistant mutation among antiretroviral treatment-naive patients in Tianjin City, and compare the integrase gene polymorphism among different genetic subtype of HIV-1. Methods 50 blood samples of antiretroviral treatment-naive patients were collected randomly in 2010. Nested polymer-ase chain reaction (PCR) method was used to amplify integrase genes sequences of HIV-1 after DNA extracted. The nucle-otide sequences of amplification products were determined, and the genetic subtype was identified by comparative analysis. Results Integrase gene fragments of HIV-1 were successfully amplified for 38 samples and 2 kinds of HIV-1 subtypes and recombinant gene were found. CRF01_AE was major subtype, accounted for 73.68% (28/38) of all positives. B was the second, accounted for 26. 32% (10/38). Only one individual was drug resistant, and the rate of drug resistance was 2.63% (1/38). It was low-level resistance for elvitegravir. The genotype was R263KR. The integrase gene polymorphism was different in different

  10. Human Immunodeficiency Virus Type 1 Cloning Vectors for Antiretroviral Resistance Testing

    OpenAIRE

    Martinez-Picado, Javier; Sutton, Lorraine; De Pasquale, Maria Pia; Savara, Anu V.; D’Aquila, Richard T.

    1999-01-01

    Better detection of minority human immunodeficiency virus type 1 (HIV-1) populations containing gene mutations may improve the usefulness of antiretroviral resistance testing for clinical management. Molecular cloning of HIV-1 PCR products which might improve minority detection can be slow and difficult, and commercially available recombinant virus assays test drug susceptibility of virus pools. We describe novel plasmids and simple methods for rapid cloning of HIV-1 PCR products from patient...

  11. Vibrational spectra and quantum mechanical calculations of antiretroviral drugs: Nevirapine

    Science.gov (United States)

    Ayala, A. P.; Siesler, H. W.; Wardell, S. M. S. V.; Boechat, N.; Dabbene, V.; Cuffini, S. L.

    2007-02-01

    Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'e][1,4]diazepin-6-one) is an antiretroviral drug belonging to the class of the non-nucleoside inhibitors of the HIV-1 virus reverse transcriptase. As most of this kind of antiretroviral drugs, nevirapine displays a butterfly-like conformation which is preserved in complexes with the HIV-1 reverse transcriptase. In this work, we present a detailed vibrational spectroscopy investigation of nevirapine by using mid-infrared, near-infrared, and Raman spectroscopies. These data are supported by quantum mechanical calculations, which allow us to characterize completely the vibrational spectra of this compound. Based on these results, we discuss the correlation between the vibrational modes and the crystalline structure of the most stable form of nevirapine.

  12. The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties

    OpenAIRE

    Gatch, Michael B.; Kozlenkov, Alexey; Huang, Ren-Qi; Yang, Wenjuan; Nguyen, Jacques D; González-Maeso, Javier; Rice, Kenner C.; France, Charles P; Dillon, Glenn H.; Forster, Michael J.; Schetz, John A

    2013-01-01

    Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indola...

  13. Drug resistance among HIV-infected adults receiving long term first-line antiretroviral treatment in China%成年艾滋病患者长期一线抗病毒治疗的耐药情况

    Institute of Scientific and Technical Information of China (English)

    赵德才; 范吉祥; 刘学真; 宫伟彦; 刘中夫; 汪宁; 马烨; 张福杰; 孙定勇; 刘伟; 李惠琴; 彭国平; 刘爱文; 原琛利

    2013-01-01

    Objective To investigate the situation of drug resistance among HIV-infected patients receiving long term first-line combination antiretroviral treatment (cART) and to assess the interrelated risk factors. Methods A prospective cohort study was established in 8 provinces in China since 2007. Baseline information was collected in a cross-sectional survey through multi-stage random sampling. Totall of 688 HIV-infected patients who had received first-line cART and achieved virologic suppression in 2009 were enrolled into the cohort. HIV-infected patients with viral load higher than 1000 copies/ml in 2010 were detected by ViroSeqM HIV-1 genotyping system. Life table analysis was applied to calculate the incidence of drug resistance. A sensitivity analysis was applied to evaluate the effect of second-line regimens. Based on the bivariable results, the risk factors were included into the Multivariable Logistic Regression model. Results Total of 688 HIV-infected patients receiving cART and achieving virologic suppression were eligible to this study. Among those cases, 10 cases died and 8 cases switched to second-line regimens after 12 months of follow-up. There were 29 cases with a viral load higher than 1000 copies/ml among whom, 22 patients were resistant to at least one antiretroviral drug based on genotypic assay. The incidence among drug resistance was (3.4-4.6)/100 person-years. All 22 patients were resistant to non-nucleoside reverse transcriptase inhibitor (NNRT1) and 16 patients were resistant to nucleoside reverse transcriptase inhibitor (NRTIs). No case was resistant to protease inhibitor (PI) or the combination of 3TC and TDF. Compared with patients who received cART in county level clinics or above and treated successfully, those who received cART in the village level clinic (95%CI: 2.1-19.6) and experienced virologic treatment failure (95%CI: 2.2-13.0) were most likely to occur drug resistance. Conclusions The incidence of drug resistance remained low among

  14. Diagnosis, antiretroviral therapy, and emergence of resistance to antiretroviral agents in HIV-2 infection: a review

    Directory of Open Access Journals (Sweden)

    Maia Hightower

    2003-02-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 and type 2 (HIV-2 are the causative agents of AIDS. HIV-2 is prevalent at moderate to high rates in West African countries, such as Senegal, Guinea, Gambia, and Cape Verde. Diagnosis of HIV-2 is made with a positive HIV-1/HIV-2 ELISA or simple/rapid assay, followed by one or two confirmatory tests specific for HIV-2. Following CD4+ T cell counts, HIV-2 viral burden and clinical signs and symptoms of immunodeficiency are beneficial in monitoring HIV-2 disease progression. Although non-nucleoside reverse transcriptase inhibitors are ineffective in treating HIV-2, nucleoside reverse transcriptase inhibitors and protease inhibitors can be effective in dual and triple antiretroviral regimens. Their use can decrease HIV-2 viral load, increase CD4+ T cell counts and improve AIDS-related symptoms. HIV-2 resistance to various nucleoside reverse transcriptase inhibitors and protease inhibitors, including zidovudine, lamivudine, ritonavir and indinavir, has been identified in some HIV-2 infected patients on antiretroviral therapy. The knowledge of HIV-2 peculiarities, when compared to HIV-1, is crucial to helping diagnose and guide the clinician in the choice of the initial antiretroviral regimen and for monitoring therapy success.

  15. HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Paraná, Brazil

    Directory of Open Access Journals (Sweden)

    Paula Virginia Michelon Toledo

    2010-08-01

    Full Text Available Antiretroviral therapy (ART has reduced morbidity and mortality related to human immunodeficiency virus (HIV infection, but in spite of this advance, HIV mutations decrease antiretroviral susceptibility, thus contributing to treatment failure in patients. Genotyping HIV-1 allows the selection of new drugs after initial drug failure. This study evaluated the genotypic profile of HIV-1 isolates from treated (drug-experienced patients in Paraná, Brazil. The prevalence of mutations in reverse transcriptase (RT and protease (PR genes were assessed. We analyzed 467 genotypes of patients with HIV-1 viral loads above 1,000 copies/mL. Mutations at HIV-1 RT and PR genes and previously used ART regimens were recorded. The most prevalent RT mutations were: 184V (68.31%, 215YF (51.6%, 103NS (46%, 41L (39.4%, 67N (38.54%, 210W (23.5%, 190ASE (23.2%, and 181C (17.4%. PR mutations were 90M (33.33%, 82ATFS (29%, 46I (26.8% and 54V (22.2%. The prevalence of mutations was in line with previous national and international reports, except to nonnucleoside analogue reverse transcriptase inhibitors related mutations, which were more prevalent in this study. Previous exposure to antiretroviral drugs was associated with genotypic resistance to specific drugs, leading to treatment failure in HIV patients.

  16. Field evaluation of dried blood spots for routine HIV-1 viral load and drug resistance monitoring in patients receiving antiretroviral therapy in Africa and Asia.

    Science.gov (United States)

    Monleau, Marjorie; Aghokeng, Avelin F; Eymard-Duvernay, Sabrina; Dagnra, Anoumou; Kania, Dramane; Ngo-Giang-Huong, Nicole; Touré-Kane, Coumba; Truong, Lien X T; Chaix, Marie-Laure; Delaporte, Eric; Ayouba, Ahidjo; Peeters, Martine

    2014-02-01

    Dried blood spots (DBS) can be used in developing countries to alleviate the logistic constraints of using blood plasma specimens for viral load (VL) and HIV drug resistance (HIVDR) testing, but they should be assessed under field conditions. Between 2009 and 2011, we collected paired plasma-DBS samples from treatment-experienced HIV-1-infected adults in Burkina Faso, Cameroon, Senegal, Togo, Thailand, and Vietnam. The DBS were stored at an ambient temperature for 2 to 4 weeks and subsequently at -20°C before testing. VL testing was performed on the plasma samples and DBS using locally available methods: the Abbott m2000rt HIV-1 test, generic G2 real-time PCR, or the NucliSENS EasyQ version 1.2 test. In the case of virological failure (VF), i.e., a plasma VL of ≥1,000 copies/ml, HIVDR genotyping was performed on paired plasma-DBS samples. Overall, we compared 382 plasma-DBS sample pairs for DBS VL testing accuracy. The sensitivities of the different assays in different laboratories for detecting VF using DBS varied from 75% to 100% for the m2000rt test in labs B, C, and D, 91% to 93% for generic G2 real-time PCR in labs A and F, and 85% for the NucliSENS test in lab E. The specificities varied from 82% to 97% for the m2000rt and NucliSENS tests and reached only 60% for the generic G2 test. The NucliSENS test showed good agreement between plasma and DBS VL but underestimated the DBS VL. The lowest agreement was observed for the generic G2 test. Genotyping was successful for 96/124 (77%) DBS tested, and 75/96 (78%) plasma-DBS pairs had identical HIVDR mutations. Significant discrepancies in resistance interpretations were observed in 9 cases, 6 of which were from the same laboratory. DBS can be successfully used as an alternative to blood plasma samples for routine VL and HIVDR monitoring in African and Asian settings. However, the selection of an adequate VL measurement method and the definition of the VF threshold should be considered, and laboratory performance

  17. Class of Antiretroviral Drugs and the Risk of Myocardial Infarction

    DEFF Research Database (Denmark)

    2007-01-01

    BACKGROUND: We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction. It is not clear whether this association differs according to the class of antiretroviral drugs. We conducted a study to investigate the association...... of cumulative exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors with the risk of myocardial infarction. METHODS: We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus....... The incidence rates of myocardial infarction during the follow-up period were calculated, and the associations between myocardial infarction and exposure to protease inhibitors or nonnucleoside reverse-transcriptase inhibitors were determined. RESULTS: Three hundred forty-five patients had a myocardial...

  18. Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

    Directory of Open Access Journals (Sweden)

    R. Chris Rathbun

    2011-10-01

    Full Text Available Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450 and uridine diphosphate glucuronosyltransferase (UGT enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide. The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

  19. Predictors of having a resistance test following confirmed virological failure of combination antiretroviral therapy: data from EuroSIDA

    DEFF Research Database (Denmark)

    Fox, Zoe V; Cozzi-Lepri, Alessandro; D'Arminio Monforte, Antonella;

    2011-01-01

    these recommendations. Methods: In EuroSIDA, virological failure (VF) was defined as confirmed VL>1,000 copies/ml after =4 months continuous use of any antiretroviral in a =3-drug regimen started during or after 2002. We assessed whether a resistance test was performed around VF (from 4 months before to 1 year after VF...

  20. The incidence rate of HIV type-1 drug resistance in patients on antiretroviral therapy: a nationwide population-based Danish cohort study 1999-2005

    DEFF Research Database (Denmark)

    Audelin, A.M.; Lohse, N.; Obel, N.;

    2009-01-01

    ,294 person-years at risk (PYR). The IR of NRTI resistance decreased from 13.1 per 1,000 PYR (95% confidence interval [CI] 4.9-35.0) in 1999 to 3.7 (1.9-7.2) in 2004-2005 (test for trend P=0.024). The IR of NNRTI resistance decreased from 15.4 (2.2-109.6) in 1999 to 7.9 (4.6-13.6) in 2004-2005 (P=0...

  1. Predictive Models for Maximum Recommended Therapeutic Dose of Antiretroviral Drugs

    Directory of Open Access Journals (Sweden)

    Michael Lee Branham

    2012-01-01

    Full Text Available A novel method for predicting maximum recommended therapeutic dose (MRTD is presented using quantitative structure property relationships (QSPRs and artificial neural networks (ANNs. MRTD data of 31 structurally diverse Antiretroviral drugs (ARVs were collected from FDA MRTD Database or package inserts. Molecular property descriptors of each compound, that is, molecular mass, aqueous solubility, lipophilicity, biotransformation half life, oxidation half life, and biodegradation probability were calculated from their SMILES codes. A training set (=23 was used to construct multiple linear regression and back propagation neural network models. The models were validated using an external test set (=8 which demonstrated that MRTD values may be predicted with reasonable accuracy. Model predictability was described by root mean squared errors (RMSEs, Kendall's correlation coefficients (tau, P-values, and Bland Altman plots for method comparisons. MRTD was predicted by a 6-3-1 neural network model (RMSE=13.67, tau=0.643, =0.035 more accurately than by the multiple linear regression (RMSE=27.27, tau=0.714, =0.019 model. Both models illustrated a moderate correlation between aqueous solubility of antiretroviral drugs and maximum therapeutic dose. MRTD prediction may assist in the design of safer, more effective treatments for HIV infection.

  2. Pharmacological interactions between rifampicin and antiretroviral drugs: challenges and research priorities for resource-limited settings

    NARCIS (Netherlands)

    Semvua, H.H.; Kibiki, G.S.; Kisanga, E.R.; Boeree, M.J.; Burger, D.M.; Aarnoutse, R.

    2015-01-01

    Coadministration of antituberculosis and antiretroviral therapy is often inevitable in high-burden countries where tuberculosis (TB) is the most common opportunistic infection associated with HIV/AIDS. Concurrent use of rifampicin and many antiretroviral drugs is complicated by pharmacokinetic drug-

  3. HIV抗病毒治疗者病毒抑制失败影响因素及耐药%Virological suppression failure and drug resistance in HIV-infected patients receiving antiretroviral therapy in Xihua county,Henan province

    Institute of Scientific and Technical Information of China (English)

    郑本锋; 刘宏伟; 袁源; 刘春华; 王哲; 杨利婷; 邢辉; 阮玉华; 邵一鸣

    2011-01-01

    Objective To study virological suppression failure and drug resistance among HIV-infected patients receiving antiretroviral therapy in Xihua county, Henan province. Methods In August 2009, participants with HIV-infection and receiving antivretroviral therapy (ART) were investigated to collect information on socio-demographics and treatments in Xihua county. Blood samples were collected for viral load test and genotypic resistance was determined in those with a viral load of > 1 000 copies/ml,and the HIV pol was amplified and sequenced using RT-nested PCR. Results Overall,23.5% of the participants demonstrating virological failure. In a multiple logistic regression model, male ( odds ratio [ OR] = 1.8,95% confidence interval[ CI]:1.1 - 3.1; P = 0. 0264 ), failing to adherence in the last month ( OR = 2. 3,95 % CI: 1.2 -4.2;P = 0. 0092 ), with a didanosine-based regimen currently prescribed ( OR = 2. 3,95 % CI:1. 2 -4. 2;P = 0. 012 4) were significantly associated with virological failure (viral load > 1 000 copies/ml). Of the participants demonstrating virological failure,63.2% (55/87) experienced drug resistance,63.2% (55/87) and 49. 3% (43/87) experienced drug resistance to nonnucleoside reverse-transcriptase inhibitor (NNRTI) and nucleoside reverse-transcriptase inhibitor (NRTI) ,respectively.There was no protease inhibitor resistance observed. Conclusion The rates of virological failure and drag resistance in patients receiving ART are high. Intervention measures should be taken to enhance adherence in order to improve outcomes of antiretroviral therapy.%目的 了解抗病毒治疗者病毒抑制失败影响因素和耐药状况.方法 2009年8月在河南省西华县整群抽取接受抗病毒治疗者371例,进行基本情况和抗病毒治疗相关因素问卷调查,同时抽取静脉血进行病毒载量检测,对病毒载量>1 000拷贝/mL的血液样本采用逆转录-套式聚合酶链反应(RT-nested PCR)方法扩增HIV-1 POL区基

  4. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

    NARCIS (Netherlands)

    L.M. Hofstra (L. Marije); N. Sauvageot (Nicolas); J. Albert (Jan); I. Alexiev (Ivailo); F. Garcia (Federico); D. Struck (Daniel); D.A.M.C. van de Vijver (David); B. Asjö (Birgitta); D. Beshkov (Danail); S. Coughlan (Suzie); D. Descamps (Diane); A. Griskevicius (Algis); O. Hamouda (Osamah); A. Horban (Andrzej); M.E.E. van Kasteren (Marjo); T. Kolupajeva (Tatjana); L.G. Kostrikis (Leondios); K. Liitsola (Kirsi); M. Linka (Marek); O. Mor (Orna); C. Nielsen (Claus); D. Otelea (Dan); D. Paraskevis (Dimitrios); R. Paredes (Roger); M. Poljak (Mario); E. Puchhammer-Stockl E. (E.); A. Sonnerborg (Anders); D. Stanekova (Danica); M. Stanojevic (Maja); K. Van Laethem (Kristel); M. Zazzi (Maurizio); S. Zidovec Lepej (Snjezana); C.A.B. Boucher (Charles A. B.); J.-C. Schmit (Jean-Claude); A.M.J. Wensing (Annemarie); E. Puchhammer-Stöckl (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.-M. Vandamme; J. Vercauteren (Jurgen); I. Derdelinckx; A. Sasse; M. Bogaert; H. Ceunen (H.); A. de Roo (Annie); S. De Wit; F. Echahidi (F.); K. Fransen; J.-C. Goffard (J.); P. Goubau; E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor; C. Liesnard (C.); M. Moutschen; L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira; L.P.R. Vandekerckhove; A. van den Heuvel (A.); B. van der Gucht (B.); M. Van Ranst; E. Van Wijngaerden; B. Vandercam; M. Vekemans; C. Verhofstede; N. Clumeck (N.); K. van Laethem (Kristel); D. Beshkov; I. Alexiev; S.Z. Lepej (Snjezana); J. Begovac; L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Linka; M. Maly; L. MacHala; C. Nielsen; L.B. Jørgensen; J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); H. Nielsen; A. Laursen (A.); B. Kvinesdal (B.); K. Liitsola (Kirsi); M. Ristola (M.); J. Suni; J. Sutinen (J.); D. Descamps; L. Assoumou; G. Castor; M. Grude; P. Flandre; A. Storto; O. Hamouda (Osamah); C. K̈ucherer (C.); T. Berg; P. Braun; G. Poggensee; M. Daumer (Martin); J. Eberle; H. Heiken; R. Kaiser; H. Knechten (H.); K. Korn; H. Müller; S. Neifer; B. Schmidt; H. Walter; B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); D. Paraskevis (Dimitrios); A. Hatzakis (Angelos); A. Zavitsanou (A.); A. Vassilakis; M. Lazanas; L. Chini; A. Lioni; V. Sakka (V.); S. Kourkounti (S.); V. Paparizos (V.); A. Antoniadou (A.); A. Papadopoulos; G. Poulakou; I. Katsarolis; K. Protopapas; G. Chryssos (G.); S. Drimis (S.); P. Gargalianos; G. Xylomenos; G. Lourida; M. Psichogiou (M.); G.L. Daikos (G.); N.V. Sipsas; A. Kontos (Angelos); M.N. Gamaletsou; G. Koratzanis (G.); H. Sambatakou; H. Mariolis; A. Skoutelis; V. Papastamopoulos; O. Georgiou; P. Panagopoulos (P.); E. Maltezos; S. Coughlan (Suzie); C. de Gascun (Cillian); C. Byrne; M. Duffy; P. Bergin; D. Reidy; G. Farrell; J. Lambert; E. O'Connor; A. Rochford; J. Low; P. Coakely (P.); S. O'Dea; W. Hall; O. Mor; I. Levi (I.); D. Chemtob (D.); Z. Grossman (Zehava); M. Zazzi; A. de Luca (Andrea); C. Balotta (Claudia); C. Riva (Chiara); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M. Colombo (Massimo); C. Rossi; F. Prati (Francesco); F. Tramuto; F. Vitale (F.); M. Ciccozzi; G. Angarano (Guiseppe); G. Rezza (G.); T. Kolupajeva; O. Vasins; A. Griskevicius (Algis); V. Lipnickiene; J.C. Schmit; D. Struck (Daniel); N. Sauvageot; R. Hemmer (R.); V. Arendt (V.); C. Michaux; T. Staub (T.); C. Sequin-Devaux; A.M.J. Wensing (Annemarie); C.A.B. Boucher (Charles); D.A.M.C. van de Vijver (David); A. Van Kessel; P.H.M. Van Bentum; K. Brinkman; B.J. Connell; M.E. van der Ende (Marchina); I.M. Hoepelman (Ilja Mohandas); M.E.E. van Kasteren (Marjo); M. Kuipers; N. Langebeek (Nienke); C. Richter; R.M.W.J. Santegoets (R. M W J); L. Schrijnders-Gudde (L.); R. Schuurman; B.J.M. van de Ven (B. J M); B. Åsjö (Birgitta); A.-M.B. Kran (A.-M. Bakken); V. Ormaasen (Vidar); P. Aavitsland (P.); A. Horban (Andrzej); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo; E. Jablonowska (E.); E. Maolepsza; M. Leszczyszyn-Pynka (M.); W. Szata (W.); R.J. Camacho (Ricardo Jorge); A. de Palma (Andre); F. Borges (F.); T. Paixão; V. Duque (V.); F. Araújo; D. Otelea; C. Paraschiv (Corina); A.M. Tudor; R. Cernat; C. Chiriac; F. Dumitrescu; L.J. Prisecariu; M. Stanojevic (Maja); D.J. Jevtovic (D.); D. Salemovic (D.); D. Stanekova; M. Habekova (M.); Z. Chabadová; T. Drobkova; P. Bukovinova; A. Shunnar; P. Truska; M. Poljak (Mario); M.M. Lunar (Maja M.); D. Babic; J. Tomazic (J.); S. Vidmar (Suzanna); T. Vovko; P. Karner (P.); F. Garcia; R. Paredes (Roger); S. Monge; S. Moreno; J. Del Amo; V. Asensi; J.L. Sirvent

    2016-01-01

    textabstractBackground. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, the

  5. Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-naive subjects in the CASTLE study.

    Directory of Open Access Journals (Sweden)

    Max Lataillade

    Full Text Available BACKGROUND: CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents. OBJECTIVES: Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS in ARV-naïve subjects in CASTLE. METHODS: A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF at Week 48 and 95 subjects with virologic successes (VS randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology. RESULTS: Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes. Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2% or non-B subtypes (30.9%. VF (51 and VS (90 had similar rates of any TDRs (25.5% vs. 33.3%, NNRTI TDRs (11.1% vs.11.8% and NRTI TDRs (24.4% vs. 25.5%. Of 9 (6.4% subjects with M184V/I (7 at <20% levels, 6 experienced VF. 16 (11.3% subjects had multiple TAMs, and 7 experienced VF. 3 (2.1% subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9% subjects with PI TDRs (11 at <20% levels: only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I at <20% levels, and had low resistance algorithm scores. CONCLUSION: Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%; B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.

  6. Cost-effectiveness of genotypic antiretroviral resistance testing in HIV-infected patients with treatment failure.

    Directory of Open Access Journals (Sweden)

    Pedram Sendi

    Full Text Available BACKGROUND: Genotypic antiretroviral resistance testing (GRT in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. METHODS: We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4% and societal (discount rate 2% perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. RESULTS: Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and $US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were $US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. CONCLUSIONS: GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large.

  7. Preferred antiretroviral drugs for the next decade of scale up

    Directory of Open Access Journals (Sweden)

    Isabelle Andrieux-Meyer

    2012-09-01

    Full Text Available Global commitments aim to provide antiretroviral therapy (ART to 15 million people living with HIV by 2015, and recent studies have demonstrated the potential for widespread ART to prevent HIV transmission. Increasingly, countries are adapting their national guidelines to start ART earlier, for both clinical and preventive benefits. To maximize the benefits of ART in resource-limited settings, six key principles need to guide ART choice: simplicity, tolerability and safety, durability, universal applicability, affordability and heat stability. Currently available drugs, combined with those in late-stage clinical development, hold great promise to simplify treatment in the short term. Over the longer term, newer technologies, such as long-acting formulations and nanotechnology, could radically alter the treatment paradigm. This commentary reviews recommendations made in an expert consultation on treatment scale up in resource-limited settings.

  8. A Randomised Trial Comparing Genotypic and Virtual Phenotypic Interpretation of HIV Drug Resistance: The CREST Study

    OpenAIRE

    Hales, Gillian; Birch, Chris; Crowe, Suzanne; Workman, Cassy; Hoy, Jennifer F.; Law, Matthew G; Kelleher, Anthony D.; Lincoln, Douglas; Emery, Sean

    2006-01-01

    Editorial Commentary Background: Antiretroviral drugs are used to treat patients with HIV infection, with good evidence that they improve prognosis. However, mutations develop in the HIV genome that allow it to evade successful treatment—known as drug resistance—and such mutations are known against every class of antiretroviral drug. Resistance can cause treatment failure and limit the treatment options available. Different types of tests are often used to detect resistance and to work out wh...

  9. Use of non-antiretroviral drugs among individuals with and without HIV-infection

    DEFF Research Database (Denmark)

    Rasmussen, Line D; Kronborg, Gitte; Larsen, Carsten S;

    2016-01-01

    AIM: We investigated the use of non-antiretroviral drugs in the HIV-infected compared to the general population. METHODS: From the Danish HIV Cohort Study, we identified all HIV-infected individuals older than 18 years at HIV diagnosis who received care in Denmark through 1995-2013 and reported...... no injection drug abuse or hepatitis C infection. Population controls were identified from The Danish Civil Registration System and matched on age and gender (5:1). We analyzed the proportion of individuals who redeemed 0-1, 2-4, 5-9, or 10 or more non-antiretroviral drugs. Data were analyzed according...... to calendar time, age, time from initiation of combination antiretroviral therapy (cART) and stratified by gender, geographical origin and route of HIV transmission. We further analyzed the use of the 25 most used non-antiretroviral drug classes. RESULTS: We identified 4,928 HIV-infected individuals (median...

  10. Central nervous system HIV infection in "less-drug regimen" antiretroviral therapy simplification strategies.

    Science.gov (United States)

    Ferretti, Francesca; Gianotti, Nicola; Lazzarin, Adriano; Cinque, Paola

    2014-02-01

    Less-drug regimens (LDR) refer to combinations of either two antiretroviral drugs or ritonavir-boosted protease inhibitor (PI) monotherapy. They may represent a simplification strategy in patients with persistently suppressed human immunodeficiency virus (HIV) viremia, with the main benefits of reducing drug-related toxicities and costs. Systemic virological efficacy of LDR is slightly lower as compared with combined antiretroviral therapy (cART), but patients with failure do not usually develop drug resistance and resuppress HIV replication after reintensification. A major concern of LDR is the lower efficacy in the virus reservoirs, especially in the central nervous system (CNS), where viral compartmentalization and independent evolution of infection may lead to CNS viral escape, often associated with neurologic symptoms. The authors reviewed studies of virological and functional CNS efficacy of LDR, particularly of boosted PI monotherapy regimens, for which more information is available. Symptomatic viral CSF escape was observed mainly in PI/r monotherapy patients with plasma failure and low nadir CD4+ cell counts, and resolved upon reintroduction of triple drug cART, whereas asymptomatic viral failure in CSF was not significantly more frequent in patients on PI/r monotherapy compared with patients on standard cART. In addition, there was no difference in functional outcomes between PI monotherapy and cART patients, irrespective of CSF viral escape. More data are needed on the CNS effect of dual ART regimens and, in general, on long-term efficacy of LDR. Simplification with LDR may be an attractive option in patients with suppressed viral load, if they are well selected and monitored for potential CNS complications.

  11. Correlates of non-adherence to antiretroviral therapy in a cohort of HIV-positive drug users receiving antiretroviral therapy in Hanoi, Vietnam.

    Science.gov (United States)

    Jordan, M R; Obeng-Aduasare, Y; Sheehan, H; Hong, S Y; Terrin, N; Duong, D V; Trung, N V; Wanke, C; Kinh, N V; Tang, A M

    2014-08-01

    The HIV epidemic in Vietnam is concentrated, with high prevalence estimates among injection drug users and commercial sex workers. Socio-demographics, substance use and clinical correlates of antiretroviral therapy non-adherence were studied in 100 HIV-1 infected drug users receiving antiretroviral therapy for at least 6 months in Hanoi, Vietnam. All study participants were men with a mean age of 29.9 ± 4.9 years. The median duration on antiretroviral therapy was 16.2 ± 12.7 months; 83% reported 'very good' or 'perfect' adherence in the past 30 days on a subjective one-item Likert scale at time of study enrollment; 48% of participants reported drug use within the previous 6 months, with 22% reporting current drug use. Injection drug use with or without non-injection drug use in the past 6 months (95% C.I. 2.19, 1.30-3.69) and years on antiretroviral therapy (95% C.I. 1.43, 1.14-1.78) were correlated with suboptimal adherence. These findings support Vietnam's ongoing scale-up of harm reduction programmes for injection drug users and their integration with antiretroviral therapy delivery. Moreover, results highlight the need to identify and implement new ways to support high levels of antiretroviral therapy adherence as duration on antiretroviral therapy increases.

  12. Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction.

    Directory of Open Access Journals (Sweden)

    Reneé de Waal

    Full Text Available BACKGROUND: Lipoatrophy and/or central fat gain are observed frequently in patients on antiretroviral therapy (ART. Both are assumed to be antiretroviral adverse drug reactions. METHODS: We conducted a systematic review to determine whether fat loss or gain was more common in HIV-infected patients on ART than in uninfected controls; was associated with specific antiretrovirals; and would reverse after switching antiretrovirals. RESULTS: Twenty-seven studies met our inclusion criteria. One cohort study reported more lipoatrophy, less subcutaneous fat gain, but no difference in central fat gain in HIV-infected patients on ART than in controls. Randomised controlled trials (RCTs showed more limb fat loss (or less fat gain with the following regimens: stavudine (versus other nucleoside reverse transcriptase inhibitors (NRTIs; efavirenz (versus protease inhibitors (PIs; and NRTI-containing (versus NRTI-sparing. RCTs showed increased subcutaneous fat after switching to NRTI-sparing regimens or from stavudine/zidovudine to abacavir/tenofovir. There were no significant between-group differences in trunk and/or visceral fat gain in RCTs of various regimens, but results from efavirenz versus PI regimens were inconsistent. There was no significant between-group differences in central fat gain in RCTs switched to NRTI-sparing regimens, or from PI-containing regimens. CONCLUSIONS: There is clear evidence of a causal relationship between NRTIs (especially thymidine analogues and lipoatrophy, with concomitant PIs possibly having an ameliorating effect or efavirenz causing additive toxicity. By contrast, central fat gain appears to be a consequence of treating HIV infection, because it is not different from controls, is not linked to any antiretroviral class, and doesn't improve on switching.

  13. The HIV antiretroviral drug efavirenz has LSD-like properties.

    Science.gov (United States)

    Gatch, Michael B; Kozlenkov, Alexey; Huang, Ren-Qi; Yang, Wenjuan; Nguyen, Jacques D; González-Maeso, Javier; Rice, Kenner C; France, Charles P; Dillon, Glenn H; Forster, Michael J; Schetz, John A

    2013-11-01

    Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT(2A) receptors. In rodents, interaction with the 5-HT(2A) receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT(2A) receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT(2A)-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT(2A) receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.

  14. Activity of antiretroviral drugs in human infections by opportunistic agents

    OpenAIRE

    Izabel Galhardo Demarchi; Daniela Maira Cardozo; Sandra Mara Alessi Aristides; Ricardo Alberto Moliterno; Thaís Gomes Verzignassi Silveira; Rosilene Fressatti Cardoso; Dennis Armando Bertolini; Terezinha Inez Estivalet Svidzinski; Jorge Juarez Vieira Teixeira; Maria Valdrinez Campana Lonardoni

    2012-01-01

    Highly active antiretroviral therapy (HAART) is used in patients infected with HIV. This treatment has been shown to significantly decrease opportunist infections such as those caused by viruses, fungi and particularly, protozoa. The use of HAART in HIV-positive persons is associated with immune reconstitution as well as decreased prevalence of oral candidiasis and candidal carriage. Antiretroviral therapy benefits patients who are co-infected by the human immunodeficiency virus (HIV), human ...

  15. Kinetically Controlled Drug Resistance

    DEFF Research Database (Denmark)

    Sun, Xin E.; Hansen, Bjarne Gram; Hedstrom, Lizbeth

    2011-01-01

    The filamentous fungus Penicillium brevicompactum produces the immunosuppressive drug mycophenolic acid (MPA), which is a potent inhibitor of eukaryotic IMP dehydrogenases (IMPDHs). IMPDH catalyzes the conversion of IMP to XMP via a covalent enzyme intermediate, E-XMP*; MPA inhibits by trapping E...... of resistance is not apparent. Here, we show that, unlike MPA-sensitive IMPDHs, formation of E-XMP* is rate-limiting for both PbIMPDH-A and PbIMPDH-B. Therefore, MPA resistance derives from the failure to accumulate the drug-sensitive intermediate....

  16. Fate of the antiretroviral drug tenofovir in agricultural soil

    Energy Technology Data Exchange (ETDEWEB)

    Al-Rajab, Abdul Jabbar; Sabourin, Lyne; Chapman, Ralph; Lapen, David R.; Topp, Edward, E-mail: ed.topp@agr.gc.ca [Agriculture and Agri-Food Canada, London, ON, N5V 4T3 (Canada)

    2010-10-15

    Tenofovir (9-(R)-(2-phosphonylmethoxypropyl)-adenine) is an antiretroviral drug widely used for the treatment of human immunodeficiency virus (HIV-1) and Hepatitis B virus (HBV) infections. Tenofovir is extensively and rapidly excreted unchanged in the urine. In the expectation that tenofovir could potentially reach agricultural lands through the application of municipal biosolids or wastewater, and in the absence of any environmental fate data, we evaluated its persistence in selected agricultural soils. Less than 10% of [adenine-8-{sup 14}C]-tenofovir added to soils varying widely in texture (sand, loam, clay loam) was mineralized in a 2-month incubation under laboratory conditions. Tenofovir was less readily extractable from clay soils than from a loam or a sandy loam soil. Radioactive residues of tenofovir were removed from the soil extractable fraction with DT{sub 50}s ranging from 24 {+-} 2 to 67 + 22 days (first order kinetic model) or 44 + 9 to 127 + 55 days (zero order model). No extractable transformation products were detectable by HPLC. Tenofovir mineralization in the loam soil increased with temperature (range 4 {sup o}C to 30 {sup o}C), and did not occur in autoclaved soil, suggesting a microbial basis. Mineralization rates increased with soil moisture content, ranging from air-dried to saturated. In summary, tenofovir was relatively persistent in soils, there were no extractable transformation products detected, and the response of [adenine-8-{sup 14}C]-tenofovir mineralization to soil temperature and heat sterilization indicated that the molecule was biodegraded by aerobic microorganisms. Sorption isotherms with dewatered biosolids suggested that tenofovir residues could potentially partition into the particulate fraction during sewage treatment.

  17. Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage

    OpenAIRE

    Bressani, Rafael F.; Nowacek, Ari S.; Singh, Sangya; Balkundi, Shantanu; Rabinow, Barrett; McMillan, JoEllyn; Gendelman, Howard E; Kanmogne, Georgette D.

    2010-01-01

    Limitations inherent to antiretroviral therapy (ART) in its pharmacokinetic properties remain despite over 15 years of broad use. Our laboratory has pioneered a means to improve ART delivery through monocyte-macrophage carriage of nanoformulated drug-encapsulated particles (nanoART). To this end, our prior works sought to optimize nanoART size, structure, and physical properties for cell uptake and antiretroviral activities. To test the functional consequences of indinavir, ritonavir, and efa...

  18. Genotypic resistance mutations to antiretroviral drugs in newly confirmed human immunodeficiency virus inferiors in Beijing%北京市未经抗病毒治疗的HIV感染者耐药突变流行性调查

    Institute of Scientific and Technical Information of China (English)

    叶景荣; 郭蕾; 卢红艳; 辛若雷; 曾毅

    2011-01-01

    Objective To examine the prevalence of drug resistance mutations among the treatmentnaive HIV ( human immunodeficiency virus) infectors living in Beijing so as to provide the basal information for clinical antiviral treatment. Methods HIV pol genes from plasma samples of 150 treatment-naive HIV-infected patients were amplified, sequenced and phylogenetically analyzed. And the drug-resistance associated mutations in protease and reverse transcriptase regions were analyzed with Stanford University HIV Drug Resistance Database. Results A total of 111 pol gene sequences were obtained. The overall prevalence of drug resistance was 8.1% (9/111) , corresponding to 3.6% (4/111) for protease inhibitors,1.8% (2/111) for nucleoside reverse transcriptase inhibitors and 3.6% (4/111) for non-nucleoside reverse transcriptase inhibitors. No drug resistance mutation was identified in 17 intravenous drug users. Conclusion The prevalence of drug resistance is relatively high in the newly confirmed HIV infectors in Beijing. Regular surveillance and monitoring of drug-resistant HIV should be implemented.%目的 了解北京市未经抗病毒治疗的HIV感染者耐药突变流行性情况.方法 选取北京市2007年新确认HIV感染者抗凝全血标本150份,提取血浆中的病毒RNA,用反转录PCR和套式PCR扩增HIV的pol基因,并进行序列测定及耐药分析.结果 成功扩增出111份标本的pol基因;未经抗病毒治疗的HIV感染者的耐药率为8.1%(9/111),蛋白酶抑制剂耐药率为3.6%(4/111),核苷类反转录酶抑制剂耐药率为1.8%(2/111),非核苷类反转录酶抑制剂耐药率为3.6%(4/111).结论 北京市未经抗病毒治疗的HIV感染者耐药性处于相对较高的水平,应当定期进行HIV耐药性监测.

  19. Activity of antiretroviral drugs in human infections by opportunistic agents

    Directory of Open Access Journals (Sweden)

    Izabel Galhardo Demarchi

    2012-03-01

    Full Text Available Highly active antiretroviral therapy (HAART is used in patients infected with HIV. This treatment has been shown to significantly decrease opportunist infections such as those caused by viruses, fungi and particularly, protozoa. The use of HAART in HIV-positive persons is associated with immune reconstitution as well as decreased prevalence of oral candidiasis and candidal carriage. Antiretroviral therapy benefits patients who are co-infected by the human immunodeficiency virus (HIV, human herpes virus 8 (HHV-8, Epstein-Barr virus, hepatitis B virus (HBV, parvovirus B19 and cytomegalovirus (CMV. HAART has also led to a significant reduction in the incidence, and the modification of characteristics, of bacteremia by etiological agents such as Staphylococcus aureus, coagulase negative staphylococcus, non-typhoid species of Salmonella, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. HAART can modify the natural history of cryptosporidiosis and microsporidiosis, and restore mucosal immunity, leading to the eradication of Cryptosporidium parvum. A similar restoration of immune response occurs in infections by Toxoplasma gondii. The decline in the incidence of visceral leishmaniasis/HIV co-infection can be observed after the introduction of protease inhibitor therapy. Current findings are highly relevant for clinical medicine and may serve to reduce the number of prescribed drugs thereby improving the quality of life of patients with opportunistic diseases.A terapia HAART (terapia antirretroviral altamente ativa é usada em pacientes infectados pelo vírus da imunodeficiência humana (HIV e demonstrou diminuição significativa de infecções oportunistas, tais como as causadas por vírus, fungos, protozoários e bactérias. O uso da HAART está associado com a reconstituição imunológica e diminuição na prevalência de candidíase oral. A terapia antirretroviral beneficia pacientes co-infectados pelo HIV, v

  20. Drug resistance in malaria

    Directory of Open Access Journals (Sweden)

    S C Parija

    2011-01-01

    Full Text Available Antimalarial chemotherapy is an important component of all malaria control programmes throughout the world. This is especially so in light of the fact that there are no antimalarial vaccines which are available for clinical use at present. Emergence and spread of malaria parasites which are resistant to many of the available antimalarials today is, therefore, a major cause for concern. Till date, resistance to all groups of antimalarials excluding artemisinin has been reported. In recent years, in vitro resistance to even artemisinin has been described. While resistance to antibacterial agents has come to prominence as a clinical problem in recent years, antiparasitic resistance in general and antimalarial resistance in particular has not received much attention, especially in the Indian scenario. The present review deals with commonly used antimalarial drugs and the mechanisms of resistance to them. Various methods of detecting antimalarial resistance and avoiding the same have also been dealt with. Newer parasite targets which can be used in developing newer antimalarial agents and antimalarials obtained from plants have also been mentioned.

  1. Evaluation of antiretroviral drug measurements by an interlaboratory quality control program.

    NARCIS (Netherlands)

    Droste, J.A.H.; Aarnoutse, R.E.; Koopmans, P.P.; Hekster, Y.A.; Burger, D.M.

    2003-01-01

    Since 1999 an ongoing international interlaboratory quality control program has analyzed antiretroviral drugs in plasma. Results of the third round of this program are presented. Quality control samples were prepared by spiking drug-free plasma with varying concentrations of the currently available

  2. Vietnamese Women's Struggle to Access Antiretroviral Drugs in a Context of Free Treatment

    DEFF Research Database (Denmark)

    Nguyen, Nam Thi Thu; Rasch, Vibeke; Bygbjerg, Ib Christian;

    2013-01-01

    This qualitative study aims to explore how HIV positive women living in a northern province of Vietnam experience seeking antiretroviral (ARV) treatment in the public health system, and how they address obstacles encountered along the way. Despite the fact that antiretroviral drugs were freely...... provided, they were not always accessible for women in need. A variety of factors at the population and health system level interacted in ways that often made access to ARV drugs a complicated and time-consuming process. We have suggested changes that could be made at the health system level that may help...

  3. Effectiveness and Safety of Concurrent Use of First-Line Antiretroviral and Antituberculous Drugs in Rwanda

    OpenAIRE

    Justin Ntokamunda Kadima; Marie Françoise Mukanyangezi; Claude Bernard Uwizeye

    2014-01-01

    Background. Overlapping toxicity between drugs used for HIV and TB could complicate the management of HIV/TB coinfected patients, particularly those carrying multiple opportunistic infections. This study aimed to evaluate the clinical outcomes and adverse drug events in HIV patients managed with first-line antiretroviral and first-line anti-TB drugs. Methods. This is a retrospective study utilizing medical dossiers from single-HIV infected and HIV/TB coinfected patients already initiated on A...

  4. Hidden costs of HIV treatment in Spain: inefficiency of the antiretroviral drug packaging

    OpenAIRE

    Llibre-Codina, Josep M; Angels Andreu-Crespo; Gloria Cardona-Peitx; Ferran Sala-Piñol; Bonaventura Clotet-Sala; Xavier Bonafont-Pujol

    2014-01-01

    Introduction: Antiretroviral drugs in Spain are delivered by law only in hospital pharmacies. Commercial packages meet variable quality standards when dispensed drugs are returned due to treatment changes or adherence problems Nearly 20–25% of the initial regimens will be changed at 48 weeks for different reasons. We evaluated the economic impact on public health system of the inability of using returned drugs due to inefficient packaging. Materials and Methods: We defined socially efficient ...

  5. Hidden costs of antiretroviral treatment: the public health efficiency of drug packaging.

    Science.gov (United States)

    Andreu-Crespo, Àngels; Llibre, Josep M; Cardona-Peitx, Glòria; Sala-Piñol, Ferran; Clotet, Bonaventura; Bonafont-Pujol, Xavier

    2015-01-01

    While the overall percentage of unused antiretroviral medicines returned to the hospital pharmacy is low, their cost is quite high. Adverse events, treatment failure, pharmacokinetic interactions, pregnancy, or treatment simplification are common reasons for unplanned treatment changes. Socially inefficient antiretroviral packages prevent the reuse of drugs returned to the hospital pharmacy. We defined antiretroviral package categories based on the excellence of drug packaging and analyzed the number of pills and costs of drugs returned during a period of 1 year in a hospital-based HIV unit attending to 2,413 treated individuals. A total of 6,090 pills (34% of all returned antiretrovirals) - with a cost of 47,139.91 € - would be totally lost, mainly due to being packed up in the lowest efficiency packages. Newer treatments are packaged in low-excellence categories of packages, thus favoring the maintenance of these hidden costs in the near future. Therefore, costs of this low-efficiency drug packaging, where medication packages are started but not completed, in high-cost medications are substantial and should be properly addressed. Any improvement in the packaging by the manufacturer, and favoring the choice of drugs supplied through efficient packages (when efficacy, toxicity, and convenience are similar), should minimize the treatment expenditures paid by national health budgets. PMID:26273190

  6. Hidden costs of antiretroviral treatment: the public health efficiency of drug packaging.

    Science.gov (United States)

    Andreu-Crespo, Àngels; Llibre, Josep M; Cardona-Peitx, Glòria; Sala-Piñol, Ferran; Clotet, Bonaventura; Bonafont-Pujol, Xavier

    2015-01-01

    While the overall percentage of unused antiretroviral medicines returned to the hospital pharmacy is low, their cost is quite high. Adverse events, treatment failure, pharmacokinetic interactions, pregnancy, or treatment simplification are common reasons for unplanned treatment changes. Socially inefficient antiretroviral packages prevent the reuse of drugs returned to the hospital pharmacy. We defined antiretroviral package categories based on the excellence of drug packaging and analyzed the number of pills and costs of drugs returned during a period of 1 year in a hospital-based HIV unit attending to 2,413 treated individuals. A total of 6,090 pills (34% of all returned antiretrovirals) - with a cost of 47,139.91 € - would be totally lost, mainly due to being packed up in the lowest efficiency packages. Newer treatments are packaged in low-excellence categories of packages, thus favoring the maintenance of these hidden costs in the near future. Therefore, costs of this low-efficiency drug packaging, where medication packages are started but not completed, in high-cost medications are substantial and should be properly addressed. Any improvement in the packaging by the manufacturer, and favoring the choice of drugs supplied through efficient packages (when efficacy, toxicity, and convenience are similar), should minimize the treatment expenditures paid by national health budgets.

  7. Drug resistance mutations in AIDS patients failing highly active antiretroviral therapy in Lincang, Yunnan province, in 2012%临沧市2012年高效抗反转录病毒治疗失败的AIDS患者耐药基因变异分析

    Institute of Scientific and Technical Information of China (English)

    杨翕然; 杨翠先; 杨绍敏; 边中启

    2014-01-01

    目的:了解临沧市2012年经高效抗反转录病毒治疗(highly active antiretroviral therapy, HAART)失败的AIDS患者耐药基因的变异情况。方法调查HAART失败AIDS患者的流行病学特征,检测CD4+T淋巴细胞计数和病毒载量,对HIV RNA>1×103 copies/ml的患者行HIV-1耐药基因检测。结果66例中有53例检出基因耐药突变。最常见的核苷类反转录酶抑制剂耐药突变位点为M184V、D67N和K70R,非核苷类反转录酶抑制剂耐药突变位点为K103N、G190A和V179D。仅发现3个蛋白酶抑制剂突变位点,分别为D33F、M46I和L76V。结论临沧市AIDS患者出现较多反转录酶抑制剂突变位点是一线抗反转录病毒治疗失败的主要原因。在选择二线治疗方案时,增加蛋白酶抑制剂可避免多重耐药导致的治疗失败。%Objective To investigate HIV drug resistance mutations in AIDS patients failing highly active antiretroviral therapy (HAART) in Lincang, Yunnan province, in 2012. Methods Epidemiological characteristics of AIDS patients failing in HAART were investigated. CD4+T lymphocyte count and viral load were detected, and HIV-1 resistance testing was conducted on those patients with viral load more than 1000 copies/ml. Results Among 66 patients failing in HAART, drug resistance mutations were found in 53 patients. The most common nucleoside reverse transcriptase inhibitor resistance mutations were M184V, D67N and K70R, and non-nucleoside reverse transcriptase inhibitor resistance mutations were K103N, G190A and V179D. Only 3 protease inhibitor (P I ) resistance mutations were found, and they were D33F, M46I and L76V, respectively. Conclusions The emergence of reverse transcriptase resistance mutations is the main reason for the failure of first-line antiretroviral therapy (ART) in AIDS patients in Lincang, Yunnan province. Therefore, when switching to second-line ART, the increased use of PI can avoid ART failure due to multidrug resistance.

  8. Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs.

    NARCIS (Netherlands)

    Boffito, M.; Acosta, E.; Burger, D.M.; Fletcher, C.V.; Flexner, C.; Garaffo, R.; Gatti, G.; Kurowski, M.; Perno, C.F.; Peytavin, G.; Regazzi, M.; Back, D.

    2005-01-01

    The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) provide a framework for the implementation of TDM in certain defined scenar

  9. Prevalence and evolution of drug resistance HIV-1 variants in Henan, China

    Institute of Scientific and Technical Information of China (English)

    Jing; Yun; LI; Han; Ping; LI; Lin; LI; Hong; LI; Zhe; WANG; Kun; YANG; Zuo; Yi; BAO; Dao; Min; ZHUANG; Si; Yang; LIU; Yong; Jian; LIU; Hui; XING; Yi; Ming; SHAO

    2005-01-01

    To understand the prevalence and evolution of drug resistant HIV strains in Henan China after the implementation of free antiretroviral therapy for AIDS patients. 45 drug naive AIDS patients, 118 AIDS patients who received three months antiretroviral therapy and 124 AIDS patients who received six months antiretroviral treatment were recruited in the southern part of Henan province. Information on general condition, antiretroviral medicines, adherence and clinical syndromes were collected by face to face interview. Meanwhile, 14ml EDTA anticoagulant blood was drawn. CD4/CD8 T cell count, viral load and genotypic drug resistance were tested. The rates of clinical improvement were 55.1% and 50.8% respectively three months and six months after antiretroviral therapy. The mean CD4 cell count after antiretroviral therapy was significantly higher than in drug naive patients. The prevalence rate of drug resistant HIV strains were 13.9%, 45.4% and 62.7% in drug naive patients, three month treatment patients and six month treatment patients, respectively.The number of resistance mutation codons and the frequency of mutations increased significantly with continued antiretroviral therapy. The mutation sites were primarily at the 103, 106 and 215 codons in the three-month treatment group and they increased to 15 codon mutations in the six-month treatment group. From this result, the evolution of drug resistant strains was inferred to begin with the high level NNRTI resistant strain, and then develop low level resistant strains to NRTIs. The HIV strains with high level resistance to NVP and low level resistance to AZT and DDI were highly prevalent because of the AZT+DDI+NVP combination therapy. These HIV strains were also cross resistant to DLV, EFV, DDC and D4T. Poor adherence to therapy was believed to be the main reason for the emergence and prevalence of drug resistant HIV strains. The prevalence of drug resistant HIV strains was increased with the continuation of

  10. Hidden costs of antiretroviral treatment: the public health efficiency of drug packaging

    Directory of Open Access Journals (Sweden)

    Andreu-Crespo À

    2015-08-01

    Full Text Available Àngels Andreu-Crespo,1,* Josep M Llibre,2,3,* Glòria Cardona-Peitx,1 Ferran Sala-Piñol,1 Bonaventura Clotet,2,4 Xavier Bonafont-Pujol1 1Pharmacy Department, 2HIV Unit and “Lluita contra la SIDA” Foundation, University Hospital Germans Trias i Pujol, Badalona, 3Universitat Autònoma de Barcelona, 4Universitat de Vic-Universitat Central de Catalunya (UVIC-UCC, Vic, Barcelona, Spain *These authors contributed equally to the work Abstract: While the overall percentage of unused antiretroviral medicines returned to the hospital pharmacy is low, their cost is quite high. Adverse events, treatment failure, pharmacokinetic interactions, pregnancy, or treatment simplification are common reasons for unplanned treatment changes. Socially inefficient antiretroviral packages prevent the reuse of drugs returned to the hospital pharmacy. We defined antiretroviral package categories based on the excellence of drug packaging and analyzed the number of pills and costs of drugs returned during a period of 1 year in a hospital-based HIV unit attending to 2,413 treated individuals. A total of 6,090 pills (34% of all returned antiretrovirals – with a cost of 47,139.91€ – would be totally lost, mainly due to being packed up in the lowest efficiency packages. Newer treatments are packaged in low-excellence categories of packages, thus favoring the maintenance of these hidden costs in the near future. Therefore, costs of this low-efficiency drug packaging, where medication packages are started but not completed, in high-cost medications are substantial and should be properly addressed. Any improvement in the packaging by the manufacturer, and favoring the choice of drugs supplied through efficient packages (when efficacy, toxicity, and convenience are similar, should minimize the treatment expenditures paid by national health budgets. Keywords: antiretroviral treatment, cost efficacy, drug packaging, treatment change

  11. Genotypic analysis on drug resistance of patients after failure of first-line highly active antiretroviral therapy%AIDS患者高效一线抗逆转录病毒治疗失败后HIV耐药基因型分析

    Institute of Scientific and Technical Information of China (English)

    李彦媚; 赵红心; 周海卫; 肖江; 张雯; 黄英秀; 曾辉

    2013-01-01

    Objective To study the genotypic drug resistance mutations of HIV after the failure of first-line highly active antiretroviral therapy ( HAART ) in patients with AIDS. Methods Total of 30 HIV-infected patients' peripheral blood and separated blood plasma who were treated in Beijing Ditan Hospital, Capital Medical University and failed after first-line HAART were collected, and nested-PCR was taken to amplify the genome sequence of the 1-99 amino acid of HIV protease and the first 300 amino acid of the reverse transcriptase, then PCR products were sequenced after purification, and the acquired nucleotide sequences were compared with resistant database of Stanford University and the interpretation of patients' drug resistance was acquired. Results There were 28 cases sequenced successfully among the 30 patients plasma and the amplification rate was 93%. Twenty-seven patients were found drug resistant mutations. Total of 48 drug resistance mutations in the reverse transcriptase ( RT ) area were detected, wherein the mutation rates of Ml84, D67G, K70R, K70K/R, A62V, K219E, K65R, V75I, T215F and D67N were greater than 10% of the incidence in nucleoside reverse transcriptase ( NRT ) area. Y181C, G190A, K103N, V179D occured greater than 10% in the non-nucleoside reverse transcriptase ( NNRT ) area. A71T, Q58E, A71V, N83D/N were the 4 minor mutations detected in the protease ( PR ) region. In the nucleoside reverse transcriptase inhibitor ( NRTI ), 89% patients were developed to high or intemediate-level of drug resistance to 3TC and FTC, which also appeared in a different proportion to ABC, AZT, D4T, DDI, TDF, and the high or intermediate level of TDF and AZT resistance rates were 14% and 29% , respectively. Among non-nucleoside reverse transcriptase inhibitor ( NNRTI ), more than 50% patients had high or intermediate drug resistance to EFV, ETR, NVP, RPV. The minor mutations in PR region induced potenitially low level drug resistance and with none high or intermediate

  12. Impact of Adherence Counseling Dose on Antiretroviral Adherence and HIV Viral Load among HIV-Infected Methadone Maintained Drug Users

    OpenAIRE

    Cooperman, Nina A.; Heo, Moonseong; Berg, Karina M.; Li, Xuan; Litwin, Alain H.; Nahvi, Shadi; Arnsten, Julia H.

    2012-01-01

    Adherence counseling can improve antiretroviral adherence and related health outcomes in HIV-infected individuals. However, little is known about how much counseling is necessary to achieve clinically significant effects. We investigated antiretroviral adherence and HIV viral load relative to the number of hours of adherence counseling received by 60 HIV-infected drug users participating in a trial of directly observed antiretroviral therapy delivered in methadone clinics. Our adherence couns...

  13. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients

    NARCIS (Netherlands)

    A. Mocroft; O. Kirk; P. Reiss; S. de Wit; D. Sedlacek; M. Beniowski; J. Gatell; A.N. Phillips; B. Ledergerber; J.D. Lundgren

    2010-01-01

    Objectives: Chronic kidney disease (CKD) in HIV-positive persons might be caused by both HIV and traditional or non-HIV-related factors. Our objective was to investigate long-term exposure to specific antiretroviral drugs and CKD. Design: A cohort study including 6843 HIV-positive persons with at le

  14. Antiretroviral therapy optimisation without genotype resistance testing: a perspective on treatment history based models

    NARCIS (Netherlands)

    M.C.F. Prosperi; M. Rosen-Zvi; A. Altman; M. Zazzi; S. Di Giambenedetto; R. Kaiser; E. Schülter; D. Struck; P. Sloot; D.A. van de Vijver; A.-M. Vandamme; A. Sönnerborg

    2010-01-01

    Background: Although genotypic resistance testing (GRT) is recommended to guide combination antiretroviral therapy (cART), funding and/or facilities to perform GRT may not be available in low to middle income countries. Since treatment history (TH) impacts response to subsequent therapy, we investig

  15. Drug resistance in mycobacterium tuberculosis

    OpenAIRE

    Abate, Getahun

    1999-01-01

    Drug-resistant tuberculosis is a global public health problem. This investigation was performed to find ways of improving regimens that could be used for the treatment of drug- and multidrug-resistant TB and also to find a rapid method of diagnosis of drug resistant TB, particularly MDR-TB. Among 107 isolates of M. tuberculosis from re-treatment cases of pulmonary TB in Ethiopia (study 1), 48% were resistant at least to one of the four first-line drugs tested and 12 % were A...

  16. Phylogeny and drug resistance of HIV PR gene among HIV patients receiving RT inhibitors in Iran

    Institute of Scientific and Technical Information of China (English)

    Kazem Baesi; Majedeh Moradbeigi; Mehrdad Ravanshad; Ashrafolnesa Baghban

    2016-01-01

    Objective: To survey the level and patterns of reverse transcriptase-based drug resistance and subtype distribution among antiretroviral-treated HIV-infected patients receiving only reverse transcriptase inhibitors in Iran. Methods: A total of 25 samples of antiretroviral therapy experienced patients with no history of using protease inhibitors were collected. After RNA extraction, reverse transcriptase-nested PCR was performed. The final products were sequenced and then analysed for drug-resistant mutations and subtypes. Results: No drug resistant mutations were observed among the 25 subjects. The results showed the following subtypes among patients:CRF 35_AD (88%), CRF 28_BF (8%), and CRF 29_BF (4%). Conclusions: A significant increase in drug resistance has been noted in recently-infected patients worldwide. Subtype distributions are needed to perform properly-designed surveillance studies to continuously monitor rates and patterns of transmitted drug resistance and subtypes to help guide therapeutic approaches and limit transmission of these variants.

  17. Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals

    OpenAIRE

    Pauline Byakika-Kibwika; Mohammed Lamorde; Harriet Mayanja-Kizza; Saye Khoo; Concepta Merry; Jean-Pierre Van geertruyden

    2011-01-01

    Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART) poses significant challenges. Artemether-lumefantrine (AL) is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine are metabolized by hepatic cytochrome P450 (CYP450) enzymes which metabolize the protease inhibitors (PIs) and nonnucle...

  18. The therapeutic efficacy and occurrence of drug resistance among patients in Xinjiang during the first 12 months of antiretroviral treatment%新疆部分艾滋病病人抗病毒治疗效果和耐药变异分析

    Institute of Scientific and Technical Information of China (English)

    佐合拉·吐尔地; 邵一鸣; 廖玲洁; 董永慧; 邢辉; 孙峰; 阮玉华; 马祥荣; 开赛尔; 地力努尔

    2011-01-01

    Objective To evaluate immune reconstitution, viral suppression and the occurrence of drug resistance among patients during the first 12 months of first-line antiretroviral treatment in Xinjiang. Methods Risk factors for failure of viral suppression and HIV drug resistance were analyzed in Logistic regression models. Results At baseline, 5.1 % of the patients had a viral load less than 1 000 copies/ml, the rates of viral suppression (<1 000 copies/ml) at 6 and 12 months of treatment were 71.1 % (69/97) and 70. 8% (80/113) respectively. The average CD4+ T cell counts were 191,324 and 327 cells/μl at 0, 6 and 12 months of treatment respectively. At 6 months, five patients (5.2% ,5/97) were detected to harbor drug resistance virus; the number was increased to 12(10. 6%, 12/113) at 12 months of treatment; none of the HIV strains from these patients revealed resistance to any antiretroviral drugs at baseline; viruses from seven patients were resistant to both NRTI and NNRTI drugs at different levels. At 12 months of treatment, the risk factor for failure of viral suppression was missingg doses in the previous month (AOR =12. 6,P=0. 0002). Having a low baseline CD4 count (<100 cells/μl) was associated with increased incidence of HIV drug resistance (Adjusted OR:AOR = 6.6, P= 0. 0026), but transmission routes other than intravenous drug using decreased the possibility of HIV drug resistance (AOR=0. 2,P=0. 0244). Conclusions A large proportion of the patients investigated had successfully suppressed HIV viral replication and had a significant increase of CD4+ T cell counts, while the rate of drug resistance was raised during the first year of treatment. It is essential to take measures to reduce the occurrence of drug resistance.%目的 观察接受中国现行一线抗病毒药物治疗的艾滋病病人,在治疗1年内免疫功能恢复、病毒抑制效果,以及耐药性产生和发展情况0方法 采用Logistic回归分析病毒抑制失败和耐

  19. Prediction of phenotypic susceptibility to antiretroviral drugs using physiochemical properties of the primary enzymatic structure combined with artificial neural networks

    DEFF Research Database (Denmark)

    Kjaer, J; Høj, L; Fox, Z;

    2008-01-01

    OBJECTIVES: Genotypic interpretation systems extrapolate observed associations in datasets to predict viral susceptibility to antiretroviral drugs (ARVs) for given isolates. We aimed to develop and validate an approach using artificial neural networks (ANNs) that employ descriptors...

  20. Drugs reverting multidrug resistance (chemosensitizers)

    Energy Technology Data Exchange (ETDEWEB)

    Gualtieri, F. [Florence Univ. (Italy). Dip. di Scienze Farmaceutiche

    1996-12-01

    Drug resistance is a phenomenon that frequently impairs proper treatment of cancer. Multidrug resistance (MDR) is a particular case of acquired drug resistance, resulting from overexpression of a protein (P-170) that functions as a pump, clearing cells from the chemotherapic. The P-170 protein functions can be inhibited by a variety of lipophilic drugs containing a hydrophilic nitrogen, protonated at physiological pH. A considerable effort is underway to identify new drugs able to reverse MDR. Few of these molecules are already undergoing clinical trials.

  1. A cross-sectional study on the prevalence of HIV drug resistance in patients receiving antiretroviral treatment in Shenqiu county, Henan province%河南省沈丘县抗病毒治疗者HIV耐药株流行状况调查

    Institute of Scientific and Technical Information of China (English)

    崔为国; 薛秀娟; 刘佳; 孙国清; 刘春华; 田随安; 王哲; 李韩平; 李敬云

    2013-01-01

    Objective To understand the prevalence of drug resistance in AIDS patients who had been receiving HAART in a long run,in Shenqiu county,Henan province.Methods This crosssectional study included 120 HIV infected patients who began receiving ART (antiretroviral therapy) in 2003.Viral loads and CD4 +T cells counts were measured,and In-house drug resistance test was performed in VL > 1000 copies/ml patients.Results 114 cases out of 120 patients had complete viral load data.Among them,33 cases having viral loads less than 50 copies/ml,and the remaining viral loads showed an average of lg (4.09 ± 1.10) copies/ml.The average of CD4+ T cell counts was (377 ±2 1 8) cells/ml,with 64 (53.3%) cases showing their CD4+ T cell counts higher than 350 cells/ml.In 67 patients,58 of them showed genotypic resistance,and 40 cases showed reverse transcriptase inhibitors (RTIs) resistance.The ratios of nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) resistance were 53.4% (31/58) and 67.2% (39/58),respectively.There were no differences of drug resistance ratio in the three treatment programs.The highest drug resistance rates in NRTIs and NNRTIs were zidovudine,lamivudin,nevirapine.However,protease inhibitors (PIs) resistance variants were not found.Conclusion The prevalence of drug-resistant strains seemed to be high in Shenqiu country,Henan province.Long-term follow-up monitoring strategy should be developed to optimize the timely treatment programs.%目的 了解河南省沈丘县艾滋病长期治疗患者耐药情况.方法 对沈丘县120例于2003年开始接受抗病毒治疗的艾滋病患者进行横断面研究,同时测定其病毒载量(VL)和CD4+T淋巴细胞计数,对VL> 1000 copies/ml的患者进行In-house方法基因型耐药检测.结果 120例患者中有114例获得VL数据,其中33例小于检测限(50 copies/ml),其余81例VL均值为lg(4.09±1.10)copies/ml.所有患者CD4+T淋

  2. The Effects Of Antiretroviral Drugs On The Absorbance Characteristics Of Blood Components

    Directory of Open Access Journals (Sweden)

    O. I. Ani

    2015-08-01

    Full Text Available Abstract The effects of antiretroviral drugs on the absorbance characteristics of blood components have been studied. The methodology involved the serial dilution of the five different antiretroviral drugs two HAARTFDC and three single drugs and the subsequent incubation with the blood samples collected from ten blood samples of HIV negative persons for the absorbance measurement using a digital Ultraviolet Visible MetaSpecAE1405031Pro Spectrophotometer. Reflectance Dielectric constant etc were derived from the absorbance data. For these drugs to be effective as HIV blockers they should be able to coat the surfaces of the lymphocytes. The question therefore arises as to what extent these drugs are able to coat the surfaces of the blood cells This was established using the extent of absorbance change. Models for coating effectiveness were formulated. The coating effectiveness was therefore calculated from peak absorbance values. Red blood cells were shown not to give reliable results. The results obtained however establish the fact that some coating of the drug had really occurred on the surfaces of the lymphocytes. The drug films were determined for lymphocytes and used to explain some observed clinical findings. The use of the findings of this work in drug design may be expected to yield good results.

  3. Trends in Genotypic HIV-1 Antiretroviral Resistance between 2006 and 2012 in South African Patients Receiving First- and Second-Line Antiretroviral Treatment Regimens.

    Directory of Open Access Journals (Sweden)

    Gert U Van Zyl

    Full Text Available South Africa's national antiretroviral (ARV treatment program expanded in 2010 to include the nucleoside reverse transcriptase (RT inhibitors (NRTI tenofovir (TDF for adults and abacavir (ABC for children. We investigated the associated changes in genotypic drug resistance patterns in patients with first-line ARV treatment failure since the introduction of these drugs, and protease inhibitor (PI resistance patterns in patients who received ritonavir-boosted lopinavir (LPV/r-containing therapy.We analysed ARV treatment histories and HIV-1 RT and protease mutations in plasma samples submitted to the Tygerberg Academic Hospital National Health Service Laboratory.Between 2006 and 2012, 1,667 plasma samples from 1,416 ARV-treated patients, including 588 children and infants, were submitted for genotypic resistance testing. Compared with 720 recipients of a d4T or AZT-containing first-line regimen, the 153 recipients of a TDF-containing first-line regimen were more likely to have the RT mutations K65R (46% vs 4.0%; p<0.001, Y115F (10% vs. 0.6%; p<0.001, L74VI (8.5% vs. 1.8%; p<0.001, and K70EGQ (7.8% vs. 0.4% and recipients of an ABC-containing first-line regimen were more likely to have K65R (17% vs 4.0%; p<0.001, Y115F (30% vs 0.6%; p<0.001, and L74VI (56% vs 1.8%; p<0.001. Among the 490 LPV/r recipients, 55 (11% had ≥1 LPV-resistance mutations including 45 (9.6% with intermediate or high-level LPV resistance. Low (20 patients and intermediate (3 patients darunavir (DRV cross resistance was present in 23 (4.6% patients.Among patients experiencing virological failure on a first-line regimen containing two NRTI plus one NNRTI, the use of TDF in adults and ABC in children was associated with an increase in four major non- thymidine analogue mutations. In a minority of patients, LPV/r-use was associated with intermediate or high-level LPV resistance with predominantly low-level DRV cross-resistance.

  4. Effects of Hormonal Contraception on Anti-Retroviral Drug Metabolism, Pharmacokinetics and Pharmacodynamics

    OpenAIRE

    THURMAN, Andrea Ries; Anderson, Sharon; Doncel, Gustavo F.

    2014-01-01

    Among women, human immunodeficiency virus type 1 (HIV-1) infection is most prevalent in those of reproductive age. These women are also at risk of unintended or mistimed pregnancies. Hormonal contraceptives (HCs) are one of the most commonly used methods of family planning world-wide. Therefore concurrent use of HC among women on anti-retroviral medications (ARVs) is increasingly common. ARVs are being investigated and have been approved for pre-exposure prophylaxis (PrEP), and therefore drug...

  5. Effectiveness and Safety of Concurrent Use of First-Line Antiretroviral and Antituberculous Drugs in Rwanda

    Directory of Open Access Journals (Sweden)

    Justin Ntokamunda Kadima

    2014-01-01

    Full Text Available Background. Overlapping toxicity between drugs used for HIV and TB could complicate the management of HIV/TB coinfected patients, particularly those carrying multiple opportunistic infections. This study aimed to evaluate the clinical outcomes and adverse drug events in HIV patients managed with first-line antiretroviral and first-line anti-TB drugs. Methods. This is a retrospective study utilizing medical dossiers from single-HIV infected and HIV/TB coinfected patients already initiated on ART. Predictors of outcomes included changes in CD4 cells/mm3, body weight, physical improvement, death rate, and adverse drug reactions. Results. Records from 60 HIV patients and 60 HIV/TB patients aged between 20 and 58 years showed that all clinical indicators of effectiveness were better in single-HIV infected than in HIV/TB coinfected patients: higher CD4 cell counts, better physical improvement, and low prevalence of adverse drug events. The most frequently prescribed regimen was TDF/3TC/EFV+RHZE. The mortality rate was 20% in HIV/TB patients compared to 8.3% in the single-HIV group. Conclusion. Treatment regimens applied are efficient in controlling the progression of the infection. However, attention should be paid to adjust dosing when combining nonnucleoside antiretrovirals (EFV and NVR with anti-TB drugs to minimize the risk of death by drug intoxication.

  6. Clinically relevant pharmacokinetic herb-drug interactions in antiretroviral therapy

    Science.gov (United States)

    For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In t...

  7. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the fetal compartment (placenta and amniotic fluid).

    Science.gov (United States)

    Else, Laura J; Taylor, Stephen; Back, David J; Khoo, Saye H

    2011-01-01

    HIV resides within anatomical 'sanctuary sites' where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect. Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivo pharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy. PMID:22155898

  8. Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART.

    Science.gov (United States)

    Vazquez-Guillen, Jose Manuel; Palacios-Saucedo, Gerardo C; Rivera-Morales, Lydia G; Garcia-Campos, Jorge; Ortiz-Lopez, Rocio; Noguera-Julian, Marc; Paredes, Roger; Vielma-Ramirez, Herlinda J; Ramirez, Teresa J; Chavez-Garcia, Marcelino; Lopez-Guillen, Paulo; Briones-Lara, Evangelina; Sanchez-Sanchez, Luz M; Vazquez-Martinez, Carlos A; Rodriguez-Padilla, Cristina

    2016-01-01

    Although Structured Treatment Interruptions (STI) are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM's) at levels under limit of detection of conventional genotyping (drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM's during STI. PMID:26807922

  9. Genetic variation of the HIV-1 integrase region in newly diagnosed anti-retroviral drug-naïve patients with HIV/AIDS in Korea.

    Science.gov (United States)

    Kim, J-Y; Kim, E-J; Choi, J-Y; Kwon, O-K; Kim, G J; Choi, S Y; Kim, S S

    2011-08-01

    The survival time of HIV/AIDS patients in Korea has increased since HAART (highly active anti-retroviral therapy) was introduced. However, the occurrence of drug-resistant strains requires new anti-retroviral drugs, one of which, an integrase inhibitor (INI), was approved by the US Food and Drug Administration (FDA) in 2007. INIs have been used for therapy in many countries and are about to be employed in Korea. Therefore, it is important to identify basic mutant variants prior to the introduction of INIs in order to estimate their efficacy. To monitor potential drug-resistant INI mutations in Korean HIV/AIDS patients, the polymorphism of the int gene was investigated together with the pol gene using a genotypic assay for 75 randomly selected Korean HIV-1 patients newly diagnosed in 2007. The drug-resistant mutation sequences were analysed using the Stanford HIV DB and the International AIDS Society resistance testing-USA panel (IAS-USA). Seventy strains of Korean subtype B were compared with foreign subtype-B strains, and there were no significantly different variants of the int gene region in the study population. Major mutation sites in the integrase (E92Q, F121Y, G140A/S, Y143C/R, Q148H/R/K and N155H) were not detected, and only a few minor mutation sites (L74M, V151I, E157Q, V165I, I203M, S230N and D232N) were identified in 21 strains (28%). Resistance due to mutations in the pol gene was observed in a single strain (1.3%) resistant to protease inhibitors (PIs) and in four strains (5.3%) resistant to reverse transcriptase inhibitors (RTIs). In summary, this demonstrates that INIs will be susceptible to drug naïve HIV/AIDS patients in Korea. PMID:20946407

  10. Genetic variation of the HIV-1 integrase region in newly diagnosed anti-retroviral drug-naïve patients with HIV/AIDS in Korea.

    Science.gov (United States)

    Kim, J-Y; Kim, E-J; Choi, J-Y; Kwon, O-K; Kim, G J; Choi, S Y; Kim, S S

    2011-08-01

    The survival time of HIV/AIDS patients in Korea has increased since HAART (highly active anti-retroviral therapy) was introduced. However, the occurrence of drug-resistant strains requires new anti-retroviral drugs, one of which, an integrase inhibitor (INI), was approved by the US Food and Drug Administration (FDA) in 2007. INIs have been used for therapy in many countries and are about to be employed in Korea. Therefore, it is important to identify basic mutant variants prior to the introduction of INIs in order to estimate their efficacy. To monitor potential drug-resistant INI mutations in Korean HIV/AIDS patients, the polymorphism of the int gene was investigated together with the pol gene using a genotypic assay for 75 randomly selected Korean HIV-1 patients newly diagnosed in 2007. The drug-resistant mutation sequences were analysed using the Stanford HIV DB and the International AIDS Society resistance testing-USA panel (IAS-USA). Seventy strains of Korean subtype B were compared with foreign subtype-B strains, and there were no significantly different variants of the int gene region in the study population. Major mutation sites in the integrase (E92Q, F121Y, G140A/S, Y143C/R, Q148H/R/K and N155H) were not detected, and only a few minor mutation sites (L74M, V151I, E157Q, V165I, I203M, S230N and D232N) were identified in 21 strains (28%). Resistance due to mutations in the pol gene was observed in a single strain (1.3%) resistant to protease inhibitors (PIs) and in four strains (5.3%) resistant to reverse transcriptase inhibitors (RTIs). In summary, this demonstrates that INIs will be susceptible to drug naïve HIV/AIDS patients in Korea.

  11. Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

    Directory of Open Access Journals (Sweden)

    SRR Simonetti

    2003-09-01

    Full Text Available Twenty-two vertically human immunodeficiency virus type 1 (HIV-1 infected Brazilian children were studied for antiretroviral drug resistance. They were separated into 2 groups according to the administration of antiretroviral therapy into those who presented disease symptoms or without symptoms and no therapy. Viral genome sequencing reactions were loaded on an automated DNA sampler (TruGene, Visible Genetics and compared to a database of wild type HIV-1. In the former group 8 of 12 children presented isolates with mutations conferring resistance to protease inhibitors (PIs, 7 presented isolates resistant to nucleoside reverse transcriptase inhibitors (NRTIs and 2 presented isolates resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs. Ten children were included in the antiretroviral naïve group. Eight were susceptible to NRTIs and all of them were susceptible to PIs; one presented the V108I mutation, which confers low-level resistance to NNRTIs. The data report HIV mutant isolates both in treated and untreated infants. However, the frequency and the level of drug resistance were more frequent in the group receiving antiretroviral therapy, corroborating the concept of selective pressure acting on the emergence of resistant viral strains. The children who presented alterations at polymorphism sites should be monitored for the development of additional mutations occurring at relevant resistance codons.

  12. Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART.

    Directory of Open Access Journals (Sweden)

    Jose Manuel Vazquez-Guillen

    Full Text Available Although Structured Treatment Interruptions (STI are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM's at levels under limit of detection of conventional genotyping (<20% of quasispecies could increase the risk of virologic failure. In this work, we analyzed the protease and reverse transcriptase regions of the pol gene by ultra-deep sequencing in pediatric patients under STI with the aim of determining the presence of high- and low-abundance DRM's in the viral rebounds generated by the STI. High-abundance mutations in protease and high- and low-abundance mutations in reverse transcriptase were detected but no one of these are directly associated with resistance to antiretroviral drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM's during STI.

  13. Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART

    Science.gov (United States)

    Vazquez-Guillen, Jose Manuel; Palacios-Saucedo, Gerardo C.; Rivera-Morales, Lydia G.; Garcia-Campos, Jorge; Ortiz-Lopez, Rocio; Noguera-Julian, Marc; Paredes, Roger; Vielma-Ramirez, Herlinda J.; Ramirez, Teresa J.; Chavez-Garcia, Marcelino; Lopez-Guillen, Paulo; Briones-Lara, Evangelina; Sanchez-Sanchez, Luz M.; Vazquez-Martinez, Carlos A.; Rodriguez-Padilla, Cristina

    2016-01-01

    Although Structured Treatment Interruptions (STI) are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM’s) at levels under limit of detection of conventional genotyping (<20% of quasispecies) could increase the risk of virologic failure. In this work, we analyzed the protease and reverse transcriptase regions of the pol gene by ultra-deep sequencing in pediatric patients under STI with the aim of determining the presence of high- and low-abundance DRM’s in the viral rebounds generated by the STI. High-abundance mutations in protease and high- and low-abundance mutations in reverse transcriptase were detected but no one of these are directly associated with resistance to antiretroviral drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM’s during STI. PMID:26807922

  14. HIV antiviral drug resistance: patient comprehension.

    Science.gov (United States)

    Racey, C Sarai; Zhang, Wendy; Brandson, Eirikka K; Fernandes, Kimberly A; Tzemis, Despina; Harrigan, P Richard; Montaner, Julio S G; Barrios, Rolando; Toy, Junine; Hogg, Robert S

    2010-07-01

    A patient's understanding and use of healthcare information can affect their decisions regarding treatment. Better patient understanding about HIV resistance may improve adherence to therapy, decrease population viral load and extend the use of first-line HIV therapies. We examined knowledge of developing HIV resistance and explored treatment outcomes in a cohort of HIV+ persons on highly active antiretroviral therapy (HAART). The longitudinal investigations into supportive and ancillary health services (LISA) cohort is a prospective study of HIV+ persons on HAART. A comprehensive interviewer-administrated survey collected socio-demographic variables. Drug resistance knowledge was determined using a three-part definition. Clinical markers were collected through linkage with the Drug Treatment Program (DTP) at the British Columbia Centre for Excellence in HIV/AIDS. Categorical variables were compared using Fisher's Exact Test and continuous variables using the Wilcoxon rank-sum test. Proportional odds logistic regression was performed for the adjusted multivariable analysis. Of 457 LISA participants, less than 4% completely defined HIV resistance and 20% reported that they had not discussed resistance with their physician. Overall, 61% of the cohort is >or=95% adherent based on prescription refills. Owing to small numbers pooling was preformed for analyses. The model showed that being younger (OR=0.97, 95% CI: 0.95-0.99), having greater than high school education (OR=1.64, 95% CI: 1.07-2.51), discussing medication with physicians (OR=3.67, 95% CI: 1.76-7.64), having high provider trust (OR=1.02, 95% CI: 1.01-1.03), and receiving one-to-one counseling by a pharmacist (OR=2.14, 95% CI: 1.41-3.24) are predictive of a complete or partial definition of HIV resistance. The probability of completely defining HIV resistance increased from 15.8 to 63.9% if respondents had discussed HIV medication with both a physician and a pharmacist. Although the understanding of HIV

  15. Antimicrobial (Drug) Resistance: Gonorrhea

    Science.gov (United States)

    ... Marketing Share this: Main Content Area Multidrug-Resistant Neisseria gonorrhoeae (Gonorrhea) During the past 50 years, the use ... Gonorrhea is a sexually transmitted disease caused by Neisseria gonorrhoeae , a bacterium that can infect areas of the ...

  16. Increased incidence of antiretroviral drug discontinuation among patients with viremic hepatitis C virus coinfection and high hyaluronic acid, a marker of liver fibrosis

    DEFF Research Database (Denmark)

    Grint, Daniel; Peters, Lars; Rockstroh, Juergen K;

    2014-01-01

    Most antiretroviral drugs are metabolized by the liver; hepatic disease or liver damage as a result of hepatitis C virus (HCV) could impair this metabolism leading to an increased risk of drug toxicity. This study aimed to determine the risk of antiretroviral drug discontinuation among HCV...

  17. Different origin of adipogenic stem cells influences the response to antiretroviral drugs

    Energy Technology Data Exchange (ETDEWEB)

    Gibellini, Lara; De Biasi, Sara; Nasi, Milena; Carnevale, Gianluca; Pisciotta, Alessandra; Bianchini, Elena; Bartolomeo, Regina [Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena (Italy); Polo, Miriam [Department of Pharmacology, University of Valencia, Av.da Blasco Ibáñez 15, Valencia (Spain); FISABIO–Hospital Universitario Dr. Peset, Av.da Gaspar Aguilar 90, Valencia (Spain); De Pol, Anto [Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena (Italy); Dipartimento Sperimentale Interaziendale, Campus San Lazzaro, University of Modena and Reggio Emilia, 42122 Reggio Emilia (Italy); Pinti, Marcello [Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena (Italy); Cossarizza, Andrea, E-mail: andrea.cossarizza@unimore.it [Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena (Italy); Dipartimento Sperimentale Interaziendale, Campus San Lazzaro, University of Modena and Reggio Emilia, 42122 Reggio Emilia (Italy)

    2015-10-01

    Lipodystrophy (LD) is a main side effect of antiretroviral therapy for HIV infection, and can be provoked by nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). LD exists in different forms, characterized by fat loss, accumulation, or both, but its pathogenesis is still unclear. In particular, few data exist concerning the effects of antiretroviral drugs on adipocyte differentiation. Adipose tissue can arise either from mesenchymal stem cells (MSCs), that include bone marrow-derived MSCs (hBM-MSCs), or from ectodermal stem cells, that include dental pulp stem cells (hDPSCs). To analyze whether the embryonal origin of adipocytes might impact the occurrence of different phenotypes in LD, we quantified the effects of several antiretroviral drugs on the adipogenic differentiation of hBM-MSCs and hDPSCs. hBM-MSCs and hDPSCs were isolated from healthy donors. Cells were treated with 10 and 50 μM stavudine (d4T), efavirenz (EFV), atazanavir (ATV), ritonavir (RTV), and ATV-boosted RTV. Viability and adipogenesis were evaluated by staining with propidium iodide, oil red, and adipoRed; mRNA levels of genes involved in adipocyte differentiation, i.e. CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), and in adipocyte functions, i.e. fatty acid synthase (FASN), fatty acid binding protein-4 (FABP4), perilipin-1 (PLIN1) and 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2), were quantified by real time PCR. We found that ATV, RTV, EFV, and ATV-boosted RTV, but not d4T, caused massive cell death in both cell types. EFV and d4T affected the accumulation of lipid droplets and induced changes in mRNA levels of genes involved in adipocyte functions in hBM-MSCs, while RTV and ATV had little effects. All drugs stimulated the accumulation of lipid droplets in hDPSCs. Thus, the adipogenic differentiation of human stem cells can be influenced by antiretroviral drugs, and depends, at least in

  18. Different origin of adipogenic stem cells influences the response to antiretroviral drugs

    International Nuclear Information System (INIS)

    Lipodystrophy (LD) is a main side effect of antiretroviral therapy for HIV infection, and can be provoked by nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). LD exists in different forms, characterized by fat loss, accumulation, or both, but its pathogenesis is still unclear. In particular, few data exist concerning the effects of antiretroviral drugs on adipocyte differentiation. Adipose tissue can arise either from mesenchymal stem cells (MSCs), that include bone marrow-derived MSCs (hBM-MSCs), or from ectodermal stem cells, that include dental pulp stem cells (hDPSCs). To analyze whether the embryonal origin of adipocytes might impact the occurrence of different phenotypes in LD, we quantified the effects of several antiretroviral drugs on the adipogenic differentiation of hBM-MSCs and hDPSCs. hBM-MSCs and hDPSCs were isolated from healthy donors. Cells were treated with 10 and 50 μM stavudine (d4T), efavirenz (EFV), atazanavir (ATV), ritonavir (RTV), and ATV-boosted RTV. Viability and adipogenesis were evaluated by staining with propidium iodide, oil red, and adipoRed; mRNA levels of genes involved in adipocyte differentiation, i.e. CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), and in adipocyte functions, i.e. fatty acid synthase (FASN), fatty acid binding protein-4 (FABP4), perilipin-1 (PLIN1) and 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2), were quantified by real time PCR. We found that ATV, RTV, EFV, and ATV-boosted RTV, but not d4T, caused massive cell death in both cell types. EFV and d4T affected the accumulation of lipid droplets and induced changes in mRNA levels of genes involved in adipocyte functions in hBM-MSCs, while RTV and ATV had little effects. All drugs stimulated the accumulation of lipid droplets in hDPSCs. Thus, the adipogenic differentiation of human stem cells can be influenced by antiretroviral drugs, and depends, at least in

  19. Multiple, Linked Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Treatment-Experienced Patients Are Missed by Standard Genotype Analysis

    OpenAIRE

    Palmer, Sarah; Kearney, Mary; Maldarelli, Frank; Halvas, Elias K.; Bixby, Christian J.; Bazmi, Holly; Rock, Diane; Falloon, Judith; Davey, Richard T; Dewar, Robin L.; Metcalf, Julia A.; Hammer, Scott; Mellors, John W.; Coffin, John M.

    2005-01-01

    To investigate the extent to which drug resistance mutations are missed by standard genotyping methods, we analyzed the same plasma samples from 26 patients with suspected multidrug-resistant human immunodeficiency virus type 1 by using a newly developed single-genome sequencing technique and compared it to standard genotype analysis. Plasma samples were obtained from patients with prior exposure to at least two antiretroviral drug classes and who were on a failing antiretroviral regimen. Sta...

  20. Use of new antiretroviral drugs and classes in Bahia, Brazil: a real life experience on salvage therapy of AIDS patients.

    Science.gov (United States)

    Brites, Carlos; Nóbrega, Isabella; Martins Netto, Eduardo

    2015-01-01

    Antiretroviral therapy has significantly evolved in the last decade, with an increasing number of new drugs and classes. Currently, even heavily experienced patients can be successfully treated with new regimens. In Brazil, the recent incorporation of some new antiretroviral drugs made it possible to suppress HIV plasma viremia in most treated patients, with significant benefits in terms of quality of life and survival. However, little has been published on outcomes of patients under new drugs-based regimens. We reviewed the safety and efficacy of antiretroviral regimens using recently introduced drugs in Bahia. Our results confirm that patients using darunavir, raltegravir, enfuvirtide, or etravirine presented with a high rate of virological suppression without significant adverse events, after one year of follow-up.

  1. Antiretroviral Strategies to Prevent Mother-to-Child Transmission of HIV: Striking a Balance between Efficacy, Feasibility, and Resistance

    OpenAIRE

    McIntyre, James A; Hopley, Mark; Moodley, Daya; Eklund, Marie; Gray, Glenda E.; Hall, David B.; Robinson, Patrick; Mayers, Douglas; Martinson, Neil A

    2009-01-01

    Editors' Summary Background Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV can be treated with combination antiretroviral therapy (ART), commonly three individual antiretroviral drugs that together efficiently suppress the replication of the virus. HIV infection of a child by an HIV-positive mother during pregnancy, labor, delivery, or breastfeeding is called mother-to-child transmission (MTCT). In 2007, an estimated 420,000...

  2. Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort

    NARCIS (Netherlands)

    I. Bartha; M. Assel; P.M.A. Sloot; M. Zazzi; C. Torti; E. Schülter; A. De Luca; A. Sönnerborg; A.B. Abecasis; K. Van Laethem; A. Rosi; J. Svärd; R. Paredes; D.A.M.C. van de Vijver; A.-M. Vandamme; V. Müller

    2013-01-01

    Background Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinf

  3. Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort

    NARCIS (Netherlands)

    I. Bartha (István); M. Assel (Matthias); P.M.A. Sloot (Peter); M. Zazzi (Maurizio); C. Torti (Carlo); E. Schülter (E.); A. Luca (Angelo); A. Sonnerborg (Anders); A.B. Abecasis (Ana ); K. van Laethem (Kristel); A. Rosi (Andrea); J. Svärd (Jenny); R. Paredes (Roger); D.A.M.C. van de Vijver (David); A.M. Vandamme (Anne Mieke); V. Müller

    2013-01-01

    textabstractBackground: Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we devel

  4. Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes

    DEFF Research Database (Denmark)

    Castagliola, Dominique; Ledergerber, Bruno; Torti, Carlo;

    2012-01-01

    Limited treatment options have been available for people with HIV who have had virological failure of the three original classes of HIV antiretroviral drugs-so-called triple-class virological failure (TCVF). However, introduction of new drugs and drug classes might have improved outcomes. We aime...

  5. Antiviral Drug Resistance: Mechanisms and Clinical Implications

    OpenAIRE

    Strasfeld, Lynne; Chou, Sunwen

    2010-01-01

    Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs as determined by phenotypic assays. Management of drug resistance includes optimization of host factors and drug delivery, selection of alternative therapies based on knowledge of...

  6. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

    Science.gov (United States)

    Günthard, Huldrych F.; Saag, Michael S.; Benson, Constance A.; del Rio, Carlos; Eron, Joseph J.; Gallant, Joel E.; Hoy, Jennifer F.; Mugavero, Michael J.; Sax, Paul E.; Thompson, Melanie A.; Gandhi, Rajesh T.; Landovitz, Raphael J.; Smith, Davey M.; Jacobsen, Donna M.; Volberding, Paul A.

    2016-01-01

    IMPORTANCE New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. OBJECTIVE To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. EVIDENCE REVIEW A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. FINDINGS Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory

  7. Extensively drug-resistant tuberculosis.

    Science.gov (United States)

    Jassal, Mandeep; Bishai, William R

    2009-01-01

    Extensively drug-resistant (XDR) tuberculosis is defined as disease caused by Mycobacterium tuberculosis with resistance to at least isoniazid and rifampicin, any fluoroquinolone, and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin). The definition has applicable clinical value and has allowed for more uniform surveillance in varied international settings. Recent surveillance data have indicated that the prevalence of tuberculosis drug resistance has risen to the highest rate ever recorded. The gold standard for drug-susceptibility testing has been the agar proportion method; however, this technique requires several weeks for results to be determined. More sensitive and specific diagnostic tests are still unavailable in resource-limited settings. Clinical manifestations, although variable in different settings and among different strains, have in general shown that XDR tuberculosis is associated with greater morbidity and mortality than non-XDR tuberculosis. The treatment of XDR tuberculosis should include agents to which the organism is susceptible, and should continue for a minimum of 18-24 months. However, treatment continues to be limited in tuberculosis-endemic countries largely because of weaknesses in national tuberculosis health-care models. The ultimate strategy to control drug-resistant tuberculosis is one that implements a comprehensive approach incorporating innovation from the political, social, economic, and scientific realms. PMID:18990610

  8. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

    DEFF Research Database (Denmark)

    Hofstra, L Marije; Sauvageot, Nicolas; Albert, Jan;

    2016-01-01

    BACKGROUND:  Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these basel......BACKGROUND:  Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management...... immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002...

  9. Hyaluronic Acid-Based Biocompatible Supramolecular Assembly for Sustained Release of Antiretroviral Drug.

    Science.gov (United States)

    Song, Byeongwoon; Puskás, István; Szente, Lajos; Hildreth, James E K

    2016-09-01

    Human immunodeficiency virus (HIV) infection and its associated diseases continue to increase despite the progress in our understanding of HIV biology and the availability of a number of antiretroviral drugs. Adherence is a significant factor in the success of HIV therapy and current HIV treatment regimens require a combination of antiviral drugs to be taken at least daily for the remainder of a patient's life. A drug delivery system that allows sustained drug delivery could reduce the medical burden and costs associated with medication nonadherence. Here, we describe a novel supramolecular assembly or matrix that contains an anionic polymer hyaluronic acid, cationic polymer poly-l-lysine, and anionic oligosaccharide sulfobutylether-beta-cyclodextrin. HIV reverse transcriptase inhibitors Zidovudine and Lamivudine were successfully encapsulated into the polymer assembly in a noncovalent manner. The physicochemical properties and antiviral activity of the polymer assemblies were studied. The results of this study suggest that the supramolecular assemblies loaded with HIV drugs exert potent antiviral activity and allow sustained drug release. A novel drug delivery formulation such as the one described here could facilitate our efforts to reduce the morbidity and mortality associated with HIV infections and could be utilized in the design of therapeutic approaches for other diseases. PMID:26975245

  10. Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

    Science.gov (United States)

    Kearney, Mary; Palmer, Sarah; Maldarelli, Frank; Shao, Wei; Polis, Michael A.; Mican, JoAnn; Rock-Kress, Diane; Margolick, Joseph B.; Coffin, John M.; Mellors, John W.

    2009-01-01

    Background Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. Objective We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. Methods A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. Results We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. Conclusions HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency. PMID:18301062

  11. 河南省81例HCV/HIV共感染者接受艾滋病二线抗病毒治疗效果及HIV耐药性分析%Effect of treatment and HIV drug resistance of 81 cases of HCV/HIV co-infected individuals who had received AIDS second-line antiretroviral treatment in Henan province

    Institute of Scientific and Technical Information of China (English)

    孙定勇; 刘佳; 王奇; 杨文杰; 岳彦超; 过智勇; 杨世梅; 朱谦; 王哲

    2015-01-01

    May to October 2012 in Xincai,Queshan and Weishi of Henan province.6-months and 12-months follow-up programs were carried out after the regimen had been changed to AIDS second-line antiretroviral treatment,CD4 +T lymphocyte count,HIV-1 virus load and HIV-1 drug resistance were performed.Results Eighty-one cases of eligible patients were selected and followed by an amelioration of CD4 median at 6-month and 12-month follow-up period.Data showed that the baseline,6-months and 12-months CD4 medians were 266 cells/μl,275 cells/μl and 299 cells/μl (x2=8.214,P =0.009).The ratio of HIV virus load suppression patients at 6-months and 12-months follow-up increased to 46.84% and 50.00%,respectively.Frequencies of HIV drug resistance also decreased at the baseline,6-months and 12-months,with ratios as 66.67%,26.58% and 27.63%(x2=29.362,P=0.000),respectively.Ratios of patients that holding NRTI and NNRTI drug resistance appeared coinstantaneous decrease at the baseline,6-months and 12-months,as 51.85%,18.99% and 17.11%(x2=14.230,P=0.005).At the baseline,the ratios of patients resisted to 3TC,ABC and FTC were all more than 50%,with AZT,D4T and DDI between 41%-44% while TDF appeared as 33.33%,then all of them declined to 12%-18% at the 6-month and 12-month follow-up periods.65.43% of the patients resisted to both NVP and EFV but declined to 24%-27% at 6 months and 12 months.Conclusion HCV/HIV co-infected patients experienced virological failure of AIDS first-line therapy were ameliorated after changing to use second-line antiretroviral treatment for 6-months,but did not show constant positive effect at the 12-month end point.

  12. Stealth anti-CD4 conjugated immunoliposomes with dual antiretroviral drugs--modern Trojan horses to combat HIV.

    Science.gov (United States)

    Ramana, Lakshmi Narashimhan; Sharma, Shilpee; Sethuraman, Swaminathan; Ranga, Udaykumar; Krishnan, Uma Maheswari

    2015-01-01

    Highly active antiretroviral therapy (HAART) is the currently employed therapeutic intervention against AIDS where a drug combination is used to reduce the viral load. The present work envisages the development of a stealth anti-CD4 conjugated immunoliposomes containing two anti-retroviral drugs (nevirapine and saquinavir) that can selectively home into HIV infected cells through the CD4 receptor. The nanocarrier was characterized using transmission electron microscopy, FTIR, differential scanning calorimetry, particle size and zeta potential. The cell uptake was also evaluated qualitatively using confocal microscopy and quantitatively by flow cytometry. The drug to lipid composition was optimized for maximum encapsulation of the two drugs. Both drugs were found to localize in different regions of the liposome. The release of the reverse transcriptase inhibitor was dominant during the early phases of the release while in the later phases, the protease inhibitor is the major constituent released. The drugs delivered via anti-CD4 conjugated immunoliposomes inhibited viral proliferation at a significantly lower concentration as compared to free drugs. In vitro studies of nevirapine to saquinavir combination at a ratio of 6.2:5 and a concentration as low as 5 ng/mL efficiently blocked viral proliferation suggesting that co-delivery of anti-retroviral drugs holds a greater promise for efficient management of HIV-1 infection. PMID:25500283

  13. Access to highly active antiretroviral therapy (HAART) for injecting drug users in the WHO European Region 2002-2004

    DEFF Research Database (Denmark)

    Donoghoe, Martin C; Bollerup, Annemarie R; Lazarus, Jeff;

    2007-01-01

    Providing equitable access to highly active antiretroviral treatment (HAART) to injecting drug users (IDUs) is both feasible and desirable. Given the evidence that IDUs can adhere to HAART as well as non-IDUs and the imperative to provide universal and equitable access to HIV/AIDS treatment for a...

  14. Pattern of drug therapy problems and interventions in ambulatory patients receiving antiretroviral therapy in Nigeria

    Directory of Open Access Journals (Sweden)

    Ojeh VB

    2015-06-01

    Full Text Available Objectives: We describe the frequency and types of drug therapy problems (DTPs, and interventions carried out to resolve them, among a cohort of HIV- infected patients on ART in Jos, Nigeria. Methods: A prospective pharmacists’ intervention study was conducted between January and August 2012 at the outpatient HIV clinic of the Jos University Teaching Hospital (JUTH. Pharmacists identified DTPs and made recommendations to resolve them. The main outcome measures were number of DTPs encountered, interventions proposed and acceptance rate of recommendations. Results: A total of 42,416 prescriptions were dispensed to 9339 patients during the eight months study. A total of 420 interventions (Intervention rate of 1 per 100 prescriptions were made to resolve DTPs in 401 (4.3% patients with a mean age of 41 (SD=10 years, and made up of 73% females. DTPs encountered were drug omission (n=89, 21.2%, unnecessary drug (n=55, 13.1% and wrong drug indication (n=55, 13.1%. Recommendations offered included; Addition of another drug to the therapy (n=87, 20.7%, rectification of incomplete prescriptions (n=85, 20.2%, change of drug or dosage (n=67, 16.0%, and discontinuation of the offending drug (n=59, 14.0%. A total of 389 (93% out of 420 of the recommendations were accepted. In all, 50.4% (212 of the problematic prescriptions were changed and dispensed, 22.2% (89 were clarified and dispensed, while wrong identities were corrected in 11.7% (49. However, 7.5% (30 prescriptions were dispensed as prescribed, 5.2% (21 were not dispensed, and 3% (12 were unresolved. Conclusion: Our findings suggest that pharmacists-initiated interventions can ameliorate DTPs in patients receiving ART given the high intervention acceptance rate recorded. The implication of this finding is that pharmacists with requisite training in HIV pharmacotherapy are an excellent resource in detecting and minimizing the effect of antiretroviral drug-related errors.

  15. Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

    Science.gov (United States)

    Sudhakar, Beeravelli; Krishna, Mylangam Chaitanya; Murthy, Kolapalli Venkata Ramana

    2016-01-01

    The aim of the present study was to formulate and evaluate the ritonavir-loaded stealth liposomes by using 32 factorial design and intended to delivered by parenteral delivery. Liposomes were prepared by ethanol injection method using 32 factorial designs and characterized for various physicochemical parameters such as drug content, size, zeta potential, entrapment efficiency and in vitro drug release. The optimization process was carried out using desirability and overlay plots. The selected formulation was subjected to PEGylation using 10 % PEG-10000 solution. Stealth liposomes were characterized for the above-mentioned parameters along with surface morphology, Fourier transform infrared spectrophotometer, differential scanning calorimeter, stability and in vivo pharmacokinetic studies in rats. Stealth liposomes showed better result compared to conventional liposomes due to effect of PEG-10000. The in vivo studies revealed that stealth liposomes showed better residence time compared to conventional liposomes and pure drug solution. The conventional liposomes and pure drug showed dose-dependent pharmacokinetics, whereas stealth liposomes showed long circulation half-life compared to conventional liposomes and pure ritonavir solution. The results of statistical analysis showed significance difference as the p value is (<0.05) by one-way ANOVA. The result of the present study revealed that stealth liposomes are promising tool in antiretroviral therapy.

  16. Stability Analysis of an HIV/AIDS Dynamics Model with Drug Resistance

    Directory of Open Access Journals (Sweden)

    Qianqian Li

    2012-01-01

    Full Text Available A mathematical model of HIV/AIDS transmission incorporating treatment and drug resistance was built in this study. We firstly calculated the threshold value of the basic reproductive number (R0 by the next generation matrix and then analyzed stability of two equilibriums by constructing Lyapunov function. When R0<1, the system was globally asymptotically stable and converged to the disease-free equilibrium. Otherwise, the system had a unique endemic equilibrium which was also globally asymptotically stable. While an antiretroviral drug tried to reduce the infection rate and prolong the patients’ survival, drug resistance was neutralizing the effects of treatment in fact.

  17. Antiretroviral drug expenditure, pricing and judicial demand: an analysis of federal procurement data in Brazil from 2004–2011

    OpenAIRE

    Luo, Jing; Oliveira, Maria A; Ramos, Mariana BC; Maia, Aurélio; Osorio-de-Castro, Claudia GS

    2014-01-01

    Background Previous studies have described expenditures for antiretroviral (ARV) medicines in Brazil through 2005. While prior studies examined overall expenditures, they have not have analyzed drug procurement data in order to describe the role of court litigation on access and pricing. Methods ARV drug procurement from private sector sources for the years 2004–2011 was obtained through the general procurement database of the Brazilian Federal Government (SIASG). Procurement was measured in ...

  18. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons

    DEFF Research Database (Denmark)

    Kovari, Helen; Sabin, Caroline A; Ledergerber, Bruno;

    2016-01-01

    Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without...... a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated....

  19. Increasing use of 'party drugs' in people living with HIV on antiretrovirals: a concern for patient safety.

    Science.gov (United States)

    Bracchi, Margherita; Stuart, David; Castles, Richard; Khoo, Saye; Back, David; Boffito, Marta

    2015-08-24

    Use of 'party drugs', a particular set of recreational drugs used in the context of 'ChemSex', is frequent among MSM living with HIV. A recently published observational study showed that more than half of HIV-infected MSM interviewed reported use of illicit substances in the previous 3 months, with frequent concomitant use of three or more drugs. These substances are a combination of 'club drugs' (methylenedioxymethamphetamine, gamma-hydroxybutyrate, ketamine, benzodiazepine) and drugs that are more specifically used in a sexualized context (methamphetamine, mephedrone, poppers and erectile dysfunction agents). Although formal data on pharmacokinetic or pharmacodynamic interactions between recreational drugs and antiretroviral agents are lacking, information regarding potentially toxic interactions can be theorized or sometimes conclusions may be drawn from case studies and cohort observational studies. However, the risk of coadministering party drugs and antiretrovirals should not be overestimated. The major risk for a drug-drug interaction is when using ritonavir-boosting or cobicistat-boosting agents, and maybe some nonnucleoside reverse transcriptase inhibitors. Knowledge of the metabolic pathways of 'party drugs' may help in advising patients on which illicit substances have a high potential for drug-drug interactions, as this is not the case for all. PMID:26372268

  20. Production of antiretroviral drugs in middle- and low-income countries.

    Science.gov (United States)

    Pinheiro, Eloan dos Santos; Brüning, Karin; Macedo, M Fernanda; Siani, Antonio C

    2014-01-01

    This review outlines the main issues concerning the production of antiretroviral (ARV) drugs in middle- and low-income countries and the relevant political, legal and technical requirements for supporting such production. The requirements for efficient local production, including the manufacture of generic and branded products and public demand, have been considered from economic, market and socio-political perspectives. A steady and consistent government policy is crucial to success. Additional crucial factors in establishing local production are adequate infrastructure, qualified human resources in technical and managerial areas, and production-distribution logistics systems. The creation or strengthening of a national drug regulatory agency is a basic requirement. Production of ARVs relies on the structure of the international market for active pharmaceutical ingredients (APIs), which are highly monopolized for inclusion in branded or patented drugs, or are concentrated in a few Asian generic companies. Countries seeking to begin local production must develop strategies to overcome the various barriers. For instance, sub-Saharan African countries may benefit from developing multilateral health agreements with neighbouring countries. Such agreements are recommended and should be complemented by technology transfers, especially for the manufacture of APIs. Achieving a production level that is sustainable in the long term is crucial to maintaining patients' access to ARVs.

  1. Production of antiretroviral drugs in middle- and low-income countries.

    Science.gov (United States)

    Pinheiro, Eloan dos Santos; Brüning, Karin; Macedo, M Fernanda; Siani, Antonio C

    2014-01-01

    This review outlines the main issues concerning the production of antiretroviral (ARV) drugs in middle- and low-income countries and the relevant political, legal and technical requirements for supporting such production. The requirements for efficient local production, including the manufacture of generic and branded products and public demand, have been considered from economic, market and socio-political perspectives. A steady and consistent government policy is crucial to success. Additional crucial factors in establishing local production are adequate infrastructure, qualified human resources in technical and managerial areas, and production-distribution logistics systems. The creation or strengthening of a national drug regulatory agency is a basic requirement. Production of ARVs relies on the structure of the international market for active pharmaceutical ingredients (APIs), which are highly monopolized for inclusion in branded or patented drugs, or are concentrated in a few Asian generic companies. Countries seeking to begin local production must develop strategies to overcome the various barriers. For instance, sub-Saharan African countries may benefit from developing multilateral health agreements with neighbouring countries. Such agreements are recommended and should be complemented by technology transfers, especially for the manufacture of APIs. Achieving a production level that is sustainable in the long term is crucial to maintaining patients' access to ARVs. PMID:25310755

  2. Pharmaceutical care interventions, their outcomes and patients’ satisfaction in antiretroviral drug therapy

    Directory of Open Access Journals (Sweden)

    Nwaozuzu, E.E.

    2013-03-01

    Full Text Available Pharmacist’s interventions (also known as pharmaceutical care plans are means of solving the drug therapy problems identified in pharmaceutical care. Outcomes are the results of pharmacists’ intervention activities. Patients’ satisfaction refers to patients’ feeling of fulfillment, pleasure or happiness with the services they have received. This study was designed to determine the types of pharmacist interventions applied in the pharmaceutical care of HIV patients receiving treatment at a tertiary hospital in southeast Nigeria, the types of outcomes of such interventions and level of patients’ satisfaction with their drug therapy. The components of the American society of health-system pharmacists (ASHP guidelines on ‘standardized method for pharmaceutical care was used as a data collection instrument to evaluate, document and intervene in the antiretroviral therapy of about one thousand four hundred and seventy three (1,473 patients. The results showed significant reductions in the frequency of the various interventions and parameters measured after the interventions. The study concluded that pharmaceutical interventions influences patients’ adherence, optimizes their drug therapy and improves rational prescribing and care resulting in significant improvements in the outcomes of their treatment and levels of satisfaction.

  3. Modeling HIV-1 drug resistance as episodic directional selection.

    Directory of Open Access Journals (Sweden)

    Ben Murrell

    Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  4. Antiretroviral therapy optimisation without genotype resistance testing: a perspective on treatment history based models.

    Directory of Open Access Journals (Sweden)

    Mattia C F Prosperi

    Full Text Available BACKGROUND: Although genotypic resistance testing (GRT is recommended to guide combination antiretroviral therapy (cART, funding and/or facilities to perform GRT may not be available in low to middle income countries. Since treatment history (TH impacts response to subsequent therapy, we investigated a set of statistical learning models to optimise cART in the absence of GRT information. METHODS AND FINDINGS: The EuResist database was used to extract 8-week and 24-week treatment change episodes (TCE with GRT and additional clinical, demographic and TH information. Random Forest (RF classification was used to predict 8- and 24-week success, defined as undetectable HIV-1 RNA, comparing nested models including (i GRT+TH and (ii TH without GRT, using multiple cross-validation and area under the receiver operating characteristic curve (AUC. Virological success was achieved in 68.2% and 68.0% of TCE at 8- and 24-weeks (n = 2,831 and 2,579, respectively. RF (i and (ii showed comparable performances, with an average (st.dev. AUC 0.77 (0.031 vs. 0.757 (0.035 at 8-weeks, 0.834 (0.027 vs. 0.821 (0.025 at 24-weeks. Sensitivity analyses, carried out on a data subset that included antiretroviral regimens commonly used in low to middle income countries, confirmed our findings. Training on subtype B and validation on non-B isolates resulted in a decline of performance for models (i and (ii. CONCLUSIONS: Treatment history-based RF prediction models are comparable to GRT-based for classification of virological outcome. These results may be relevant for therapy optimisation in areas where availability of GRT is limited. Further investigations are required in order to account for different demographics, subtypes and different therapy switching strategies.

  5. Antiretroviral Drug Use in a Cohort of HIV-Uninfected Women in the United States: HIV Prevention Trials Network 064.

    Directory of Open Access Journals (Sweden)

    Iris Chen

    Full Text Available Antiretroviral (ARV drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009-2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2% of 1,806 participants: 27/181 (15% in Baltimore, MD and 12/179 (7% in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1-4 drugs/sample. These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals.

  6. Antiretroviral Drug Use in a Cohort of HIV-Uninfected Women in the United States: HIV Prevention Trials Network 064

    Science.gov (United States)

    Chen, Iris; Clarke, William; Ou, San-San; Marzinke, Mark A.; Breaud, Autumn; Emel, Lynda M.; Wang, Jing; Hughes, James P.; Richardson, Paul; Haley, Danielle F.; Lucas, Jonathan; Rompalo, Anne; Justman, Jessica E.; Hodder, Sally L.; Eshleman, Susan H.

    2015-01-01

    Antiretroviral (ARV) drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009–2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2%) of 1,806 participants: 27/181 (15%) in Baltimore, MD and 12/179 (7%) in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1–4 drugs/sample). These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals. PMID:26445283

  7. Antiretroviral drug supply challenges in the era of scaling up ART in Malawi

    Directory of Open Access Journals (Sweden)

    Schouten Erik J

    2011-07-01

    Full Text Available Abstract The number of people receiving antiretroviral treatment (ART has increased considerably in recent years and is expected to continue to grow in the coming years. A major challenge is to maintain uninterrupted supplies of antiretroviral (ARV drugs and prevent stock outs. This article discusses issues around the management of ARVs and prevention of stock outs in Malawi, a low-income country with a high HIV/AIDS burden, and a weak procurement and supply chain management system. This system for ARVs, paid for by the Global Fund to Fight AIDS, Tuberculosis and Malaria, and bypassing the government Central Medical Stores, is in place, using the United Nations Children’s Fund’s (UNICEF’s procurement services. The system, managed by a handful of people who spend limited time on supply management, is characterized by a centrally coordinated quantification based on verified data from all national ART clinics, parallel procurement through UNICEF, and direct distribution to ART clinics. The model worked well in the first years of the ART programme with a single first-line ARV regimen, but with more regimens becoming available (e.g., alternative first-line, second-line and paediatric regimens, it has become more difficult to administer. Managing supplies through a parallel system has the advantage that weaknesses in the national system have limited influence on the ARV procurement and supply chain management system. However, as the current system operates without a central warehouse and national buffer stock capacity, it diminishes the ability to prevent ARV stock outs. The process of ordering ARVs, from the time that estimates are made to the arrival of supplies in health facilities, takes approximately one year. Addressing the challenges involved in maintaining ARVs through an efficient procurement and supply chain management system that prevents ARV stock outs through the establishment of a dedicated procurement team, a central warehouse and

  8. Antiretroviral drug supply challenges in the era of scaling up ART in Malawi.

    Science.gov (United States)

    Schouten, Erik J; Jahn, Andreas; Ben-Smith, Anne; Makombe, Simon D; Harries, Anthony D; Aboagye-Nyame, Francis; Chimbwandira, Frank

    2011-01-01

    The number of people receiving antiretroviral treatment (ART) has increased considerably in recent years and is expected to continue to grow in the coming years. A major challenge is to maintain uninterrupted supplies of antiretroviral (ARV) drugs and prevent stock outs. This article discusses issues around the management of ARVs and prevention of stock outs in Malawi, a low-income country with a high HIV/AIDS burden, and a weak procurement and supply chain management system. This system for ARVs, paid for by the Global Fund to Fight AIDS, Tuberculosis and Malaria, and bypassing the government Central Medical Stores, is in place, using the United Nations Children's Fund's (UNICEF's) procurement services. The system, managed by a handful of people who spend limited time on supply management, is characterized by a centrally coordinated quantification based on verified data from all national ART clinics, parallel procurement through UNICEF, and direct distribution to ART clinics. The model worked well in the first years of the ART programme with a single first-line ARV regimen, but with more regimens becoming available (e.g., alternative first-line, second-line and paediatric regimens), it has become more difficult to administer. Managing supplies through a parallel system has the advantage that weaknesses in the national system have limited influence on the ARV procurement and supply chain management system. However, as the current system operates without a central warehouse and national buffer stock capacity, it diminishes the ability to prevent ARV stock outs. The process of ordering ARVs, from the time that estimates are made to the arrival of supplies in health facilities, takes approximately one year. Addressing the challenges involved in maintaining ARVs through an efficient procurement and supply chain management system that prevents ARV stock outs through the establishment of a dedicated procurement team, a central warehouse and/or national buffer stock is a

  9. Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.

    Directory of Open Access Journals (Sweden)

    Karolin Hijazi

    Full Text Available Anti-retroviral (ARV -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on

  10. Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies.

    Science.gov (United States)

    Shafer, Robert W; Rhee, Soo-Yon; Bennett, Diane E

    2008-01-01

    Programmes that monitor local, national and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 drug resistance and has recommended the adoption of a consensus definition of genotypic drug resistance. Such a definition is necessary to accurately compare transmitted drug resistance rates across geographical regions and time periods. HIV-1 diversity and the large number of mutations associated with antiretroviral drug resistance complicate the development of a consensus definition for genotypic drug resistance. This paper reviews the data that must be considered to determine which of the many HIV-1 drug resistance mutations are likely to be both sensitive and specific indicators of transmitted drug resistance. The process used to create a previously published list of drug resistance mutations for HIV-1 surveillance is reviewed and alternative approaches to this process are discussed. PMID:18575192

  11. Hidden costs of HIV treatment in Spain: inefficiency of the antiretroviral drug packaging

    Directory of Open Access Journals (Sweden)

    Josep M Llibre-Codina

    2014-11-01

    Full Text Available Introduction: Antiretroviral drugs in Spain are delivered by law only in hospital pharmacies. Commercial packages meet variable quality standards when dispensed drugs are returned due to treatment changes or adherence problems Nearly 20–25% of the initial regimens will be changed at 48 weeks for different reasons. We evaluated the economic impact on public health system of the inability of using returned drugs due to inefficient packaging. Materials and Methods: We defined socially efficient packaging as the best adapted one to being delivered in unit dose to outpatients and classified: Class A - Drug packed in unit doses with complete info (name of drug, dosage in mg, lot, and expiring date in each unit, maintaining complete information of the drug if returned when the external package is opened. Class B - packed in blisters with complete info in the blister, but not in unit doses, without special conservation conditions (should be re-packed in unit doses in the pharmacy before its dispensation to assure a class A excellence. Class C - packed in plastic containers with complete info written only on a label over the container, would allow repackaging only before its initial delivery, but not when returned. Class D - drug packed in plastic containers with manufacturer's warning that the product cannot be placed outside of the original package due to special conditions of conservation (fridge, humidity that doesn’t allow a unit dose repackaging or reusing an opened container. We analysed a 12-month period (July 2011–June 2012 in a hospital-based HIV outpatient pharmacy that serves 2413 treated individuals. Results: Patients generated 23,574 visits to pharmacy, and received 48,325 drug packages, with 2.529.137 pills delivered. The patients suffered 1051 treatment changes for any reason. A total amount of 122.945€ in treatment were returned to pharmacy in opened packages during the study period. 47.139.91€ would be totally lost, mainly due

  12. Potential drug–drug interactions in HIV-infected children on antiretroviral therapy in Lagos, Nigeria

    Directory of Open Access Journals (Sweden)

    Oshikoya KA

    2014-04-01

    Full Text Available Kazeem A Oshikoya,1 Ibrahim A Oreagba,2 Saheed Lawal,2 Olufunsho Awodele,2 Olayinka O Ogunleye,1 Idowu O Senbanjo,3 Sunday O Olayemi,2 Veronica C Ezeaka,4,5 Edamisan O Temiye,4,5 Titilope A Adeyemo,4,6 Oluranti Opanuga,4,7 Olufunmilayo A Lesi,4,8 Sulaimon A Akanmu4,6 1Department of Pharmacology, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria; 2Department of Pharmacology, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria; 3Department of Paediatrics, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria; 4APIN Clinic, Lagos University Teaching Hospital, Lagos, Nigeria; 5Department of Paediatrics, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria; 6Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria; 7Department of Pharmacy, Lagos University Teaching Hospital, Idi-Araba Lagos, Nigeria; 8Department of Medicine, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria Background: Multi-therapy is common in HIV-infected children, and the risk for clinically significant drug interactions (CSDIs is high. We investigated the prevalence of CSDIs between antiretroviral (ARV and co-prescribed drugs for children attending a large HIV clinic in Lagos, Nigeria. Methods: The case files of pediatric patients receiving treatment at the HIV clinic of the Lagos University Teaching Hospital (LUTH, Idi-Araba, between January 2005 and December 2010 were reviewed. The ARV and co-prescribed drug pairs were evaluated for potential interactions using the Liverpool HIV Pharmacology Group website. The potential interactions were rated as A (no known interaction, B (minor/no action needed, C (moderate/monitor therapy, D (major/therapy modification, and X (contraindicated/avoid combination. Results: Of the 310 cases reviewed, 208 (67.1% patients were at risk of CSDIs. Artemisinin-based combination therapy was prescribed for over one

  13. Pattern and Determinants of Antiretroviral Drug Adherence among Nigerian Pregnant Women

    Directory of Open Access Journals (Sweden)

    S. O. Ekama

    2012-01-01

    Full Text Available Background. The need for a high level of adherence to antiretroviral drugs has remained a major hurdle to achieving maximal benefit from its use in pregnancy. This study was designed to determine the level of adherence and identify factors that influence adherence during pregnancy. Method. This is a cross-sectional study utilizing a semistructured questionnaire. Bivariate and multiple logistic regression models were used to determine factors independently associated with good drug adherence during pregnancy. Result. 137 (80.6% of the interviewed 170 women achieved adherence level of ≥95% using 3 day recall. The desire to protect the unborn child was the greatest motivation (51.8% for good adherence. Fear of being identified as HIV positive (63.6% was the most common reason for nonadherence. Marital status, disclosure of HIV status, good knowledge of ART, and having a treatment supporter were found to be significantly associated with good adherence at bivariate analysis. However, after controlling for confounders, only HIV status disclosure and having a treatment partner retained their association with good adherence. Conclusion. Disclosure of HIV status and having treatment support are associated with good adherence. Maternal desire to protect the child was the greatest motivator for adherence.

  14. Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model

    NARCIS (Netherlands)

    M. Pingen (Marieke); R. Sarrami-Forooshani (Ramin); A.M.J. Wensing (Annemarie); P. van Ham (Petra); A. Drewniak (Agata); C.A.B. Boucher (Charles); T.B.H. Geijtenbeek (Teunis); M. Nijhuis (Monique)

    2014-01-01

    textabstractBackground: Different patterns of drug resistance are observed in treated and therapy naïve HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral

  15. HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

    NARCIS (Netherlands)

    Harrison, L.; Melvin, A.; Fiscus, S.; Saidi, Y.; Nastouli, E.; Harper, L.; Compagnucci, A.; Babiker, A.; McKinney, R.; Gibb, D.; Tudor-Williams, G.; Burger, D.M.

    2015-01-01

    BACKGROUND: The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. METHODS: PENPACT-1 had a 2 x 2 factorial desi

  16. Drug Interactions between Antiretroviral Medications and Medications Used in the Treatment of Drug Addiction: Research Needs

    OpenAIRE

    Khalsa, Jag H.; Elkashef, Ahmed

    2010-01-01

    Today substance dependence is one of the major public health problems in the world with millions of people abusing legal and illegal drugs. In addition, almost one-third of the world’s population suffers with one or more infections. Both drugs of abuse and infections are associated with serious medical and health consequences, some of which may be exacerbated by the occurrence of pharmacokinetic and/or pharmacodynamic interactions between medications used in the treatment of these conditions ...

  17. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system

    Directory of Open Access Journals (Sweden)

    Gomes MJ

    2014-04-01

    Full Text Available Maria João Gomes,1 José das Neves,1,2 Bruno Sarmento1,2 1Instituto de Engenharia Biomédica (INEB, Porto, Portugal; 2Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS, Instituto Superior de Ciências da Saúde-Norte, CESPU, Gandra, Portugal Abstract: Antiretroviral drug therapy plays a cornerstone role in the treatment of human immunodeficiency virus (HIV/acquired immunodeficiency syndrome patients. Despite obvious advances over the past 3 decades, new approaches toward improved management of infected individuals are still required. Drug distribution to the central nervous system (CNS is required in order to limit and control viral infection, but the presence of natural barrier structures, in particular the blood–brain barrier, strongly limits the perfusion of anti-HIV compounds into this anatomical site. Nanotechnology-based approaches may help providing solutions for antiretroviral drug delivery to the CNS by potentially prolonging systemic drug circulation, increasing the crossing and reducing the efflux of active compounds at the blood–brain barrier, and providing cell/tissue-targeting and intracellular drug delivery. After an initial overview on the basic features of HIV infection of the CNS and barriers to active compound delivery to this anatomical site, this review focuses on recent strategies based on antiretroviral drug-loaded solid nanoparticles and drug nanosuspensions for the potential management of HIV infection of the CNS. Keywords: HIV/AIDS, blood–brain barrier, protease inhibitors, efflux transporters, drug targeting

  18. Molecular Recognition of the Antiretroviral Drug Abacavir: Towards the Development of a Novel Carbazole-Based Fluorosensor

    OpenAIRE

    Idzik, Krzysztof Ryszard; Cywinski, Piotr J.; Cranfield, Charles G.; Mohr, Gerhard J.; Beckert, Rainer

    2011-01-01

    Due to their optical and electro-conductive attributes, carbazole derivatives are interesting materials for a large range of biosensor applications. In this study, we present the synthesis routes and fluorescence evaluation of newly designed carbazole fluorosensors that, by modification with uracil, have a special affinity for antiretroviral drugs via either Watson–Crick or Hoogsteen base pairing. To an N-octylcarbazole-uracil compound, four different groups were attached, namely thiophene, f...

  19. Maternal and infant health is protected by antiretroviral drug strategies that preserve breastfeeding by HIV-positive women

    Directory of Open Access Journals (Sweden)

    Louise Kuhn

    2012-03-01

    Full Text Available The South African Department of Health is justified in withdrawing support for free infant formula. By so doing, it recognises that any intervention that might detract from breast feeding poses a serious threat to infant survival. Since evidence is now strong that antiretroviral drugs used during lactation prevent transmission of infection from a seropositive mother, strategies that promote breastfeeding can now be recommended for enhancing the health of mothers and infants.

  20. Understanding drug resistance in human intestinal protozoa.

    Science.gov (United States)

    El-Taweel, Hend Aly

    2015-05-01

    Infections with intestinal protozoa continue to be a major health problem in many areas of the world. The widespread use of a limited number of therapeutic agents for their management and control raises concerns about development of drug resistance. Generally, the use of any antimicrobial agent should be accompanied by meticulous monitoring of its efficacy and measures to minimize resistance formation. Evidence for the occurrence of drug resistance in different intestinal protozoa comes from case studies and clinical trials, sometimes with a limited number of patients. Large-scale field-based assessment of drug resistance and drug sensitivity testing of clinical isolates are needed. Furthermore, the association of drug resistance with certain geographic isolates or genotypes deserves consideration. Drug resistance has been triggered in vitro and has been linked to modification of pyruvate:ferredoxin oxidoreductase, nitroreductases, antioxidant defense, or cytoskeletal system. Further mechanistic studies will have important implications in the development of second generation therapeutic agents.

  1. Evolution of primary HIV drug resistance in a subtype C dominated epidemic in Mozambique.

    Directory of Open Access Journals (Sweden)

    Dulce Celina Adolfo Bila

    Full Text Available OBJECTIVE: In Mozambique, highly active antiretroviral treatment (HAART was introduced in 2004 followed by decentralization and expansion, resulting in a more than 20-fold increase in coverage by 2009. Implementation of HIV drug resistance threshold surveys (HIVDR-TS is crucial in order to monitor the emergence of transmitted viral resistance, and to produce evidence-based recommendations to support antiretroviral (ARV policy in Mozambique. METHODS: World Health Organization (WHO methodology was used to evaluate transmitted drug resistance (TDR in newly diagnosed HIV-1 infected pregnant women attending ante-natal clinics in Maputo and Beira to non-nucleoside reverse transcriptase inhibitors (NNRTI, nucleoside reverse transcriptase inhibitors (NRTI and protease inhibitors (PI. Subtypes were assigned using REGA HIV-1 subtyping tool and phylogenetic trees constructed using MEGA version 5. RESULTS: Although mutations associated with resistance to all three drug were detected in these surveys, transmitted resistance was analyzed and classified as <5% in Maputo in both surveys for all three drug classes. Transmitted resistance to NNRTI in Beira in 2009 was classified between 5-15%, an increase from 2007 when no NNRTI mutations were found. All sequences clustered with subtype C. CONCLUSIONS: Our results show that the epidemic is dominated by subtype C, where the first-line option based on two NRTI and one NNRTI is still effective for treatment of HIV infection, but intermediate levels of TDR found in Beira reinforce the need for constant evaluation with continuing treatment expansion in Mozambique.

  2. Drug-resistant tuberculosis in Sindh

    International Nuclear Information System (INIS)

    Objective: To assess the prevalence of primary and secondary drug resistance amongst the clinical isolates of M.tuberculosis, to identify risk factors and how to overcome this problem. Design: A case series of 50 indoor patients with sputum smear-positive pulmonary tuberculosis. Place and duration of Study: Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, Sindh, (Pakistan) from January 1999 to December 2000. Patients and methods: Four first line anti-tuberculous drugs rifampicine, ethambutol and streptomycin were tested for sensitivity pattern. Results: Twelve (26.66%) were sensitive to all four drugs, 12(26.66%) were resistant to one drug, 14 (31.11%) were resistant to two drugs, 2 (4.44%) were resistant to three drugs, and 5(11.11%) were resistant to all four drugs. Resistance to isoniazid was the most common in 27 cases (60%) with primary resistance in 6(13.33%) and secondary resistance in 21(46.66%), followed by resistance to streptomycin in 17 cases (37.77%) with primary resistance in 5(11.11%) and secondary resistance in 12 (26.66%). Resistance to ethambutol in 10 cases (22.22%) and rifampicine in 11 (24.44%) and all cases were secondary. Similarly multi-drugs resistance (MRD) TB was found in 11(24.44%) isolates. Conclusion: This study showed high prevalence of drug resistance among clinical isolates of M. tuberculosis. Their is a need to establish centers at number of places with adequate facilities for susceptibility testing so that the resistant pattern could be ascertained and treatment regimens tailored accordingly. (author)

  3. Drug-Resistant Tuberculosis: Challenges and Progress.

    Science.gov (United States)

    Kurz, Sebastian G; Furin, Jennifer J; Bark, Charles M

    2016-06-01

    Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment. PMID:27208770

  4. Drug-Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation : A Review

    NARCIS (Netherlands)

    van Maarseveen, Erik M.; Rogers, Christin C.; Trofe-Clark, Jennifer; van Zuilen, Arjan D.; Mudrikova, Tania

    2012-01-01

    Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive ther

  5. Identification of drug resistance mutations in HIV from constraints on natural evolution

    Science.gov (United States)

    Butler, Thomas C.; Barton, John P.; Kardar, Mehran; Chakraborty, Arup K.

    2016-02-01

    Human immunodeficiency virus (HIV) evolves with extraordinary rapidity. However, its evolution is constrained by interactions between mutations in its fitness landscape. Here we show that an Ising model describing these interactions, inferred from sequence data obtained prior to the use of antiretroviral drugs, can be used to identify clinically significant sites of resistance mutations. Successful predictions of the resistance sites indicate progress in the development of successful models of real viral evolution at the single residue level and suggest that our approach may be applied to help design new therapies that are less prone to failure even where resistance data are not yet available.

  6. Trends in Decline of Antiretroviral Resistance among ARV-Experienced Patients in the HIV Outpatient Study: 1999–2008

    Directory of Open Access Journals (Sweden)

    Kate Buchacz

    2012-01-01

    Full Text Available Background. Little is known about temporal trends in frequencies of clinically relevant ARV resistance mutations in HIV strains from U.S. patients undergoing genotypic testing (GT in routine HIV care. Methods. We analyzed cumulative frequency of HIV resistance among patients in the HIV Outpatient Study (HOPS who, during 1999–2008 and while prescribed antiretrovirals, underwent GT with plasma HIV RNA >1,000 copies/mL. Exposure ≥4 months to each of three major antiretroviral classes (NRTI, NNRTI and PI was defined as triple-class exposure (TCE. Results. 906 patients contributed 1,570 GT results. The annual frequency of any major resistance mutations decreased during 1999–2008 (88% to 79%, P=0.05. Resistance to PIs decreased among PI-exposed patients (71% to 46%, P=0.010 as exposure to ritonavir-boosted PIs increased (6% to 81%, P<0.001. Non-significant declines were observed in resistance to NRTIs among NRTI-exposed (82% to 67%, and triple-class-resistance among TCE patients (66% to 41%, but not to NNRTIs among NNRTI-exposed. Conclusions. HIV resistance was common but declined in HIV isolates from subgroups of ARV-experienced HOPS patients during 1999–2008. Resistance to PIs among PI-exposed patients decreased, possibly due to increased representation of patients whose only PI exposures were to boosted PIs.

  7. Importance of polar solvation and configurational entropy for design of antiretroviral drugs targeting HIV-1 protease.

    Science.gov (United States)

    Kar, Parimal; Lipowsky, Reinhard; Knecht, Volker

    2013-05-16

    Both KNI-10033 and KNI-10075 are high affinity preclinical HIV-1 protease (PR) inhibitors with affinities in the picomolar range. In this work, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method has been used to investigate the potency of these two HIV-1 PR inhibitors against the wild-type and mutated proteases assuming that potency correlates with the affinity of the drugs for the target protein. The decomposition of the binding free energy reveals the origin of binding affinities or mutation-induced affinity changes. Our calculations indicate that the mutation I50V causes drug resistance against both inhibitors. On the other hand, we predict that the mutant I84V causes drug resistance against KNI-10075 while KNI-10033 is more potent against the I84V mutant compared to wild-type protease. Drug resistance arises mainly from unfavorable shifts in van der Waals interactions and configurational entropy. The latter indicates that neglecting changes in configurational entropy in the computation of relative binding affinities as often done is not appropriate in general. For the bound complex PR(I50V)-KNI-10075, an increased polar solvation free energy also contributes to the drug resistance. The importance of polar solvation free energies is revealed when interactions governing the binding of KNI-10033 or KNI-10075 to the wild-type protease are compared to the inhibitors darunavir or GRL-06579A. Although the contributions from intermolecular electrostatic and van der Waals interactions as well as the nonpolar component of the solvation free energy are more favorable for PR-KNI-10033 or PR-KNI-10075 compared to PR-DRV or PR-GRL-06579A, both KNI-10033 and KNI-10075 show a similar affinity as darunavir and a lower binding affinity relative to GRL-06579A. This is because of the polar solvation free energy which is less unfavorable for darunavir or GRL-06579A relative to KNI-10033 or KNI-10075. The importance of the polar solvation as revealed here

  8. Aripiprazole Improves Depressive Symptoms and Immunological Response to Antiretroviral Therapy in an HIV-Infected Subject with Resistant Depression

    OpenAIRE

    Chiara Cecchelli; Giacomo Grassi; Stefano Pallanti

    2010-01-01

    Aripiprazole is the first medication approved by the FDA as an add-on treatment for MDD. The impact of aripiprazole on the response to HIV is unknown. The patient we report on was diagnosed HIV-positive in 1997 and has been treated with antiretroviral therapy since then. In 2008, we diagnosed resistant major depression, hypochondria, and panic disorder. On that occasion, blood tests showed a significantly reduced CD4 count and a positive viral load. We treated this patient with aripiprazole...

  9. Pharmacovigilance for antiretroviral drugs in Africa, lessons from a study in Abidjan, Cote d’Ivoire

    Science.gov (United States)

    Jaquet, Antoine; Djima, Mariam Mama; Coffie, Patrick; Kacou, Henri Die; Eholie, Serge P.; Messou, Eugene; Minga, Albert; Guehi, Calixte; Yavo, Jean Claude; Bissagnene, Emmanuel; Dabis, Francois; Ekouevi, Didier K.

    2011-01-01

    Background While antiretroviral treatment (ART)-related adverse drug reactions (ADR) are documented in industrialized countries, there is no pre-existing surveillance system dedicated to ADR monitoring in most African countries. We assessed knowledge towards pharmacovigilance among ART prescribers and available capacity of HIV clinics to conduct ADR monitoring in Abidjan, Côte d’Ivoire. Methods A questionnaire was administered to ART prescribers, to assess their knowledge towards the occurrence of ADRs. A retrospective ADR survey was also conducted, based on a data query of treatment modification/interruptions in three HIV clinics. Clinical monitors went back to medical charts to review and validate the reasons of the treatment modification/interruptions. Results Of the 81 ART prescribers interviewed, 25 (31%) declared not grading ADRs and 12 (14.8%) declared notifying ADRs to the national regulatory authorities. Among 5,252 adult ART-treated patients who attended the participating clinics in 2008, 599 treatment modifications were identified. Reasons for treatment modification/interruptions identified in the electronic database were documented in the medical charts in 554 (92.5%) cases, ADR accounting for 273 (45.5%) cases. Toxicity related to ART was graded in only 58 (21%) cases in the medical charts. Discussion This study describes challenges limiting the implementation of reliable pharmacovigilance activities in HIV clinics in Côte d’Ivoire. The lack of knowledge of ART prescribers concerning ADR grading does not support the spontaneous reporting of ADRs. Using treatment modification/interruptions for ADR monitoring appears feasible but improvements are needed to respond to key questions related to drug toxicities in the context of ART scale up in Africa. PMID:21735508

  10. Unanticipated Effects of New Drug Availability on Antiretroviral Durability: Implications for Comparative Effectiveness Research

    Science.gov (United States)

    Eaton, Ellen F.; Tamhane, Ashutosh R.; Burkholder, Greer A.; Willig, James H.; Saag, Michael S.; Mugavero, Michael J.

    2016-01-01

    Background. Durability of antiretroviral (ARV) therapy is associated with improved human immunodeficiency virus (HIV) outcomes. Data on ARV regimen durability in recent years and clinical settings are lacking. Methods. This retrospective follow-up study included treatment-naive HIV-infected patients initiating ARV therapy between January 2007 and December 2012 in a university-affiliated HIV clinic in the Southeastern United States. Outcome of interest was durability (time to discontinuation) of the initial regimen. Durability was evaluated using Kaplan-Meier survival analyses. Cox proportional hazard analyses was used to evaluate the association among durability and sociodemographic, clinical, and regimen-level factors. Results. Overall, 546 patients were analyzed. Median durability of all regimens was 39.5 months (95% confidence interval, 34.1–44.4). Commonly prescribed regimens were emtricitabine and tenofovir with efavirenz (51%; median duration = 40.1 months) and with raltegravir (14%; 47.8 months). Overall, 67% of patients had an undetectable viral load at the time of regimen cessation. Discontinuation was less likely with an integrase strand transfer inhibitor (adjusted hazards ratio [aHR] = 0.35, P = .001) or protease inhibitor-based regimen (aHR = 0.45, P = .006) and more likely with a higher pill burden (aHR = 2.25, P = .003) and a later treatment era (aHR = 1.64, P drugs and combinations. Reduced durability mostly results from a preference for newly approved regimens rather than indicating failing therapy, as indicated by viral suppression observed in a majority of patients (67%) prior to regimen cessation. Durability is influenced by extrinsic factors including new drug availability and provider preference. Medication durability must be interpreted carefully in the context of a dynamic treatment landscape.

  11. Perinatal genotoxicity and carcinogenicity of anti-retroviral nucleoside analog drugs

    International Nuclear Information System (INIS)

    The current worldwide spread of the human immunodeficiency virus-1 (HIV-1) to the heterosexual population has resulted in approximately 800 000 children born yearly to HIV-1-infected mothers. In the absence of anti-retroviral intervention, about 25% of the approximately 7000 children born yearly to HIV-1-infected women in the United States are HIV-1 infected. Administration of zidovudine (AZT) prophylaxis during pregnancy reduces the rate of infant HIV-1 infection to approximately 7%, and further reductions are achieved with the addition of lamivudine (3TC) in the clinical formulation Combivir. Whereas clinically this is a remarkable achievement, AZT and 3TC are DNA replication chain terminators known to induce various types of genotoxicity. Studies in rodents have demonstrated AZT-DNA incorporation, HPRT mutagenesis, telomere shortening, and tumorigenicity in organs of fetal mice exposed transplacentally to AZT. In monkeys, both AZT and 3TC become incorporated into the DNA from multiple fetal organs taken at birth after administration of human-equivalent protocols to pregnant dams during gestation, and telomere shortening has been found in monkey fetuses exposed to both drugs. In human infants, AZT-DNA and 3TC-DNA incorporation as well as HPRT and GPA mutagenesis have been documented in cord blood from infants exposed in utero to Combivir. In infants of mice, monkeys, and humans, levels of AZT-DNA incorporation were remarkably similar, and in newborn mice and humans, mutation frequencies were also very similar. Given the risk-benefit ratio, these highly successful drugs will continue to be used for prevention of vertical viral transmission, however evidence of genotoxicity in mouse and monkey models and in the infants themselves would suggest that exposed children should be followed well past adolescence for early detection of potential cancer hazard

  12. Evolution of drug resistance in HIV infected patients remaining on a virologically failing cART regimen

    DEFF Research Database (Denmark)

    Cozzi-Lepri, A; Phillips, AN; Ruiz, L;

    2007-01-01

    OBJECTIVE: To estimate the extent of drug resistance accumulation in patients kept on a virologically failing regimen and its determinants in the clinical setting. DESIGN: The study focused on 110 patients of EuroSIDA on an unchanged regimen who had two genotypic tests performed at two time points...... (t0 and t1) when viral load was > 400 copies/ml. METHODS: Accumulation of resistance between t0 and t1 was measured using genotypic susceptibility scores (GSS) obtained by counting the total number of active drugs (according to the Rega system v6.4.1) among all licensed antiretrovirals as of 1...... January 2006. Patients were grouped according to the number of active drugs in the failing regimen at t0 (GSS_f-t0). RESULTS: At t0, patients had been on the failing combination antiretroviral therapy (cART) for a median of 11 months (range, 6-50 months). Even patients with extensive resistance...

  13. Factors linked to transitions in adherence to antiretroviral therapy among HIV-infected illicit drug users in a Canadian setting

    OpenAIRE

    Joseph, Brenden; Kerr, Thomas; Puskas, Cathy M; Montaner, Julio; Wood, Evan; Milloy, M-J

    2015-01-01

    HIV-positive people who use illicit drugs typically achieve lower levels of adherence to antiretroviral therapy and experience higher rates of sub-optimal HIV/AIDS treatment outcomes. Given the dearth of longitudinal research into ART adherence dynamics, we sought to identify factors associated with transitioning into and out of optimal adherence to ART in a longitudinal study of HIV-infected people who use illicit drugs (PWUD) in a setting of universal no-cost HIV/AIDS treatment. Using data ...

  14. Regional changes over time in initial virologic response rates to combination antiretroviral therapy across Europe

    DEFF Research Database (Denmark)

    Bannister, Wendy P; Kirk, Ole; Gatell, Jose M;

    2006-01-01

    BACKGROUND: Changes in virologic response to initial combination antiretroviral therapy (cART) over calendar time may indicate improvements in cART or emergence of primary resistance. Regional variations may identify differences in available antiretroviral drugs or patient management. METHODS: Vi...

  15. Regional changes over time in initial virological response rates to combination antiretroviral therapy across Europe

    DEFF Research Database (Denmark)

    Bannister, W; Kirk, O; Gatell, J;

    2006-01-01

    BACKGROUND: Changes in virologic response to initial combination antiretroviral therapy (cART) over calendar time may indicate improvements in cART or emergence of primary resistance. Regional variations may identify differences in available antiretroviral drugs or patient management. METHODS: Vi...

  16. Provider and clinic-level correlates of deferring antiretroviral therapy for people who inject drugs: a survey of North American HIV providers

    Directory of Open Access Journals (Sweden)

    Westergaard Ryan P

    2012-02-01

    Full Text Available Abstract Background Injection drug users (IDUs face numerous obstacles to receiving optimal HIV care, and have been shown to underutilize antiretroviral therapy (ART. We sought to estimate the degree to which providers of HIV care defer initiation of ART because of injection drug use and to identify clinic and provider-level factors associated with resistance to prescribing ART to IDUs. Methods We administered an Internet-based survey to 662 regular prescribers of ART in the United States and Canada. Questionnaire items assessed characteristics of providers' personal demographics and training, site of clinical practice and attitudes about drug use. Respondents then rated whether they would likely prescribe or defer ART for hypothetical patients in a series of scenarios involving varying levels of drug use and HIV disease stage. Results Survey responses were received from 43% of providers invited by email and direct mail, and 8.5% of providers invited by direct mail only. Overall, 24.2% of providers reported that they would defer ART for an HIV-infected patient with a CD4+ cell count of 200 cells/mm3 if the patient actively injected drugs, and 52.4% would defer ART if the patient injected daily. Physicians were more likely than non-physician providers to defer ART if a patient injected drugs (adjusted odds ratio 2.6, 95% CI 1.4-4.9. Other predictors of deferring ART for active IDUs were having fewer years of experience in HIV care, regularly caring for fewer than 20 HIV-infected patients, and working at a clinic serving a population with low prevalence of injection drug use. Likelihood of deferring ART was directly proportional to both CD4+ cell count and increased frequency of injecting. Conclusions Many providers of HIV care defer initiation of antiretroviral therapy for patients who inject drugs, even in the setting of advanced immunologic suppression. Providers with more experience of treating HIV, those in high injection drug use prevalence

  17. A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.

    Science.gov (United States)

    Pinheiro, Eloan Dos Santos; Antunes, Octavio Augusto Ceva; Fortunak, Joseph M D

    2008-09-01

    It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely

  18. Prevalence and type of drug-drug interactions involving antiretrovirals in patients attending a specialist outpatient clinic in Kampala, Uganda

    Directory of Open Access Journals (Sweden)

    K Seden

    2012-11-01

    Full Text Available Scale-up of HIV services in countries such as Uganda has resulted in a rapid increase in facilities offering antiretrovirals (ARVs and an increase in healthcare workers trained to deliver care. Consequently, evaluating medication safety is increasingly important in these settings. Data from developed countries suggest that drug-drug interactions (DDIs involving ARVs are common, occurring at rates of 14–58%. Few data are available from low resource settings, however a study of 996 Kenyan patients found that 33.5% were at risk of clinically significant DDIs. We evaluated the prevalence and type of ARV DDIs and the patients most at risk in an African outpatient setting. A random sample of patients taking current ARVs and accessing care at the Infectious Diseases Institute, Makerere University, Kampala was selected from the clinic database. The most recent prescription for each patient was screened for DDIs using www.hiv-druginteractions.org. Clinical significance of DDIs was assessed by two of us using a previously developed technique evaluating: likelihood of interaction, therapeutic index of affected drug and severity of potential adverse effect. From 1000 consecutive patients 99.6% were taking≥1 co-medication alongside their ARV regimen (mean 1.89. 24.5% had≥1 potential DDI, with a total of 335 DDIs observed. Of these, 255 DDIs were considered clinically significant, affecting 18.8% of patients. Only 0.3% of DDIs involved a contraindicated combination. There was a higher rate of potential DDIs observed in patients taking TB treatment (p=0.0047, who were WHO stage 3 or 4 (p=0.001, or patients taking ≥2 co-medications alongside ARVs (p<0.0001 (Fishers exact test. Patient age, gender, CD4 count and weight did not affect risk for DDIs. Co-medications commonly associated with potential DDIs were antibiotics (6.2% of 1000 patients, anthelminthics (4.6% and antifungals (3.5%. Potential DDIs involving ARVs occur at similar rates in resource

  19. Patent Pooling for Promoting Access to Antiretroviral Drugs (ARVs) - A Strategic Option for India.

    Science.gov (United States)

    Satyanarayana, Kanikaram; Srivastava, Sadhana

    2010-01-01

    The current HIV/AIDS scenario in India is quite grim with an estimated 2.4 million people living with HIV/AIDS (PLHA) in 2008, just behind South Africa and Nigeria. The anti-retroviral drugs (ARVs) remain the main stay of global HIV/AIDS treatment. Over 30 ARVs (single and FDCs) available under six categories viz., NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), Protease inhibitors, the new Fusion inhibitors, Entry inhibitors-CCR5 co-receptor antagonists and HIV integrase strand transfer inhibitors. The major originator companies for these ARVs are: Abbott, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Gilead, GlaxoSmithKline (GSK), Merck, Pfizer, Roche, and Tibotec. Beginning with zidovidine in 1987, all the drugs are available in the developed countries. In India, about 30 ARVs are available as generics manufactured by Aurobindo, Hyderabad, Andhra Pradesh; Cipla Limited, Goa; Emcure Pharmaceuticals, Pune, Maharashtra; Hetero Drugs, Hyderabad, Andhra Pradesh; Macleods Pharmaceuticals, Daman; Matrix Laboratories, Nashik, Maharashtra; Ranbaxy, Sirmour, Himachal Pradesh; and Strides Arcolab, Bangalore, Karnataka. The National AIDS Control Organization (NACO) set up in 1992 by the Govt. of India provides free ARVs to HIV positive patients in India since 2004. The drugs available in India include both single drugs and FDCs covering both first line and second line ARVs. Even while there are claims of stabilization of the disease load, there is still huge gap of those who require ARVs as only about 150,000 PLHA receive the ARVs from the Govt. and other sources. Access to ARVs therefore is still a cause of serious concern ever since India became fully Trade Related Aspects of Intellectual Property Rights (TRIPS)-complaint in 2005. Therefore, the Indian pharmaceutical companies cannot make generics for those for drugs introduced post-2005 due to product patent regime. Other concerns include heat stable

  20. Overcoming drug resistance by regulating nuclear receptors

    OpenAIRE

    Chen, Taosheng

    2010-01-01

    Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (N...

  1. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

    Directory of Open Access Journals (Sweden)

    Soo-Yon Rhee

    Full Text Available The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART in the low- and middle-income countries (LMICs hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR and enable care-providers to determine which individuals with virological failure (VF on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs. This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI-associated DRMs (M184V and K65R and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

  2. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

    Science.gov (United States)

    Rhee, Soo-Yon; Jordan, Michael R; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zyl, Gert U; Mukui, Irene; Hosseinipour, Mina C; Frenkel, Lisa M; Ndembi, Nicaise; Hamers, Raph L; Rinke de Wit, Tobias F; Wallis, Carole L; Gupta, Ravindra K; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F; De Oliveira, Tulio; Wensing, Annemarie M J; Gallant, Joel E; Wainberg, Mark A; Richman, Douglas D; Fitzgibbon, Joseph E; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy. PMID:26717411

  3. Antiretroviral drugs saquinavir and ritonavir reduce inhibitory concentration values of itraconazole against Histoplasma capsulatum strains in vitro

    Directory of Open Access Journals (Sweden)

    Raimunda Sâmia Nogueira Brilhante

    2016-04-01

    Full Text Available Abstract Recent studies have shown that some drugs that are not routinely used to treat fungal infections have antifungal activity, such as protease inhibitor antiretroviral drugs. This study investigated the in vitro susceptibility of Histoplasma capsulatum var. capsulatum to saquinavir and ritonavir, and its combination with the antifungal itraconazole. The susceptibility assay was performed according to Clinical and Laboratory Standards Institute guidelines. All strains were inhibited by the protease inhibitor antiretroviral drugs. Saquinavir showed minimum inhibitory concentrations ranging from 0.125 to 1 μg mL−1 for both phases, and ritonavir presented minimum inhibitory concentrations ranging from 0.0312 to 4 μg mL−1and from 0.0625 to 1 μg mL−1 for filamentous and yeast phase, respectively. Concerning the antifungal itraconazole, the minimum inhibitory concentration values ranged from 0.0019 to 0.125 μg mL−1 and from 0.0039 to 0.0312 μg mL−1 for the filamentous and yeast phase, respectively. The combination of saquinavir or ritonavir with itraconazole was synergistic against H. capsulatum, with a significant reduction in the minimum inhibitory concentrations of both drugs against the strains (p < 0.05. These data show an important in vitro synergy between protease inhibitors and itraconazole against the fungus H. capsulatum.

  4. Adverse drug reactions to antiretroviral therapy: Results from spontaneous reporting system in Nigeria

    Directory of Open Access Journals (Sweden)

    Kenneth A Agu

    2013-01-01

    Full Text Available Aim: This study evaluated the suspected adverse drug reactions (ADR reported from a spontaneous reporting program in Human Immunodeficiency Virus (HIV positive patients receiving antiretroviral therapy (ART in Nigeria Materials and Methods: This descriptive study analyzed individual case safety reports (ICSRs in HIV-positive patients receiving ART between January 2011 and December 2011 in 38 secondary hospitals. All ICSRs during this period were included. Chi-square was used to test the association between variables at 95% confidence interval. Results: From 1237 ICSRs collated, only 1119 (90.5% were valid for analysis. Mean age of patients was 35.3 (95%CI, 35.1-35.5 years; and 67.1% were females. A total of 1679 ADR cases were reported, a mean (± Standard Deviation, SD of 1.5 (± 0.8 ADR cases per patient. Of reported ADRs, 63.2%, 8.2% and 19.3% occurred in patients on Zidovudine-based, Stavudine-based and Tenofovir-based regimens, respectively. The commonest ADRs included (12.0% peripheral neuropathy, (11.4% skin rash, (10.1% pruritus and (6.5% dizziness. ADR occurrence was associated with ART regimens, concomitant medicines and age (P < 0.05 unlike gender. Anaemia was associated with Zidovudine (AZT/ Lamivudine (3TC /Nevirapine (NEV regimen [Odds ratio, OR = 6.4 (3.0-13.8; P < 0.0001], and peripheral neuropathy with Stavudine (d4T/3TC/NEV regimen [OR = 8.7 (5.8-30.0, P < 0.0001] and Tenofovir (TDF/Emtricitabine (FTC/Efavirenz (EFV regimen [OR = 2.1 (1.0-4.1, P = 0.0446]. Skin rash and peripheral neuropathy were associated with patients aged < 15years [OR = 3.0 (1.3-6.6, P = 0.0056] and 45-59years [OR = 1.9 (1.3-2.7, P = 0.0006] respectively. Palpitation and polyuria were associated with Salbutamol [OR = 55.7 (4.9-349.6, P = 0.0000] and Nonsteroidal anti-inflammatory drugs (NSAIDS [OR = 50.2 (0.9-562.1, P = 0.0040] respectively. Conclusion: ADRs were less likely to occur in patients on stavudine-based and tenofovir-based regimens compared to

  5. Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries

    DEFF Research Database (Denmark)

    Ballif, M; Nhandu, V; Wood, R;

    2014-01-01

    SETTING: Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE: To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN......%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS: Capacity to...... diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance....

  6. Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV/HCV Coinfected Patients.

    Directory of Open Access Journals (Sweden)

    Isabelle Poizot-Martin

    Full Text Available Development of direct acting antivirals (DAA offers new benefits for patients with chronic hepatitis C. The combination of these drugs with antiretroviral treatment (cART is a real challenge in HIV/HCV coinfected patients. The aim of this study was to describe potential drug-drug interactions between DAAs and antiretroviral drugs in a cohort of HIV/HCV coinfected patients.Cross-sectional study of all HIV/HCV coinfected patients attending at least one visit in 2012 in the multicenter French Dat'AIDS cohort. A simulation of drug-drug interactions between antiretroviral treatment and DAAs available in 2015 was performed.Of 16,634 HIV-infected patients, 2,511 had detectable anti-HCV antibodies, of whom 1,196 had a detectable HCV-RNA and were not receiving HCV treatment at the time of analysis. 97.1% of these patients were receiving cART and 81.2% had a plasma HIV RNA <50 copies/mL. cART included combinations of nucleoside reverse transcriptase inhibitors with a boosted protease inhibitor in 43.6%, a non-nucleoside reverse transcriptase inhibitor in 17.3%, an integrase inhibitor in 15.4% and various combinations or antiretroviral drugs in 23.7% of patients. A previous treatment against HCV had been administered in 64.4% of patients. Contraindicated associations/potential interactions were expected between cART and respectively sofosbuvir (0.2%/0%, sofosbuvir/ledipasvir (0.2%/67.6%, daclatasvir (0%/49.4%, ombitasvir/boosted paritaprevir (with or without dasabuvir (34.4%/52.2% and simeprevir (78.8%/0%.Significant potential drug-drug interactions are expected between cART and the currently available DAAs in the majority of HIV/HCV coinfected patients. Sofosbuvir/ledipasvir and sofosbuvir/daclatasvir with or without ribavirin appeared the most suitable combinations in our population. A close collaboration between hepatologists and HIV/AIDS specialists appears necessary for the management of HCV treatment concomitantly to cART.

  7. Drug-Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection.

    Science.gov (United States)

    Berretta, Massimiliano; Caraglia, Michele; Martellotta, Ferdinando; Zappavigna, Silvia; Lombardi, Angela; Fierro, Carla; Atripaldi, Luigi; Muto, Tommaso; Valente, Daniela; De Paoli, Paolo; Tirelli, Umberto; Di Francia, Raffaele

    2016-01-01

    The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug-drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug-drug interaction, a useful list of pharmacogenomic markers is provided.

  8. Multidrug resistant to extensively drug resistant tuberculosis: What is next?

    Indian Academy of Sciences (India)

    Amita Jain; Pratima Dixit

    2008-11-01

    Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer anti-tubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.

  9. Absence of antiretroviral therapy and other risk factors for morbidity and mortality in Malaysian compulsory drug detention and rehabilitation centers.

    Directory of Open Access Journals (Sweden)

    Jeannia J Fu

    Full Text Available Throughout Asia, people who use drugs are confined in facilities referred to as compulsory drug detention and rehabilitation centers. The limited transparency and accessibility of these centers has posed a significant challenge to evaluating detainees and detention conditions directly. Despite HIV being highly prevalent in this type of confined setting, direct evaluation of detainees with HIV and their access to medical care has yet to be reported in the literature.We evaluated the health status of 100 adult male detainees with HIV and their access to medical care in the two largest Malaysian compulsory drug detention and rehabilitation centers holding HIV-infected individuals.Approximately 80% of all detainees with HIV were surveyed in each detention center. Most participants reported multiple untreated medical conditions. None reported being able to access antiretroviral therapy during detention and only 9% reported receiving any HIV-related clinical assessment or care. Nearly a quarter screened positive for symptoms indicative of active tuberculosis, yet none reported having been evaluated for tuberculosis. Although 95% of participants met criteria for opioid dependence prior to detention, none reported being able to access opioid substitution therapy during detention, with 86% reporting current cravings for opioids and 87% anticipating relapsing to drug use after release. Fourteen percent of participants reported suicidal ideation over the previous two weeks.We identified a lack of access to antiretroviral therapy in two of the six compulsory drug detention and rehabilitation centers in Malaysia designated to hold HIV-infected individuals and found significant, unmet health needs among detainees with HIV. Individuals confined under such conditions are placed at considerably high risk for morbidity and mortality. Our findings underscore the urgent need for evidence-based drug policies that respect the rights of people who use drugs and seek

  10. Emerging pathogens: Dynamics, mutation and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Perelson, A.S.; Goldstein, B.; Korber, B.T. [and others

    1997-10-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.

  11. Multi-drug-resistant tuberculosis in HIV positive patients in Eastern Europe

    DEFF Research Database (Denmark)

    Post, Frank A; Grint, Daniel; Efsen, Anne Marie Werlinrud;

    2014-01-01

    Observational data from Eastern Europe on the management and outcome of multi-drug-resistant tuberculosis (MDR TB) in HIV positive populations remain sparse in the English-language literature.We compared clinical characteristics and outcomes of 55 patients who were diagnosed with HIV and MDR TB...... in Eastern Europe between 2004 and 2006 to 89 patients whose Mycobacterium tuberculosis isolates were susceptible to isoniazid and rifampicin.Patients with HIV and MDR TB were young and predominantly male with high rates of intravenous drug use, imprisonment and hepatitis C co-infection. Eighty-four per cent...... of patients with MDR TB had no history of previous TB drug exposure suggesting that the majority of MDR TB resulted from transmission of drug-resistant M. tuberculosis. The use of non-standardized tuberculosis treatment was common, and the use of antiretroviral therapy infrequent. Compared to those...

  12. Characterizing the emergence and persistence of drug resistant mutations in HIV-1 subtype C infections using 454 ultra deep pyrosequencing

    Directory of Open Access Journals (Sweden)

    Bansode Vijay

    2013-01-01

    Full Text Available Abstract Background The role of HIV-1 RNA in the emergence of resistance to antiretroviral therapies (ARTs is well documented while less is known about the role of historical viruses stored in the proviral DNA. The primary focus of this work was to characterize the genetic diversity and evolution of HIV drug resistant variants in an individual’s provirus during antiretroviral therapy using next generation sequencing. Methods Blood samples were collected prior to antiretroviral therapy exposure and during the course of treatment from five patients in whom drug resistance mutations had previously been identified using consensus sequencing. The spectrum of viral variants present in the provirus at each sampling time-point were characterized using 454 pyrosequencing from multiple combined PCR products. The prevalence of viral variants containing drug resistant mutations (DRMs was characterized at each time-point. Results Low abundance drug resistant viruses were identified in 14 of 15 sampling time-points from the five patients. In all individuals DRMs against current therapy were identified at one or more of the sampling time-points. In two of the five individuals studied these DRMs were present prior to treatment exposure and were present at high prevalence within the amplified and sequenced viral population. DRMs to drugs other than those being currently used were identified in four of the five individuals. Conclusion The presence of DRMs in the provirus, regardless of their observed prevalence did not appear to have an effect on clinical outcomes in the short term suggesting that the drug resistant viral variants present in the proviral DNA do not appear to play a role in the short term in facilitating the emergence of drug resistance.

  13. Facing multi-drug resistant tuberculosis.

    Science.gov (United States)

    Sotgiu, Giovanni; Migliori, Giovanni Battista

    2015-06-01

    Multi-drug resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least two of the most effective anti-tuberculosis drugs (i.e., isoniazid and rifampicin). Therapeutic regimens based on second- and third-line anti-tuberculosis medicines showed poor efficacy, safety, and tolerability profiles. It was estimated that in 2012 the multi-drug resistant tuberculosis incidence ranged from 300,000 to 600,000 cases, mainly diagnosed in the Eastern European and Central Asian countries. The highest proportion of cases is among individuals previously exposed to anti-tuberculosis drugs. Three main conditions can favour the emergence and spread of multi-drug resistant tuberculosis: the poor implementation of the DOTS strategy, the shortage or the poor quality of the anti-tuberculosis drugs, and the poor therapeutic adherence of the patients to the prescribed regimens. Consultation with tuberculosis experts (e.g., consilium) is crucial to tailor the best anti-tuberculosis therapy. New therapeutic options are necessary: bedaquiline and delamanid seem promising drugs; in particular, during the development phase they demonstrated a protective effect against the emergence of further resistances towards the backbone drugs. In the recent past, other antibiotics have been administered off-label: the most relevant efficacy, safety, and tolerability profile was proved in linezolid-, meropenem/clavulanate-, cotrimoxazole-containing regimens. New research and development activities are needed in the diagnostic, therapeutic, preventive fields. PMID:24792579

  14. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  15. Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals

    Directory of Open Access Journals (Sweden)

    Pauline Byakika-Kibwika

    2011-01-01

    Full Text Available Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART poses significant challenges. Artemether-lumefantrine (AL is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine are metabolized by hepatic cytochrome P450 (CYP450 enzymes which metabolize the protease inhibitors (PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs used for HIV treatment. Coadministration of NNRTIs and PIs with AL could potentially cause complex pharmacokinetic drug interactions. NNRTI by inducing CYP450 3A4 enzyme and PIs by inhibiting CYP450 3A4 enzymes could influence both artemether and lumefantrine concentrations and their active metabolites dihydroartemisinin and desbutyl-lumefantrine, predisposing patients to poor treatment response, toxicity, and risk for development of resistance. There are scanty data on these interactions and their consequences. Pharmacokinetic studies to evaluate these interactions in the target populations are urgently needed.

  16. Antifungal drugs and resistance: Current concepts

    Directory of Open Access Journals (Sweden)

    Pramod Kumar Nigam

    2015-04-01

    Full Text Available Recently, clinical failure and relapses have been observed in patients treated with antifungals. Drug resistance has become an important problem leading to significant negative social, psychological, and occupational health effects and quality of life. Early recognition and treatment is essential to reduce morbidity and possibility of transmission. The increased use, inappropriate prescribing and over the counter sale of antifungal agents has also added in the development of resistance to these drugs. The main biochemical and molecular mechanisms that contribute to antifungal resistance include reduced uptake of the drug, an active transport out of the cell or modified drug metabolic degradation of the cell, changes in the interaction of the drug to the target site or other enzymes involved in the process by point mutations, overexpression of the target molecule, overproduction or mutation of the target enzyme, amplification and gene conversion (recombination, and increased cellular efflux and occurrence of biofilm. Although, there is considerable knowledge concerning the biochemical, genetic and clinical aspects of resistance to antifungal agents, expansion of our understanding of the mechanisms by which antifungal resistance emerges and spreads, quicker methods for the determination of resistance, targetting efflux pumps, especially ATP binding cassette (ABC transporters and heat shock protein 90, new drug delivery systems, optimizing therapy according to pharmacokinetic and pharmacodynamic characteristics, new classes of antifungal drugs that are active against azole-resistant isolates, and use of combinations of antifungal drugs or use of adjunctive immunostimulatory therapy and other modalities of treatment will clearly be important for future treatment strategies and in preventing development of resistance.

  17. Antimalarial drug resistance and combination chemotherapy.

    OpenAIRE

    White, N.

    1999-01-01

    Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the cha...

  18. Plasmodium falciparum drug resistance in Angola

    OpenAIRE

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-01-01

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information ...

  19. Emergence of Extensively Drug Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2007-03-01

    Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat.  Created: 3/1/2007 by Emerging Infectious Diseases.   Date Released: 3/26/2007.

  20. Drug resistance in Schistosomiasis: a review

    Directory of Open Access Journals (Sweden)

    John I. Bruce

    1987-01-01

    Full Text Available Drug resistance associated with the treatment of human schistosomiasis appears to be an emerging problem requiring more attention from the scientific community than the subject currently receives. Drug-resistant strains of Schistosoma mansoni have been isolated by various investigators as a result of laboratory experimentation or from a combination of field and laboratory studies. Review of this data appears to indicate that the lack of susceptibility observed for some of the isolated strains cannot be ascribed solely to previous administration of antischistosome drugs and thus further studies are required to elucidate this phenomena. Strains of S. mansoni have now been identified from Brazil which are resistant to oxamniquine, hycanthone and niridazole; from Puerto Rico which are resistant to hycanthone and oxamniquine; and from Kenya which are resistant to niridazole and probably oxamniquine. Strains derived by in vitro selection and resistant to oxamniquine and possibly to oltipraz are also available. All of these strains are currently maintained in the laboratory in snails and mice, thus providing for the first time an opportunity for indepth comparative studies. Preliminary data indicates that S. haematobium strains resistant to metrifonate may be occurring in Kenya. This problem could poise great difficulty in the eventual development of antischistosomal agents. Biomphalaria glabrata from Puerto Rico and Brazil were found to be susceptible to drug-resistant S. mansoni from each country.

  1. Drug Resistance Proteins and Refractory Epilepsy

    OpenAIRE

    J Gordon Millichap

    2002-01-01

    Expression of multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) in refractory epilepsy was studied at the Epilepsy Research Group, Institutes of Neurology and Child Health, University College, London, and Radcliffe Infirmary, Oxford, UK.

  2. Malaria Epidemic and Drug Resistance, Djibouti

    OpenAIRE

    Rogier, Christophe; Pradines, Bruno; Bogreau, H.; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-01-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  3. Antifungal Drug Resistance - Concerns for Veterinarians

    Directory of Open Access Journals (Sweden)

    Bharat B. Bhanderi

    2009-10-01

    Full Text Available In the 1990s, there were increased incidences of fungal infectious diseases in human population which might be due to increase in immunosuppressive diseases. But the major concern was increase in prevalence of resistance to antifungal drugs which were reported both in the fungal isolates of human beings and that of animal origin. In both animals and human beings, resistance to antimicrobial agents has important implications for morbidity, mortality and health care costs, because resistant strains are responsible for bulk of infection in animals and human beings, and large number of antimicrobial classes offers more diverse range of resistance mechanisms to study and resistance determinants move into standard well-characterized strains that facilitates the detailed study of molecular mechanisms of resistance in microorganisms. Studies on resistance to antifungal agents has been lagging behind that of antibacterial resistance for several reasons, the foremost reason might be fungal agents were not recognized as important animal and human pathogens, until relatively in recent past. But the initial studies of antifungal drug resistance in the early 1980s, have accumulated a wealth of knowledge concerning the clinical, biochemical, and genetic aspects of this phenomenon. Presently, exploration of the molecular aspects for antifungal drug resistance has been undertaken. Recently, the focus was on several points like developing a more detailed understanding of the mechanisms of antimicrobial resistance, improved methods to detect resistance when it occurs, methods to prevent the emergence and spread of resistance and new antimicrobial options for the treatment of infections caused by resistant organisms. [Vet. World 2009; 2(5.000: 204-207

  4. Multiple drug resistance and bacterial infection

    Institute of Scientific and Technical Information of China (English)

    Asad U Khan

    2008-01-01

    Drug resistance is becoming a great problem in developing countries due to excessive use and misuse of antibi-otics.The emergence of new pathogenic strains with resistance developed against most of the antibiotics which may cause,difficult to treat infection.To understand the current scenario in different mode of infection is most important for the clinicians and medical practitioners.This article summarized some common infections and an-tibiotic resistance pattern found among these pathogens.

  5. Molecular recognition of the antiretroviral drug abacavir: towards the development of a novel carbazole-based fluorosensor.

    Science.gov (United States)

    Idzik, Krzysztof Ryszard; Cywinski, Piotr J; Cranfield, Charles G; Mohr, Gerhard J; Beckert, Rainer

    2011-05-01

    Due to their optical and electro-conductive attributes, carbazole derivatives are interesting materials for a large range of biosensor applications. In this study, we present the synthesis routes and fluorescence evaluation of newly designed carbazole fluorosensors that, by modification with uracil, have a special affinity for antiretroviral drugs via either Watson-Crick or Hoogsteen base pairing. To an N-octylcarbazole-uracil compound, four different groups were attached, namely thiophene, furane, ethylenedioxythiophene, and another uracil; yielding four different derivatives. Photophysical properties of these newly obtained derivatives are described, as are their interactions with the reverse transcriptase inhibitors such as abacavir, zidovudine, lamivudine and didanosine. The influence of each analyte on biosensor fluorescence was assessed on the basis of the Stern-Volmer equation and represented by Stern-Volmer constants. Consequently we have demonstrated that these structures based on carbazole, with a uracil group, may be successfully incorporated into alternative carbazole derivatives to form biosensors for the molecular recognition of antiretroviral drugs. PMID:21222147

  6. [Drug resistant epilepsy. Clinical and neurobiological concepts].

    Science.gov (United States)

    Espinosa-Jovel, Camilo A; Sobrino-Mejía, Fidel E

    2015-08-16

    Drug-resistant epilepsy, is a condition defined by the International League Against Epilepsy as persistent seizures despite having used at least two appropriate and adequate antiepileptic drug treatments. Approximately 20-30% of patients with epilepsy are going to be resistant to antiepileptic drugs, with different patterns of clinical presentation, which are related to the biological basis of this disease (de novo resistance, relapsing-remitting and progressive). Drug resistant epilepsy, impacts negatively the quality of life and significantly increases the risk of premature death. From the neurobiological point of view, this medical condition is the result of the interaction of multiple variables related to the underlying disease, drug interactions and proper genetic aspects of each patient. Thanks to advances in pharmacogenetics and molecular biology research, currently some hypotheses may explain the cause of this condition and promote the study of new therapeutic options. Currently, overexpression of membrane transporters such as P-glycoprotein, appears to be one of the most important mechanisms in the development of drug resistant epilepsy. The objective of this review is to deepen the general aspects of this clinical condition, addressing the definition, epidemiology, differential diagnosis and the pathophysiological bases.

  7. Short communication: high prevalence of drug resistance in HIV type 1-infected children born in Honduras and Belize 2001 to 2004.

    Science.gov (United States)

    Parham, Leda; de Rivera, Ivette Lorenzana; Murillo, Wendy; Naver, Lars; Largaespada, Natalia; Albert, Jan; Karlsson, Annika C

    2011-10-01

    Antiretroviral therapy has had a great impact on the prevention of mother-to-child transmission (MTCT) of HIV-1. However, development of drug resistance, which could be subsequently transmitted to the child, is a major concern. In Honduras and Belize the prevalence of drug resistance among HIV-1-infected children remains unknown. A total of 95 dried blood spot samples was obtained from HIV-1-infected, untreated children in Honduras and Belize born during 2001 to 2004, when preventive antiretroviral therapy was often suboptimal and consisted of monotherapy with nevirapine or zidovudine. Partial HIV-1 pol gene sequences were successfully obtained from 66 children (Honduras n=55; Belize n=11). Mutations associated with drug resistance were detected in 13% of the Honduran and 27% of the Belizean children. Most of the mutations detected in Honduras (43%) and all mutations detected in Belize were associated with resistance to nonnucleoside reverse transcriptase inhibitors, which was expected from the wide use of nevirapine to prevent MTCT during the study period. In addition, although several mothers reported that they had not received antiretroviral therapy, mutations associated with resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors were found in Honduras. This suggests prior and unreported use of these drugs, or that these women had been infected with resistant virus. The present study demonstrates, for the first time, the presence of drug resistance-associated mutations in HIV-1-infected Honduran and Belizean children.

  8. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    Directory of Open Access Journals (Sweden)

    Veitch Zachary

    2008-11-01

    Full Text Available Abstract Background Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2, epirubicin (MCF-7EPI, paclitaxel (MCF-7TAX-2, or docetaxel (MCF-7TXT. During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. Results In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. Conclusion This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does

  9. Development and Evaluation of an Oligonucleotide Ligation Assay for Detection of Drug Resistance-Associated Mutations in the Human Immunodeficiency Virus Type 2 pol Gene▿

    OpenAIRE

    Jallow, Sabelle; Kaye, Steve; Schutten, Martin; Brandin, Eleonor; Albert, Jan; McConkey, Samuel J; Corrah, Tumani; Whittle, Hilton; Vanham, Guido; Rowland-Jones, Sarah; Janssens, Wouter

    2007-01-01

    Human immunodeficiency virus type 2 (HIV-2) is naturally resistant to several antiretroviral drugs, including all of the non-nucleoside reverse transcriptase inhibitors and the entry inhibitor T-20, and may have reduced susceptibility to some protease inhibitors. These resistance properties make treatment of HIV-2 patients difficult, with very limited treatment options. Therefore, early detection of resistance mutations is important for understanding treatment failures and guiding subsequent ...

  10. Retention in an antiretroviral therapy programme during an era of decreasing drug cost in Limbe, Cameroon

    OpenAIRE

    Mosoko Jembia J; Akam Wilfred; Weidle Paul J; Brooks John T; Aweh Asabi J; Kinge Thompson N; Pals Sherri; Raghunathan Pratima L

    2011-01-01

    Abstract Background In 2002, Cameroon initiated scale up of antiretroviral therapy (ART); on 1 October 2004, a substantial reduction in ART cost occurred. We assessed the impact of this event and other factors on enrolment and retention in care among HIV-infected patients initiating ART from February 2002 to December 2005 at the single ART clinic serving the Southwest Region in Limbe, Cameroon. Methods We retrospectively analyzed clinical and pharmacy payment records of HIV-infected patients ...

  11. Long-term postpartum adherence to antiretroviral drugs among women in Latin America.

    Science.gov (United States)

    Kreitchmann, Regis; Coelho, Debora Fernandes; Kakehasi, Fabiana Maria; Hofer, Cristina Barroso; Read, Jennifer S; Losso, Marcelo; Haberer, Jessica E; Siberry, George K; Harris, D Robert; Yu, Qilu

    2016-04-01

    Antiretroviral adherence in the postpartum period is crucial for maternal health and decreasing the risk of mother-to-child HIV transmission and transmission to sexual partners. Self-reported antiretroviral adherence was examined between 6- to 12-weeks and 30 months postpartum among 270 HIV-infected women enrolled in a prospective cohort study from 2008 to 2010 at multiple sites in Latin America. Adherence data were collected at each study visit to quantify the proportion of prescribed antiretrovirals taken during the previous three days, assess the timing of the last missed dose, and identify predictors of adherence. Mean adherence rates were 89.5% at 6-12 weeks and 92.4% at 30 months; the proportions with perfect adherence were 80.3% and 83.6%, respectively. The overall trend for perfect adherence was not significant (p = 0.71). In adjusted regression modelling, younger age was associated with an increased probability of non-perfect adherence at 18 and 24 months postpartum. Other factors associated with increased probability of non-perfect adherence were higher parity, current use of alcohol and tobacco, and more advanced HIV disease. Women with perfect adherence had lower viral loads. Interventions for alcohol and tobacco use cessation, and support for young women and those with advanced HIV disease should be considered to improve postpartum adherence. PMID:25931238

  12. The “Connection” Between HIV Drug Resistance and RNase H

    Directory of Open Access Journals (Sweden)

    Krista A. Delviks-Frankenberry

    2010-07-01

    Full Text Available Currently, nucleoside reverse transcriptase inhibitors (NRTIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol domain of reverse transcriptase (RT, most genotypic analysis for drug resistance is limited to the first ~300 amino acids of RT. However, recent studies have demonstrated that mutations in the C-terminal domain of RT, specifically the connection subdomain and RNase H domain, can also increase resistance to both NRTIs and NNRTIs. In this review we will present the potential mechanisms by which mutations in the C-terminal domain of RT influence NRTI and NNRTI susceptibility, summarize the prevalence of the mutations in these regions of RT identified to date, and discuss their importance to clinical drug resistance.

  13. Coinfection and the evolution of drug resistance.

    Science.gov (United States)

    Hansen, J; Day, T

    2014-12-01

    Recent experimental work in the rodent malaria model has shown that when two or more strains share a host, there is competitive release of drug-resistant strains upon treatment. In other words, the propagule output of a particular strain is repressed when competing with other strains and increases upon the removal of this competition. This within-host effect is predicted to have an important impact on the evolution and growth of resistant strains. However, how this effect translates to epidemiological parameters at the between-host level, the level at which disease and resistance spread, has yet to be determined. Here we present a general, between-host epidemiological model that explicitly takes into account the effect of coinfection and competitive release. Although our model does show that when there is coinfection competitive release may contribute to the emergence of resistance, it also highlights an additional between-host effect. It is the combination of these two effects, the between-host effect and the within-host effect, that determines the overall influence of coinfection on the emergence of resistance. Therefore, even when competitive release of drug-resistant strains occurs, within an infected individual, it is not necessarily true that coinfection will result in the increased emergence of resistance. These results have important implications for the control of the emergence and spread of drug resistance. PMID:25417787

  14. Antimicrobial Drugs in Fighting against Antimicrobial Resistance.

    Science.gov (United States)

    Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

    2016-01-01

    The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants), the community level resistance (i.e., bilofilms and persisters) is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals. PMID:27092125

  15. Antimicrobial Drugs in Fighting against Antimicrobial Resistance

    Directory of Open Access Journals (Sweden)

    Guyue eCheng

    2016-04-01

    Full Text Available The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants, the community level resistance (i.e., bilofilms and persisters is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals.

  16. Epithelial-mesenchymal Transition and Tumor Drug Resistance

    Directory of Open Access Journals (Sweden)

    Linlin ZHANG

    2013-01-01

    Full Text Available Resistance to antineoplastic drugs is a common problem in cancer treatments. Epithelial-mesenchymal transition (EMT, which plays an important role in the process of drug resistance, may provide opportunity to solve this problem. This article reviews the characteristics of EMT, relationship between EMT and drug resistance, mechanism of EMT in tumor drug resistance in details.

  17. Epithelial-mesenchymal Transition and Tumor Drug Resistance

    OpenAIRE

    Zhang, Linlin; Wu, Zhihao; Zhou, Qinghua

    2013-01-01

    Resistance to antineoplastic drugs is a common problem in cancer treatments. Epithelial-mesenchymal transition (EMT), which plays an important role in the process of drug resistance, may provide opportunity to solve this problem. This article reviews the characteristics of EMT, relationship between EMT and drug resistance, mechanism of EMT in tumor drug resistance in details.

  18. Drug resistance genomics of the antimalarial drug artemisinin.

    Science.gov (United States)

    Winzeler, Elizabeth A; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene. PMID:25470531

  19. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

    OpenAIRE

    Kovari, Helen; Sabin, Caroline A.; Ledergerber, Bruno; Ryom, Lene; Reiss, Peter; Law, Matthew; Pradier, Christian; Dabis, Francois; D'Arminio Monforte, Antonella; Smith, Colette; De Wit, Stephane; Kirk, Ole; Lundgren, Jens D.; Weber, Rainer

    2016-01-01

    Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as fol...

  20. High-Level Cross-Resistance to Didanosine Observed in South African Children Failing an Abacavir- or Stavudine-Based 1st-Line Regimen

    OpenAIRE

    Kim Steegen; Leon Levin; Irene Ketseoglou; Michelle Bronze; Papathanasopoulos, Maria A.; Sergio Carmona; Wendy Stevens

    2014-01-01

    BACKGROUND: The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure. METHODS: A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n...

  1. Distinctive Drug-resistant Mutation Profiles and Interpretations of HIV-1 Proviral DNA Revealed by Deep Sequencing in Reverse Transcriptase

    Institute of Scientific and Technical Information of China (English)

    YIN Qian Qian; SHAO Yi Ming; MA Li Ying; LI Zhen Peng; ZHAO Hai; PAN Dong; WANG Yan; XU Wei Si; XING Hui; FENGYi; JIANG Shi Bo

    2016-01-01

    ObjectiveTo investigate distinctive features in drug-resistant mutations(DRMs) and interpretations for reverse transcriptase inhibitors (RTIs) between proviral DNA and paired viral RNA in HIV-1-infected patients. MethodsForty-three HIV-1-infected individuals receiving first-line antiretroviral therapy were recruited to participate in a multicenter AIDS Cohort Study in Anhui and Henan Provinces in China in 2004. Drug resistance genotyping was performed by bulk sequencing and deep sequencing on the plasma and whole blood of 77 samples, respectively. Drug-resistance interpretation was compared between viral RNA and paired proviral DNA. ResultsCompared with bulk sequencing, deep sequencing could detect more DRMs and samples with DRMs in both viral RNA and proviral DNA. The mutations M184I and M230I were more prevalent in proviral DNA than in viral RNA (Fisher’s exact test,P ConclusionCompared with viral RNA, the distinctive information of DRMsand drug resistance interpretations for proviral DNA could be obtained by deep sequencing, which could provide more detailed and precise information for drug resistance monitoring and the rational design of optimal antiretroviral therapy regimens.

  2. Declining prevalence of HIV-infected individuals at risk of transmitting drug-resistant HIV in Denmark during 1997-2004

    DEFF Research Database (Denmark)

    Lohse, Nicolai; Obel, Niels; Kronborg, Gitte;

    2006-01-01

    BACKGROUND: Transmission of drug-resistant HIV is a potential threat to the substantial clinical benefit of highly active antiretroviral therapy (HAART). To explore the background for the low rates of drug resistance transmission (2.5%) in our population, we estimated acquisition of HIV drug...... resistance and examined temporal trends in the prevalence of patients at risk of transmitting drug-resistant HIV. METHODS: The study population included all 4,025 patients from The Danish HIV Cohort Study seen during the period 1995-2004. Virological failure to a given drug class was defined as a viral load......-resistant virus in subsequent observation time. Patients with a current VL > 1,000 copies/ml were considered at risk of transmitting HIV. RESULTS: We found a decrease from 1997 to 2004 in the prevalence of potential transmitters of drug-resistant HIV. The number of these patients with previous NRTI failure...

  3. Paradoxes in antiretroviral treatment for injecting drug users: access, adherence and structural barriers in Asia and the former Soviet Union.

    Science.gov (United States)

    Wolfe, Daniel

    2007-08-01

    Offered proper support, injection drug users (IDUs) can achieve the same levels of adherence to and clinical benefit from antiretroviral treatment (ARV) as other patients with HIV. Nonetheless, in countries of Asia and the former Soviet Union where IDUs represent the largest share of HIV cases, IDUs have been disproportionately less likely to receive ARV. While analysis of adherence amongst IDUs has focused on individual patient ability to adhere to medical regimens, HIV treatment systems themselves are in need of examination. Structural impediments to provision of ARV for IDUs include competing, vertical systems of care; compulsory drug treatment and rehabilitation services that often offer neither ARV nor effective treatment for chemical dependence; lack of opiate substitution treatments demonstrated to increase adherence to ARV; and policies that explicitly or implicitly discourage ARV delivery to active IDUs. Labeling active drug users as socially untrustworthy or unproductive, health systems can create a series of paradoxes that ensure confirmation of these stereotypes. Needed reforms include professional education and public campaigns that emphasize IDU capacity for health protection and responsible choice; recognition that the chronic nature of injecting drug use and its links to HIV infection require development of ARV treatment delivery that includes active drug users; and integrated treatment that strengthens links between health providers and builds on, rather than seeks to bypass, IDU social networks and organizations.

  4. A Paradigm Shift to Prevent HIV Drug Resistance

    OpenAIRE

    Bisson, Gregory P.; Robert Gross; Scarlett Bellamy; Jesse Chittams; Michael Hislop; Leon Regensberg; Ian Frank; Gary Maartens; Nachega, Jean B

    2008-01-01

    Editors' Summary Background. Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Combinations of antiretroviral drugs that hold HIV in check (viral suppression) have been available since 1996. Unfortunately, most of the people affected by HIV/AIDS live in developing countries and cannot afford these expensive drugs. As a result, life expectancy has plummeted and economic growth has reversed in ...

  5. Antifungal drugs and resistance: Current concepts

    OpenAIRE

    Pramod Kumar Nigam

    2015-01-01

    Recently, clinical failure and relapses have been observed in patients treated with antifungals. Drug resistance has become an important problem leading to significant negative social, psychological, and occupational health effects and quality of life. Early recognition and treatment is essential to reduce morbidity and possibility of transmission. The increased use, inappropriate prescribing and over the counter sale of antifungal agents has also added in the development of resistance to the...

  6. Challenges of drug-resistant malaria

    OpenAIRE

    Sinha Shweta; Medhi Bikash; Sehgal Rakesh

    2014-01-01

    Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia–Thailand border threatened all the previous success. This review addresses the glob...

  7. When to start antiretroviral therapy

    DEFF Research Database (Denmark)

    Lundgren, Jens D; Babiker, Abdel G; Gordin, Fred M;

    2013-01-01

    Strategies for use of antiretroviral therapy (ART) have traditionally focused on providing treatment to persons who stand to benefit immediately from initiating the therapy. There is global consensus that any HIV+ person with CD4 counts less than 350 cells/μl should initiate ART. However...... always been vigorously debated. The lack of an evidence base from randomized trials, in conjunction with varying degrees of therapeutic aggressiveness and optimism tempered by the risks of drug resistance and side effects, has resulted in divided expert opinion and inconsistencies among treatment...

  8. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Rajmohan Rajamuthiah

    Full Text Available Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC: 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs. The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively, but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  9. The Place of protease inhibitors in antiretroviral treatment

    Directory of Open Access Journals (Sweden)

    S.B. Tenore

    2009-10-01

    Full Text Available With the introduction of highly active antiretroviral therapy, a number of drugs have been developed. The best choice concerning which antiretroviral analogs to start is always under discussion, especially in the choice between non-nucleoside reverse transcriptase inhibitors-based therapies and ritonavir-boosted protease inhibitors. Both are proven to control viral replication and lead to immunological gain. The choice between a non-nucleoside analog reverse transcriptase inhibitor and a protease inhibitor as a third antiretroviral drug in the therapy should consider factors related to the individual, as well as the inclusion of the best therapy in the patient's daily activities and potential adherence. The protease inhibitor-based therapies showed similar efficacy among the various inhibitors with characteristics concerning the adverse events from each medicine. For the treatment of protease-resistant patients, darunavir and tipranavir showed good efficacy with higher genetic barrier to resistance.

  10. [Estimation of Probiotic Lactobacilli Drug Resistance].

    Science.gov (United States)

    Bruslik, N L; Akhatova, D R; Toimentseva, A A; Abdulkhakov, S R; Ilyinskaya, O N; Yarullina, D R

    2015-01-01

    An actual problem of analysis of probiotic lactobacilli resistance to antibiotics and other drugs used in the treatment of gastro-intestinal disturbances has been for the first time solved. The levels of resistance of 19 strains of Lactobacillus (14 strains of L. fermentum, 4 strains of L.plantarum and 1 strain of L.rhamnosus) isolated from commercial probiotics and sour milk products to 14 antibiotics of various nature, i.e. β-lactams, aminoglycosides, macrolides, clindamycin, vancomycin, rifampicin, ciprofloxacin, tetracycline and chloramphenicol were determined. All the isolates were practically susceptible to the drugs of the first line antihelicobacterial therapy, i.e. amoxicillin and clarithromycin, that makes inexpedient the parallel use of the probiotics containing the above lactobacilli in the treatment of gastritis and gastric ulcer, despite the lactobacilli antagonism with respect to Helicobacter pylory. Lactobacilli are as well resistant to mesalazin and can be used for correction of dysbiosis in inflammatory affections of the intestine.

  11. [Travellers and multi-drug resistance bacteria].

    Science.gov (United States)

    Takeshita, Nozomi

    2012-02-01

    The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers. PMID:22413540

  12. The influence of oral and written information on antiretroviral drugs in the knowledge of users with HIV/AIDS - doi:10.5020/18061230.2010.p251

    Directory of Open Access Journals (Sweden)

    Regina Flávia de Castro Almeida

    2012-01-01

    Full Text Available Objective: To assess the influence of oral and written transmission of information on antiretroviral drugs in knowledge generation in their users and in the retention of information by them. Method: In the first phase, 18 individuals with HIV/AIDS treated at a referral hospital analyzed three brochures containing information on antiretroviral drugs and chose the best. In the second phase, three groups of 47 individuals with HIV/AIDS who received antiretroviral drugs in the same hospital were formed. The first group, considered the control group (group “C” received their medication at the pharmacy as usual, without any additional information; the second group (group “F” received a brochure with information about the drug in use, which should be read at that moment; and the third group (group “O” received orally, the same information detailed in the brochure. All answered a questionnaire that assessed their knowledge on the referred drug. Results: The responses of group “O” had a higher level of agreement with the information they received regarding action of the drug in the body (78.7%, duration of treatment (83%, procedure when missing a dose (91.5% and storage (95.7%. Conclusion: The transmission of information, whether oral or written, generates knowledge and the instructions and information when orally transmitted, in a detailed manner and in appropriate language, are more easily understood and assimilated. It appears also that, in the studied group, oral information resulted more immediately effective than written one.

  13. Aripiprazole Improves Depressive Symptoms and Immunological Response to Antiretroviral Therapy in an HIV-Infected Subject with Resistant Depression

    Directory of Open Access Journals (Sweden)

    Chiara Cecchelli

    2010-01-01

    Full Text Available Aripiprazole is the first medication approved by the FDA as an add-on treatment for MDD. The impact of aripiprazole on the response to HIV is unknown. The patient we report on was diagnosed HIV-positive in 1997 and has been treated with antiretroviral therapy since then. In 2008, we diagnosed resistant major depression, hypochondria, and panic disorder. On that occasion, blood tests showed a significantly reduced CD4 count and a positive viral load. We treated this patient with aripiprazole and citalopram. Mood, somatic symptoms, and occupational functioning progressively improved. The last blood examination showed an increase in the CD4 count and a negative viral load. On the basis of the present case study and the review of the literature concerning the effects of psychotropic agents on viral replication, we suggest that the use of aripiprazole in HIV-infected subjects warrants further research.

  14. The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

    Science.gov (United States)

    Vasan, Ashwin; Hoos, David; Mukherjee, Joia S; Farmer, Paul E; Rosenfield, Allan G; Perriëns, Joseph H

    2006-05-01

    The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world. PMID:16710550

  15. Challenges of drug-resistant malaria.

    Science.gov (United States)

    Sinha, Shweta; Medhi, Bikash; Sehgal, Rakesh

    2014-01-01

    Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia-Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria. PMID:25402734

  16. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study

    DEFF Research Database (Denmark)

    Worm, Signe Westring; Sabin, Caroline; Weber, Rainer;

    2010-01-01

    developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz...... factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with >30,000 person-years of exposure. RESULTS. Over 178,835 person-years, 580 patients......, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95...

  17. Drug resistance genomics of the antimalarial drug artemisinin

    OpenAIRE

    Elizabeth A Winzeler; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast...

  18. Adherence as therapeutic citizenship: impact of the history of access to antiretroviral drugs on adherence to treatment.

    Science.gov (United States)

    Nguyen, Vinh-Kim; Ako, Cyriaque Yapo; Niamba, Pascal; Sylla, Aliou; Tiendrébéogo, Issoufou

    2007-10-01

    A dramatic increase in the use of antiretroviral drugs in Africa has increased focus on adherence to treatment, which has so far been equivalent if not superior to that in northern contexts. The reasons for this exceptional adherence are poorly understood. In this paper, we examine adherence in the historical and ethnographic context of access to treatment in Burkina Faso, Côte d'Ivoire and Mali. Living where there is no social security and minimal, if any, medical care, individuals diagnosed with HIV are faced with the threat of illness, death, ostracism and destitution, and were obliged to negotiate conflicting networks of obligation, reciprocity, and value. HIV and AIDS programmes value efforts to address social, and indeed biological, vulnerability. In contrast, kinship-based social relationships may value individuals in other ways. These conflicting moral economies often intersect in the worlds of people living with HIV. HIV status can be used to claim resources from the public or non-governmental organization programmes. This may interfere with social networks that are the most stable source of material and emotional support. Self-help and empowerment techniques provided effective tools for people living with HIV to fashion themselves into effective advocates. In the early years of the use of antiretroviral therapy (ART), access to treatment was thus mediated by confessional practices and forms of social triage. We introduce the term 'therapeutic citizenship' to describe the way in which people living with HIV appropriate ART as a set of rights and responsibilities to negotiate these at times conflicting moral economies. Exemplary adherence should be viewed through the lens of therapeutic citizenship. PMID:18090265

  19. Multi Drug Resistant (MDR and Extensively Resistant (XDR Tuberculosis

    Directory of Open Access Journals (Sweden)

    Salih Cesur

    2013-08-01

    Full Text Available Multi drug resistant tuberculosis (MDR-TB is defined as tuberculosis that is resistant to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs. Extensively drug resistant tuberculosis (XDR-TB is defined as tuberculosis that is resistant to resistant to isoniazid and rifampin and to any fluoroquinolone and at least one of three injectable second-line drugs (namely, amikacin, kanamicin, or capreomycin. MDR-TB and XDR- TB are great dangers that threaten the public health. XDR-TB has been reported from many countries including the United States. In Turkey, among newly diagnosed cases, it was reported that the number of MDR-TB patients was 101 (3.1%, MDR-TB rate in the retreatment cases was 17.7% (90 patients, and MDR-TB rate in all cases was 5.1 (191 patients in 2005. The percentages were calculated through the number of patients who were tested in terms of susceptibility for both isoniazide and rifampin. In 2009, it was reported that the number of MDR-TB patients was 99 (2.7% among newly diagnosed cases, it was 123 (20.5 % in the retreatment cases and the total number of MDR-TB cases was 222 (5.1%. The first patient with XDR-TB was identified in 2010 in Turkey. Diagnosis of XDR TB takes several weeks by using conventional culture-based methods, although (however some molecular test can detect it rapidly. Treatment of XDR-TB patients is difficult and usually requiring at least 18-24 months of four to six second-line anti-TB drugs. The success rate with the treatment is about 30-50%, and mortality rate is higher in HIV-infected patients. Prevention of contact to XDR-TB patients is more complicated by the lack of a proven effective preventive treatment for XDR latent tuberculosis infection. Rapid diagnostic tests and new anti-TB drugs are needed to control the spread of this worldwide public health problem. [Dis Mol Med 2013; 1(4.000: 72-76

  20. An insight into the drug resistance profile & mechanism of drug resistance in Neisseria gonorrhoeae.

    Science.gov (United States)

    Patel, Achchhe Lal; Chaudhry, Uma; Sachdev, Divya; Sachdeva, Poonam Nagpal; Bala, Manju; Saluja, Daman

    2011-10-01

    Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea. PMID:22089602

  1. Antituberculosis drug resistance patterns in adults with tuberculous meningitis

    DEFF Research Database (Denmark)

    Senbayrak, Seniha; Ozkutuk, Nuri; Erdem, Hakan;

    2015-01-01

    BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to antituberculosis drugs is an increasingly common clinical problem. This study aimed to evaluate drug resistance profiles of TBM isolates in adult patients in nine European countries involving 32 centers to ...

  2. Evolution of antiretroviral drug costs in Brazil in the context of free and universal access to AIDS treatment.

    Directory of Open Access Journals (Sweden)

    Amy S Nunn

    2007-11-01

    Full Text Available BACKGROUND: Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs, procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005. METHODS AND FINDINGS: We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir-ritonavir (lopinavir/r have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase

  3. Antibacterial Cleaning Products and Drug Resistance

    OpenAIRE

    Aiello, Allison E.; Marshall, Bonnie; Levy, Stuart B.; Della-Latta, Phyllis; Lin, Susan X.; Larson, Elaine

    2005-01-01

    We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug–resistant bacteria on hands of household members. Households (N = 224) were randomized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in homes. Antibacterial product use did not lead to a significant increase in antimicrobial drug re...

  4. The challenge of developing robust drugs to overcome resistance

    OpenAIRE

    Anderson, Amy C; Schiffer, Celia; Pollastri, Michael; Peet, Norton P.

    2011-01-01

    Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Feature, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust dru...

  5. Transmitted drug resistance in persons with acute/early HIV-1 in San Francisco, 2002-2009.

    Directory of Open Access Journals (Sweden)

    Vivek Jain

    Full Text Available BACKGROUND: Transmitted HIV-1 drug resistance (TDR is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009. METHODOLOGY/PRINCIPAL FINDINGS: We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005-2007 vs. 2008-2009. From 2003-2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008-2009 compared to 2005-2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31-1.38; p = 0.27. CONCLUSIONS: Our study suggests that transmitted drug resistance rose from 2003-2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008-2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.

  6. Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

    Science.gov (United States)

    Jain, Vivek; Liegler, Teri; Vittinghoff, Eric; Hartogensis, Wendy; Bacchetti, Peter; Poole, Lauren; Loeb, Lisa; Pilcher, Christopher D.; Grant, Robert M.; Deeks, Steven G.; Hecht, Frederick M.

    2010-01-01

    Background Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009. Methodology/Principal Findings We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27). Conclusions Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications. PMID:21170322

  7. Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning

    NARCIS (Netherlands)

    Avihingsanon, A.; Ramautarsing, R.A.; Suwanpimolkul, G.; Chetchotisakd, P.; Bowonwatanuwong, C.; Jirajariyavej, S.; Kantipong, P.; Tantipong, H.; Ohata, J.P.; Suankratay, C.; Ruxrungtham, K.; Burger, D.M.

    2014-01-01

    Ergotism is a toxic condition resulting from overexposure to the ergot compounds produced by various fungi of the genus Claviceps. Traditionally, such exposure was due to ingestion of infected grains, but long-term or excessive use of medications containing ergot derivatives or drug-drug interaction

  8. Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells

    Directory of Open Access Journals (Sweden)

    Kanmogne GD

    2012-05-01

    Full Text Available Georgette D Kanmogne1, Sangya Singh1, Upal Roy1, Xinming Liu1, JoEllyn McMillan1, Santhi Gorantla1, Shantanu Balkundi1, Nathan Smith1, Yazen Alnouti2, Nagsen Gautam2, You Zhou3, Larisa Poluektova1, Alexander Kabanov2, Tatiana Bronich2, Howard E Gendelman11Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, 2Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE; 3Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE, USAAbstract: Despite the successes of antiretroviral therapy (ART, HIV-associated neurocognitive disorders remain prevalent in infected people. This is due, in part, to incomplete ART penetration across the blood–brain barrier (BBB and lymph nodes and to the establishment of viral sanctuaries within the central nervous system. In efforts to improve ART delivery, our laboratories developed a macrophage-carriage system for nanoformulated crystalline ART (nanoART (atazanavir, ritonavir, indinavir, and efavirenz. We demonstrate that nanoART transfer from mononuclear phagocytes (MP to human brain microvascular endothelial cells (HBMEC can be realized through cell-to-cell contacts, which can facilitate drug passage across the BBB. Coculturing of donor MP containing nanoART with recipient HBMEC facilitates intercellular particle transfer. NanoART uptake was observed in up to 52% of HBMEC with limited cytotoxicity. Folate coating of nanoART increased MP to HBMEC particle transfer by up to 77%. To translate the cell assays into relevant animal models of disease, ritonavir and atazanavir nanoformulations were injected into HIV-1-infected NOD/scid-γcnull mice reconstituted with human peripheral blood lymphocytes. Atazanavir and ritonavir levels in brains of mice treated with folate-coated nanoART were three- to four-fold higher than in mice treated with noncoated particles. This was associated with decreased viral load in the spleen and

  9. Retention in an antiretroviral therapy programme during an era of decreasing drug cost in Limbe, Cameroon

    Directory of Open Access Journals (Sweden)

    Mosoko Jembia J

    2011-06-01

    Full Text Available Abstract Background In 2002, Cameroon initiated scale up of antiretroviral therapy (ART; on 1 October 2004, a substantial reduction in ART cost occurred. We assessed the impact of this event and other factors on enrolment and retention in care among HIV-infected patients initiating ART from February 2002 to December 2005 at the single ART clinic serving the Southwest Region in Limbe, Cameroon. Methods We retrospectively analyzed clinical and pharmacy payment records of HIV-infected patients initiating ART according to national guidelines. We compared two cohorts of patients, enrolled before and after 1 October 2004, to determine if price reduction was associated with enhanced enrolment. We assessed factors associated with retention and survival by Cox proportional hazards models. Retention in care implied patients who had contact with the healthcare system as of 31 December 2005 (including those who were transferred to continue care in other ART centres, although these patients may have interrupted therapy at some time. A patient who was not retained in care may have dropped out (lost to follow up or died. Results Mean enrolment rates for 2920 patients who initiated ART before and after the price reduction were 46.5 and 95.5 persons/month, respectively (p Conclusions Reducing the cost of ART increased enrolment of clients in the programme, but did not change retention in care. In a system where most clients pay for ART, an accessible clinic location may be more important than the cost of medication for retention in care. Decentralizing ART clinics might improve retention and survival among patients on ART.

  10. Budget impact analysis of antiretroviral less drug regimen simplification in HIV-positive patients on the Italian National Health Service

    Directory of Open Access Journals (Sweden)

    Restelli U

    2014-09-01

    Full Text Available Umberto Restelli,1,2 Massimo Andreoni,3 Andrea Antinori,4 Marzia Bonfanti,2 Giovanni Di Perri,5 Massimo Galli,6 Adriano Lazzarin,7 Giuliano Rizzardini,8,9 Davide Croce1,2 1Department of Community Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 2Centro di Ricerca in Economia e Management in Sanità e nel Sociale (CREMS, Università Carlo Cattaneo – LIUC, Castellanza (VA, Italy; 3Clinical Infectious Diseases, Tor Vergata University (PTV, Rome, Italy; 4Clinical Department, National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy; 5Department of Medical Sciences, Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy; 6Third Division of Infectious Diseases, "Luigi Sacco" Hospital, Milan, Italy; 7Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy; 8First and Second Divisions of Infectious Diseases, "Luigi Sacco" Hospital, Milan, Italy; 9School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Background: Deintensification and less drug regimen (LDR antiretroviral therapy (ART strategies have proved to be effective in terms of maintaining viral suppression in human immunodeficiency virus (HIV-positive patients, increasing tolerability, and reducing toxicity of antiretroviral drugs administered to patients. However, the economic impact of these strategies have not been widely investigated. The aim of the study is to evaluate the economic impact that ART LDR could have on the Italian National Health Service (INHS budget. Methods: A budget impact model was structured to assess the potential savings for the INHS by the use of ART LDR for HIV-positive patients with a 3 year perspective. Data concerning ART cost, patient distribution within different ARTs, and probabilities for patients to change ART on a yearly basis were collected within four Italian infectious diseases departments, providing

  11. Approved Generic Formulations of Antiretroviral Drugs Used in the Treatment of HIV Infection

    Science.gov (United States)

    ... 03-Dec-04 6 months * Including time until patent and exclusivity protections for originator product expires. † Not ... back Food Drugs Medical Devices Radiation-Emitting Products Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products

  12. P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses

    Energy Technology Data Exchange (ETDEWEB)

    DeGoey, David A.; Grampovnik, David J.; Chen, Hui-Ju; Flosi, William J.; Klein, Larry L.; Dekhtyar, Tatyana; Stoll, Vincent; Mamo, Mulugeta; Molla, Akhteruzzaman; Kempf, Dale J. (Abbott)

    2013-03-07

    Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.

  13. Comparison of predicted susceptibility between genotype and virtual phenotype HIV drug resistance interpretation systems among treatment-naive HIV-infected patients in Asia: TASER-M cohort analysis

    OpenAIRE

    Jiamsakul Awachana; Kantor Rami; Li Patrick CK; Sirivichayakul Sunee; Sirisanthana Thira; Kantipong Pacharee; Lee Christopher KC; Kamarulzaman Adeeba; Ratanasuwan Winai; Ditangco Rossana; Singtoroj Thida; Sungkanuparph Somnuek

    2012-01-01

    Abstract Background Accurate interpretation of HIV drug resistance (HIVDR) testing is challenging, yet important for patient care. We compared genotyping interpretation, based on the Stanford University HIV Drug Resistance Database (Stanford HIVdb), and virtual phenotyping, based on the Janssen Diagnostics BVBA’s vircoTYPE™ HIV-1, and investigated their level of agreement in antiretroviral (ARV) naive patients in Asia, where non-B subtypes predominate. Methods Sequences from 1301 ARV-naive pa...

  14. Relationship between food insecurity and mortality among HIV-positive injection drug users receiving antiretroviral therapy in British Columbia, Canada.

    Directory of Open Access Journals (Sweden)

    Aranka Anema

    Full Text Available OBJECTIVES: Little is known about the potential impact of food insecurity on mortality among people living with HIV/AIDS. We examined the potential relationship between food insecurity and all-cause mortality among HIV-positive injection drug users (IDU initiating antiretroviral therapy (ART across British Columbia (BC. METHODS: Cross-sectional measurement of food security status was taken at participant ART initiation. Participants were prospectively followed from June 1998 to September 2011 within the fully subsidized ART program. Cox proportional hazard models were used to ascertain the association between food insecurity and mortality, controlling for potential confounders. RESULTS: Among 254 IDU, 181 (71.3% were food insecure and 108 (42.5% were hungry. After 13.3 years of median follow-up, 105 (41.3% participants died. In multivariate analyses, food insecurity remained significantly associated with mortality (adjusted hazard ratio [AHR] = 1.95, 95% CI: 1.07-3.53, after adjusting for potential confounders. CONCLUSIONS: HIV-positive IDU reporting food insecurity were almost twice as likely to die, compared to food secure IDU. Further research is required to understand how and why food insecurity is associated with excess mortality in this population. Public health organizations should evaluate the possible role of food supplementation and socio-structural supports for IDU within harm reduction and HIV treatment programs.

  15. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

    Directory of Open Access Journals (Sweden)

    Russell Barrett Van Dyke

    2016-05-01

    Full Text Available The Surveillance Monitoring for ART Toxicities (SMARTT cohort of the Pediatric HIV/AIDS Cohort Study (PHACS includes over 3500 HIV-exposed but uninfected (HEU infants and children at 22 sites in the U.S. including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARV and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental, behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain with exposure to combination ARVs (cARV, any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a neurodevelopmental case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With neurodevelopmental testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir were associated with lower performance, although all groups were within the normal range. No ARVs or classes were

  16. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs.

    Science.gov (United States)

    Van Dyke, Russell B; Chadwick, Ellen Gould; Hazra, Rohan; Williams, Paige L; Seage, George R

    2016-01-01

    The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13

  17. Liquid anti-solvent recrystallization to enhance dissolution of CRS 74, a new antiretroviral drug.

    Science.gov (United States)

    de Paiva Lacerda, Suênia; Espitalier, Fabienne; Hoffart, Valérie; Ré, Maria Inês

    2015-01-01

    This study concerns a new compound named CRS 74 which has the property of inhibiting Human Immunodeficiency Virus (HIV) protease, an essential enzyme involved in HIV replication process. It is proved in this study that the original CRS 74 exhibits poor aqueous solubility and a very low dissolution rate, which can influence its bioavailability and clinical response. In an attempt to improve the dissolution rate, CRS 74 was recrystallized by liquid anti-solvent (LAS) crystallization. Ethanol was chosen as solvent and water as the anti-solvent. Recrystallized solids were compared with the original drug crystals in terms of physical and dissolution properties. Recrystallization without additives did not modify the CRS 74 dissolution profile compared to the original drug. CRS 74 was then recrystallized using different additives to optimize the process and formulate physicochemical properties. Steric stabilizer in organic phase ensured size-controlling effect, whereas electrostatic stabilizer in aqueous phase decreased particle agglomeration. Cationic additives avoided drug adsorption onto stainless steel T-mixer. In general, additive improved drug dissolution rate due to improvement of wetting properties by specific interactions between the drug and the additives, and ensured continuous production of CRS 74 by electrostatic repulsion.

  18. Drug Resistant Tuberculosis — Is There Hope?

    OpenAIRE

    Manish Kumar Goel; Pardeep Khanna

    2010-01-01

    Tuberculosis remains a worldwide public healthproblem. India has the highest burden of tuberculosis inthe world and accounts for nearly 2/5th of global burdenand 2/3rd of burden in SEAR countries. The XDR- TB wasfirst described in March 2006 and has also beenreported in India. The emergence of XDR – TB isassociated with a very low probability cure and a highcase fatality as evidenced by various researchers.Extensively drug-resistant tuberculosis is rapidly fatal ifnot treated. Some studies re...

  19. Aberrant splicing and drug resistance in AML.

    Science.gov (United States)

    de Necochea-Campion, Rosalia; Shouse, Geoffrey P; Zhou, Qi; Mirshahidi, Saied; Chen, Chien-Shing

    2016-01-01

    The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets. PMID:27613060

  20. Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    B Akshaya Srikanth

    2012-01-01

    Full Text Available To estimate the incidence of adverse drug reactions (ADRs in Human immune deficiency virus (HIV patients on highly active antiretroviral therapy (HAART. To identify the risk factors associated with ADRs in HIV patients. To analyze reported ADRs based on various parameters like causality, severity, predictability, and preventability. Retrospective case-control study. An 18-month retrospective case-control study of 208 patients newly registered in ART center, RIMS hospital, Kadapa, were intensively monitored for ADRs to HAART. Predictability was calculated based on the history of previous exposure to drug. Multivariate logistic regressions were used to identify the risk factors for ADRs. Data were analyzed using the chi-square test for estimating the correlation between ADRs and different variables. All statistical calculations were performed using EpiInfo version 3.5.3. Monitoring of 208 retrospective patients by active Pharmacovigilance identified 105 ADRs that were identified in 71 patients. Skin rash and anemia were the most commonly observed ADRs. The organ system commonly affected by ADR was skin and appendages (31.57%. The ADRs that were moderate were 90.14% of cases. The incidence of ADRs (53.52% was higher with Zidovudine + Lamivudine + Nevirapine combination. CD4 cell count less than <250 cells/μl were 80.28%, male gender were observed to be the risk factors for ADRs. Our study finding showed that there is a need of active pharmaceutical care with intensive monitoring for ADRs in Indian HIV-positive patients who are illiterate, of male and female gender, with CD4 count ≤250 cells/mm 3 with comorbid conditions.

  1. Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy.

    Science.gov (United States)

    Srikanth, B Akshaya; Babu, S Chandra; Yadav, Harlokesh Narayan; Jain, Sunil Kumar

    2012-01-01

    To estimate the incidence of adverse drug reactions (ADRs) in Human immune deficiency virus (HIV) patients on highly active antiretroviral therapy (HAART). To identify the risk factors associated with ADRs in HIV patients. To analyze reported ADRs based on various parameters like causality, severity, predictability, and preventability. Retrospective case-control study. An 18-month retrospective case-control study of 208 patients newly registered in ART center, RIMS hospital, Kadapa, were intensively monitored for ADRs to HAART. Predictability was calculated based on the history of previous exposure to drug. Multivariate logistic regressions were used to identify the risk factors for ADRs. Data were analyzed using the chi-square test for estimating the correlation between ADRs and different variables. All statistical calculations were performed using EpiInfo version 3.5.3. Monitoring of 208 retrospective patients by active Pharmacovigilance identified 105 ADRs that were identified in 71 patients. Skin rash and anemia were the most commonly observed ADRs. The organ system commonly affected by ADR was skin and appendages (31.57%). The ADRs that were moderate were 90.14% of cases. The incidence of ADRs (53.52%) was higher with Zidovudine + Lamivudine + Nevirapine combination. CD4 cell count less than <250 cells/μl were 80.28%, male gender were observed to be the risk factors for ADRs. Our study finding showed that there is a need of active pharmaceutical care with intensive monitoring for ADRs in Indian HIV-positive patients who are illiterate, of male and female gender, with CD4 count ≤250 cells/mm(3) with comorbid conditions. PMID:22470896

  2. Identification of HIV-1 Genotypic Resistance in Patients on First-line Antiretroviral Therapy Using Polymerase Chain Reaction and Sequencing

    Institute of Scientific and Technical Information of China (English)

    Jiang Xiao; Gui-ju Gao; Hong-xin Zhao; Yan-mei Li; Ying-xiu Huang; Wen Zhang; Wen-jing Su; Wei Zhang; Ning Han; Di Yang; Xin Li

    2013-01-01

    Objective The aim of the study was to evaluate the characteristics of HIV drug-genotypic resistance among patients taking ifrst-line ARV regimens using polymerase chain reaction and sequencing, and guide to design optimal ARV regimens for these patients. Methods HIV reverse transcriptase-encoded gene was ampliifed with RT-PCR and ampliifed PCR products were aligned and comparatively analyzed with HIV resistance database to ifnd drug-resistance mutations. Results Twenty-eight PCR products were amplified and sequenced successfully in 30 serum samples of recruited HIV-infected patients with virologic failure. The resistance rate was 96%, mutations in NRT region were found in 26 patients (93%), while mutations in NNRT region were found in 27 patients (96%). M184V was the most common mutation (86%), K65R was selected in 14%of recruited individuals and TAMs occurred in 50%of patients, which resulted in resistance to NRTIs. Y181C and V179D were the most common mutations in NNRTIs and prevalence was 43%(12/28) and 36%(10/28), respectively, which resulted in cross-resistance to NNRTIs due to low-genetic barrier. Conclusions Virologic failure may occur in long-term administration of ifrst-line ARV regimens, and drug-resistance mutations can be found in these patients, which resulted in resistance to ifrst-line ARV regimens. We emphasized that HIV viral load assay and resistance assay were important tools to guide healthcare workers to design an optimal second-line ARV regimens for HAART-experienced individuals with virologic failure.

  3. Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy.

    NARCIS (Netherlands)

    Boffito, M.; Acosta, E.; Burger, D.M.; Fletcher, C.V.; Flexner, C.; Garaffo, R.; Gatti, G.; Kurowski, M.; Perno, C.F.; Peytavin, G.; Regazzi, M.; Back, D.

    2005-01-01

    The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical

  4. Sentinel Surveillance of HIV-1 Transmitted Drug Resistance, Acute Infection and Recent Infection

    Science.gov (United States)

    Truong, Hong-Ha M.; Kellogg, Timothy A.; McFarland, Willi; Louie, Brian; Klausner, Jeffrey D.; Philip, Susan S.; Grant, Robert M.

    2011-01-01

    -line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug resistance, recent infection, and acute infection testing should be considered for existing HIV/STI surveillance and prevention activities, particularly in an era of enhanced efforts for early diagnosis and treatment. PMID:22046237

  5. Sentinel surveillance of HIV-1 transmitted drug resistance, acute infection and recent infection.

    Directory of Open Access Journals (Sweden)

    Hong-Ha M Truong

    Full Text Available HIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection.A consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI clinic from 2004 to 2006 (N = 9,868 were evaluated by standard enzyme-linked immunoassays (EIA. HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36. Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI was the most common pattern detected, present in 28 cases of resistance (59.6%. Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001, unprotected anal intercourse (AOR = 2.27; p<0.001, sex with a known HIV-infected partner (AOR = 1.64; p = 0.02, and history of gonorrhea (AOR = 1.62; p = 0.03.New HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug

  6. The medical and surgical treatment of drug-resistant tuberculosis

    OpenAIRE

    Calligaro, Gregory L.; Moodley, Loven; Symons, Greg; Dheda, Keertan

    2014-01-01

    Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migrat...

  7. Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning.

    Science.gov (United States)

    Avihingsanon, Anchalee; Ramautarsing, Reshmie A; Suwanpimolkul, Gompol; Chetchotisakd, Ploenchan; Bowonwatanuwong, Chureeratana; Jirajariyavej, Supunnee; Kantipong, Patcharee; Tantipong, Hutsaya; Ohata, June Pirapon; Suankratay, Chusana; Ruxrungtham, Kiat; Burger, David M

    2014-01-01

    Ergotism is a toxic condition resulting from overexposure to the ergot compounds produced by various fungi of the genus Claviceps. Traditionally, such exposure was due to ingestion of infected grains, but long-term or excessive use of medications containing ergot derivatives or drug-drug interactions between these medications can result in ergotism. Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4). Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism. A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997 (most recently reviewed by Frohlich et al). PMID:24531557

  8. Evaluation of Idaho's DARE "Drug Abuse Resistance Education Projects."

    Science.gov (United States)

    Silva, Roberta K.

    The goal of DARE (Drug Abuse Resistance Education) is not to completely eliminate the drug and alcohol problems of society. It is a proactive prevention program designed to equip youth (focusing on elementary school) with skills for resisting peer pressure to experiment with drugs, and to manage anger without resorting to violence or the use of…

  9. Evaluation of Idaho's DARE "Drug Abuse Resistance Education" Projects.

    Science.gov (United States)

    Silva, Roberta K.

    The DARE (Drug Abuse Resistance Education) program teaches students decision-making skills, shows them how to resist peer pressure to experiment with drugs and alcohol, and provides positive alternatives to drug use. This report looks at one state's DARE programs. Included are an overview of the implementation process, a program appraisal with…

  10. Bedaquiline: A novel antitubercular drug for multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    H Nagabushan

    2014-01-01

    Full Text Available Multidrug-resistant and extensively drug-resistant tuberculosis (TB are emerging global health threats. Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. It is a bactericidal and long-acting drug. It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment. This drug has been approved by the Food and Drug Administration in December 2012 for the management of multidrug resistant-TB. The drug marks the introduction of a new addition to the TB armamentarium after four decades.

  11. Predicted levels of HIV drug resistance

    DEFF Research Database (Denmark)

    Cambiano, Valentina; Bertagnolio, Silvia; Jordan, Michael R;

    2014-01-01

    -term effects. METHODS: The previously validated HIV Synthesis model was calibrated to South Africa. Resistance was modeled at the level of single mutations, transmission potential, persistence, and effect on drug activity. RESULTS: We estimate 652 000 people (90% uncertainty range: 543 000-744 000) are living...... are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500......  cells/μl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500  copies/ml carrying NRMV is not projected to differ markedly according to future ART...

  12. Transmitted drug resistance in recently infected HIV-positive Individuals from four urban locations across Asia (2007–2010) – TASER-S

    OpenAIRE

    Jiamsakul, Awachana; Sirivichayakul, Sunee; Ditangco, Rossana; Wong, Ka-Hing; Li, Patrick CK; Praparattanapan, Jutarat; Phanuphak, Praphan; Segubre-Mercado, Edelwisa; Yam, Wing-Cheong; Sirisanthana, Thira; Singtoroj, Thida; Law, Matthew; ,

    2015-01-01

    Background The availability of HIV antiretroviral therapy (ART) has been associated with the development of transmitted drug resistance-associated mutations (TDRM). TDRM can compromise treatment effectiveness in patients initiating ART and the prevalence can vary in different clinical settings. In this study, we investigated the proportion of TDRM in treatment-naïve, recently infected HIV-positive individuals sampled from four urban locations across Asia between 2007–2010. Methods Patients en...

  13. An exploration of compulsory licensing as an effective policy tool for antiretroviral drugs in India.

    Science.gov (United States)

    Jain, Dipika; Darrow, Jonathan J

    2013-01-01

    Access to affordable drugs for the treatment of HIV/AIDS and other diseases is increasingly challenging in many developing countries such as Brazil, South Africa, and India. These challenges are in part the result of strengthened patent laws mandated by the 1994 Trade-Related Aspects of Intellectual Property Rights (TRIPS) treaty. However, there are underutilized instruments within TRIPS that governments can use to limit the adverse effects of patent protection and thereby ensure a supply of affordable generic drugs to their people. One such instrument is compulsory licensing, which allows generic manufacturers to produce pharmaceutical products that are currently subject to patent protection. Compulsory licensing has been used by a number of countries in the last few years, including the United States, Canada, Indonesia, Malaysia, Brazil, and Thailand, and is particularly significant for countries such as India, where large numbers of people are infected with HIV. This Article explores the feasibility of compulsory licensing as a tool to facilitate access to essential medicines within the current patent regime in India, drawing on the experiences of other countries. PMID:24341078

  14. Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean.

    Science.gov (United States)

    Spaulding, Alicen B; Yu, Qilu; Civitello, Lucy; Mussi-Pinhata, Marisa M; Pinto, Jorge; Gomes, Ivete M; Alarcón, Jorge O; Siberry, George K; Harris, D Robert; Hazra, Rohan

    2016-04-01

    To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6-12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (≥3 drugs from ≥2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than -2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1-11.2), microcephaly in 105 (7.5%; 95% CI: 6.2-9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6-3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p > 0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR] = 1.9; 95% CI: 1.3-2.8), birth weight <2.5 kg (OR = 3.1; 95% CI: 2.1-4.8), 1-min Apgar score <7 (OR = 2.5; 95% CI: 1.4-4.4), and infant infections (OR = 2.5; 95% CI: 1.5-4.1). No ARV investigated was associated with adverse neurologic outcomes. Continued investigation of such associations may be warranted as new ARVs are used during pregnancy and cART exposure during the first trimester becomes increasingly common. PMID:26879281

  15. Comparison of efavirenz and protease inhibitor based combination antiretroviral therapy regimens in treatment-naïve people living with HIV with baseline resistance.

    Science.gov (United States)

    Lim, Charlotte; McFaul, Katie; Kabagambe, Samuel; Sonecha, Sonali; Jones, Rachael; Asboe, David; Pozniak, Anton; Nwokolo, Nneka; Boffito, Marta

    2016-07-17

    A retrospective cohort analysis comparing the efficacy of boosted protease inhibitor-based and efavirenz-based combination antiretroviral therapy in treatment-naïve people living with HIV with baseline resistance found that efavirenz-based treatment led to a shorter mean time to undetectable viral load. A higher proportion of patients with nonnucleoside reverse transcriptase inhibitor related baseline resistance mutations in the efavirenz-treatment group achieved an undetectable viral load at both 6 and 12 months post-treatment initiation, compared with the boosted protease-inhibitor-treatment group.Supplementary content: http://links.lww.com/QAD/A930. PMID:27139315

  16. Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

    International Nuclear Information System (INIS)

    To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

  17. Occurrence of intestinal parasites amongst persons on highly active antiretroviral drug therapy in Calabar, Cross River State, Nigeria

    Directory of Open Access Journals (Sweden)

    Paul C. Inyang-Etoh

    2015-02-01

    Full Text Available Opportunistic and intestinal parasite infections are common health problem among HIV/AIDS patients. Early detection and treatment of these parasites are important to improve the quality of life of this category of patients. The occurrence of intestinal parasites among 400 patients on highly active anti-retroviral drug therapy (HAART aged 11-60 years was investigated. Standard parasitological techniques like direct microscopy, formol ether concentration and modified Ziehl- Neelsen staining techniques were used to analyze the stool samples. Intestinal parasite infections were positive in 116 (29% of the subjects on HAART while control subjects had 12 (12% and the difference was statistically significant (P<0.05. Subjects in the age group 21-30 years had the highest infection rate 54 (35.1%. There was no statistically significant difference in infection according to age (P>0.05. Females 76 (32.5% had a higher prevalence rate than males 40 (24.1%. But there was no statistically significant difference in infection according to gender (P<0.05. Patients with CD4 count of less than 200 cells/mm3 were observed to be more infected than those with CD4 count of more than 200 cells/mm3. There was a strong positive correlation (r=0.94 between CD4 count and the occurrence of intestinal parasite infection. Protozoan parasites 84 (21.0% accounted for a higher prevalence rate than helminthic parasites 32 (8.0%. These findings has revealed a high prevalence of intestinal parasite infection among patients on HAART thus the routine screening of stool samples from these category of patients for intestinal parasites is advocated for effective management of the disease.

  18. Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model

    OpenAIRE

    Pingen, Marieke; Sarrami-Forooshani, Ramin; Wensing, Annemarie MJ; van Ham, Petra; Drewniak, Agata; Boucher, Charles Ab; Geijtenbeek, Teunis BH; Nijhuis, Monique

    2014-01-01

    Background Different patterns of drug resistance are observed in treated and therapy naïve HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral naïve population. M184I/V mutations are known to have a profound effect on viral replication and tend to revert over time in the new host. However it is debated whether a diminished transmission efficacy of HIV...

  19. Molecular phylogenetics of transmitted drug resistance in newly diagnosed HIV Type 1 individuals in Denmark: a nation-wide study

    DEFF Research Database (Denmark)

    Audelin, Anne Margrethe; Gerstoft, Jan; Obel, Niels;

    2011-01-01

    Abstract Highly active antiretroviral treatment is compromised by viral resistance mutations. Transmitted drug resistance (TDR) is therefore monitored closely, but follow-up studies of these patients are limited. Virus from 1405 individuals diagnosed with HIV-1 in Denmark between 2001 and 2009...... resulting in a prevalence of 6.1%, with no changes over time. The main resistance mutations were nucleoside reverse transcriptase inhibitor (NRTI) mutation 215 revertants, as well as nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation 103N/S and protease inhibitor (PI) mutations 90M and 85V....... Phylogenetic analysis confirmed 12 transmission chains involving 37 TDR individuals. Of these 21 were also documented epidemiologically. The virus included in the transmission chain carried similar resistance mutations to the TDR index case, whereas controls chains from index cases without TDR were generally...

  20. Molecular Phylogenetics of Transmitted Drug Resistance in Newly Diagnosed HIV Type 1 Individuals in Denmark, a Nation-Wide Study

    DEFF Research Database (Denmark)

    Audelin, Anne Margrethe; Gerstoft, Jan; Obel, Niels;

    2011-01-01

    Abstract Highly active antiretroviral treatment is compromised by viral resistance mutations. Transmitted drug resistance (TDR) is therefore monitored closely, but follow-up studies of these patients are limited. Virus from 1405 individuals diagnosed with HIV-1 in Denmark between 2001 and 2009...... resulting in a prevalence of 6.1%, with no changes over time. The main resistance mutations were nucleoside reverse transcriptase inhibitor (NRTI) mutation 215 revertants, as well as nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation 103N/S and protease inhibitor (PI) mutations 90M and 85V....... Phylogenetic analysis confirmed 12 transmission chains involving 37 TDR individuals. Of these 21 were also documented epidemiologically. The virus included in the transmission chain carried similar resistance mutations to the TDR index case, whereas controls chains from index cases without TDR were generally...

  1. Stop the Spread of Superbugs: Help Fight Drug Resistant Bacteria

    Science.gov (United States)

    ... the Spread of Superbugs Help Fight Drug-Resistant Bacteria For nearly a century, bacteria-fighting drugs known as antibiotics have helped to control and destroy many of the harmful bacteria that can make us sick. But in recent ...

  2. Nanomedicine therapeutic approaches to overcome cancer drug resistance.

    Science.gov (United States)

    Markman, Janet L; Rekechenetskiy, Arthur; Holler, Eggehard; Ljubimova, Julia Y

    2013-11-01

    Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment. PMID:24120656

  3. Drug–Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection

    Science.gov (United States)

    Berretta, Massimiliano; Caraglia, Michele; Martellotta, Ferdinando; Zappavigna, Silvia; Lombardi, Angela; Fierro, Carla; Atripaldi, Luigi; Muto, Tommaso; Valente, Daniela; De Paoli, Paolo; Tirelli, Umberto; Di Francia, Raffaele

    2016-01-01

    The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug–drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug–drug interaction, a useful list of pharmacogenomic markers is provided. PMID:27065862

  4. Klebsiella pneumoniae Antimicrobial Drug Resistance, United States, 1998–2010

    OpenAIRE

    Sanchez, Guillermo V.; Master, Ronald N; Clark, Richard B.; Fyyaz, Madiha; Duvvuri, Padmaraj; Ekta, Gupta; Bordon, Jose

    2013-01-01

    We studied antimicrobial-resistant Klebsiella pneumoniae for 1998–2010 by using data from The Surveillance Network. Susceptibility results (n = 3,132,354) demonstrated significant increases in resistance to all antimicrobial drugs studied, except tetracycline. Cross-resistance among carbapenem-resistant K. pneumoniae was lower for tetracycline and amikacin.

  5. New Developments in Antiepileptic Drug Resistance: An Integrative View

    OpenAIRE

    Schmidt, Dieter; Löscher, Wolfgang

    2009-01-01

    Current theories on drug resistance in epilepsy include the drug transporter hypothesis, the drug target hypothesis, and a novel approach called the inherent severity model of epilepsy, which posits that the severity of the disease determines its relative response to medication. Valuable as each of these hypotheses is, none is currently a stand-alone theory that is able to convincingly explain drug resistance in human epilepsy. As a consequence, it may be of interest to update and integrate t...

  6. Bedaquiline: A novel antitubercular drug for multidrug-resistant tuberculosis

    OpenAIRE

    Nagabushan, H.; H. S. Roopadevi

    2014-01-01

    Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are emerging global health threats. Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. It is a bactericidal and long-acting drug. It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment. This drug has been approved by the Food and Dr...

  7. Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Joanne D Stekler

    Full Text Available OBJECTIVE: To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA but not consensus sequencing among subjects with primary HIV-1 infection. DESIGN/METHODS: Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL among subjects with minority variants conferring intermediate or high-level resistance. RESULTS: Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62-147 days for 63 treated subjects without detectable mutations, 84 (IQR 56-109 days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60-162 days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9. Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6-2.4, p = .6 and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4-2.4, p = .9. Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure. CONCLUSIONS: Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.

  8. Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea.

    Science.gov (United States)

    Moon, Changsuk; Zhang, Weiqiang; Ren, Aixia; Arora, Kavisha; Sinha, Chandrima; Yarlagadda, Sunitha; Woodrooffe, Koryse; Schuetz, John D; Valasani, Koteswara Rao; de Jonge, Hugo R; Shanmukhappa, Shiva Kumar; Shata, Mohamed Tarek M; Buddington, Randal K; Parthasarathi, Kaushik; Naren, Anjaparavanda P

    2015-05-01

    Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.

  9. Targeting efflux pumps to overcome antifungal drug resistance.

    Science.gov (United States)

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps. PMID:27463566

  10. Explaining risk factors for drug-resistant tuberculosis in England and Wales: contribution of primary and secondary drug resistance

    OpenAIRE

    Conaty, S. J.; Hayward, A. C.; Story, A; Glynn, J.R.; Drobniewski, F A; Watson, J.M.

    2004-01-01

    Drug-resistant tuberculosis can be transmitted (primary) or develop during the course of treatment (secondary). We investigated risk factors for each type of resistance. We compared all patients in England and Wales with isoniazid- and multidrug-resistant tuberculosis in two time-periods (1993-1994 and 1998-2000) with patients with fully sensitive tuberculosis, examining separately patients without and with previous tuberculosis (a proxy for primary and secondary drug-resistant tuberculosis)....

  11. Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase.

    Science.gov (United States)

    Melody, Kevin; McBeth, Sarah; Kline, Christopher; Kashuba, Angela D M; Mellors, John W; Ambrose, Zandrea

    2015-12-01

    Preexposure prophylaxis (PrEP) using antiretroviral drugs is effective in reducing the risk of human immunodeficiency virus type 1 (HIV-1) infection, but adherence to the PrEP regimen is needed. To improve adherence, a long-acting injectable formulation of the nonnucleoside reverse transcriptase (RT) inhibitor rilpivirine (RPV LA) has been developed. However, there are concerns that PrEP may select for drug-resistant mutations during preexisting or breakthrough infections, which could promote the spread of drug resistance and limit options for antiretroviral therapy. To address this concern, we administered RPV LA to macaques infected with simian immunodeficiency virus containing HIV-1 RT (RT-SHIV). Peak plasma RPV levels were equivalent to those reported in human trials and waned over time after dosing. RPV LA resulted in a 2-log decrease in plasma viremia, and the therapeutic effect was maintained for 15 weeks, until plasma drug concentrations dropped below 25 ng/ml. RT mutations E138G and E138Q were detected in single clones from plasma virus in separate animals only at one time point, and no resistance mutations were detected in viral RNA isolated from tissues. Wild-type and E138Q RT-SHIV displayed similar RPV susceptibilities in vitro, whereas E138G conferred 2-fold resistance to RPV. Overall, selection of RPV-resistant variants was rare in an RT-SHIV macaque model despite prolonged exposure to slowly decreasing RPV concentrations following injection of RPV LA. PMID:26438501

  12. Treatment of falciparum malaria in the age of drug resistance

    Directory of Open Access Journals (Sweden)

    Shanks G

    2006-01-01

    Full Text Available The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rather than curing them, leading to increasedtransmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs.Antifolate drug resistance (i.e. pyrimethamine means that new combinations are urgently needed particularlybecause addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance toeach having been documented soon after drug introduction. Drug combinations delay further transmission ofresistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currentlyrecommended drug combinations for falciparum malaria are variants of artemisinin combination therapy wherea rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisininsused include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard ofcare must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only tothe successful treatment of individual patients but also for public health control of malaria.

  13. Change in the Prevalence of HIV-1 and the Rate of Transmitted Drug-Resistant HIV-1 in Haiphong, Northern Vietnam.

    Science.gov (United States)

    Pham, Hung Viet; Ishizaki, Azumi; Nguyen, Cuong Hung; Saina, Matilda Chelimo; Hoang, Huyen Thi Thanh; Tran, Vuong Thi; Bi, Xiuqiong; Pham, Thuc Van; Ichimura, Hiroshi

    2015-07-01

    We previously reported a significant decrease in HIV-1 prevalence, with no increase in drug-resistant HIV-1 among injecting drug users (IDU), female sex workers (FSW), and blood donors (BD), in Haiphong, Vietnam, from 2007 to 2009. In 2012, 388 IDU, 51 FSW, and 200 BD were recruited for further analysis. None had a history of antiretroviral treatment. From 2007 to 2012, HIV-1 prevalence was reduced from 35.9% to 18.6% (pNonnucleoside RT inhibitor-resistant mutations, Y181C/I, were detected in three subjects; one had the nucleoside RT inhibitor-resistant mutations L74V and M184V and one had E138K. The prevalence of transmitted drug-resistant HIV-1 in Haiphong increased slightly from 1.8% in 2007 to 6.6% in 2012 (p=0.06). PMID:25970090

  14. Adaptation and evolution of drug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    I.L. Bergval

    2013-01-01

    Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive mech

  15. Genetic Barriers to Resistance and Impact on Clinical Response

    Directory of Open Access Journals (Sweden)

    Luber Andrew D

    2005-07-01

    Full Text Available Abstract The development of drug resistance and cross-resistance continues to pose a challenge to successful long-term antiretroviral therapy despite the availability of new antiretroviral agents. The genetic barrier to resistance of a regimen does not directly correlate with its effectiveness. For some regimens with a low genetic barrier to resistance, however, the emergence of only 1 or 2 key resistance mutations may confer drug resistance not only to that regimen but also to other agents, thereby limiting subsequent treatment options. In addition to the genetic barrier to resistance, factors such as efficacy, safety, tolerability, convenience, and adherence must be considered when choosing a regimen.

  16. Epidemiological control of drug resistance and compensatory mutation under resistance testing and second-line therapy.

    Science.gov (United States)

    Saddler, Clare A; Wu, Yue; Valckenborgh, Frank; Tanaka, Mark M

    2013-12-01

    The fitness cost of antibiotic resistance in the absence of treatment raises the possibility that prudent use of drugs may slow or reverse the rise of resistance. Unfortunately, compensatory mutations that lower this cost may lead to entrenched resistance. Here, we develop a mathematical model of resistance evolution and compensatory mutation to determine whether reversion to sensitivity can occur, and how disease control might be facilitated by a second-line therapy. When only a single antibiotic is available, sensitive bacteria reach fixation only under treatment rates so low that hardly any cases are treated. We model a scenario in which drug sensitivity can be accurately tested so that a second-line therapy is administered to resistant cases. Before the rise of resistance to the second drug, disease eradication is possible if resistance testing and second-line treatment are conducted at a high enough rate. However, if double drug resistance arises, the possibility of disease eradication is greatly reduced and compensated resistance prevails in most of the parameter space. The boundary separating eradication from fixation of compensated resistance is strongly influenced by the underlying basic reproductive number of the pathogen and drug efficacy in sensitive cases, but depends less on the resistance cost and compensation. When double resistance is possible, the boundary is affected by the relative strengths of resistance against the two drugs in the double-resistant-compensated strain.

  17. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Guillaume Chevereau

    Full Text Available The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation

  18. Impact of drug stock-outs on death and retention to care among HIV-infected patients on combination antiretroviral therapy in Abidjan, Cote d'Ivoire.

    Directory of Open Access Journals (Sweden)

    Armelle Pasquet

    Full Text Available BACKGROUND: To evaluate the type and frequency of antiretroviral drug stock-outs, and their impact on death and interruption in care among HIV-infected patients in Abidjan, Côte d'Ivoire. METHODS AND FINDINGS: We conducted a cohort study of patients who initiated combination antiretroviral therapy (cART in three adult HIV clinics between February 1, 2006 and June 1, 2007. Follow-up ended on February 1, 2008. The primary outcome was cART regimen modification, defined as at least one drug substitution, or discontinuation for at least one month due to drug stock-outs at the clinic pharmacy. The secondary outcome for patients who were on cART for at least six months was interruption in care, or death. A Cox regression model with time-dependent variables was used to assess the impact of antiretroviral drug stock-outs on interruption in care or death. Overall, 1,554 adults initiated cART and were followed for a mean of 13.2 months. During this time, 72 patients discontinued treatment and 98 modified their regimen because of drug stock-outs. Stock-outs involved nevirapine and fixed-dose combination zidovudine/lamivudine in 27% and 51% of cases. Of 1,554 patients, 839 (54% initiated cART with fixed-dose stavudine/lamivudine/nevirapine and did not face stock-outs during the study period. Among the 975 patients who were on cART for at least six months, stock-out-related cART discontinuations increased the risk of interruption in care or death (adjusted hazard ratio [HR], 2.83; 95%CI, 1.25-6.44 but cART modifications did not (adjusted HR, 1.21; 95%CI, 0.46-3.16. CONCLUSIONS: cART stock-outs affected at least 11% of population on treatment. Treatment discontinuations due to stock-outs were frequent and doubled the risk of interruption in care or death. These stock-outs did not involve the most common first-line regimen. As access to cART continues to increase in sub-Saharan Africa, first-line regimens should be standardized to decrease the probability of

  19. Overcome Cancer Cell Drug Resistance Using Natural Products

    Directory of Open Access Journals (Sweden)

    Pu Wang

    2015-01-01

    Full Text Available Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1 in vitro studies using cell line models; (2 serum pharmacology; (3 in vivo studies using animal models; and (4 clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time. In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studies in vivo showed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance.

  20. Mycobacterium tuberculosis resistance to antituberculosis drugs in Mozambique

    Directory of Open Access Journals (Sweden)

    Germano Manuel Pires

    2014-04-01

    Full Text Available OBJECTIVE: To determine the drug resistance profile of Mycobacterium tuberculosis in Mozambique. METHODS: We analyzed secondary data from the National Tuberculosis Referral Laboratory, in the city of Maputo, Mozambique, and from the Beira Regional Tuberculosis Referral Laboratory, in the city of Beira, Mozambique. The data were based on culture-positive samples submitted to first-line drug susceptibility testing (DST between January and December of 2011. We attempted to determine whether the frequency of DST positivity was associated with patient type or provenance. RESULTS: During the study period, 641 strains were isolated in culture and submitted to DST. We found that 374 (58.3% were resistant to at least one antituberculosis drug and 280 (43.7% were resistant to multiple antituberculosis drugs. Of the 280 multidrug-resistant tuberculosis cases, 184 (65.7% were in previously treated patients, most of whom were from southern Mozambique. Two (0.71% of the cases of multidrug-resistant tuberculosis were confirmed to be cases of extensively drug-resistant tuberculosis. Multidrug-resistant tuberculosis was most common in males, particularly those in the 21-40 year age bracket. CONCLUSIONS: M. tuberculosis resistance to antituberculosis drugs is high in Mozambique, especially in previously treated patients. The frequency of M. tuberculosis strains that were resistant to isoniazid, rifampin, and streptomycin in combination was found to be high, particularly in samples from previously treated patients.

  1. Impact of therapeutic drug monitoring of antiretroviral drugs in routine clinical management of patients infected with human immunodeficiency virus and related health care costs: a real-life study in a large cohort of patients

    Science.gov (United States)

    Perrone, Valentina; Cattaneo, Dario; Radice, Sonia; Sangiorgi, Diego; Federici, Augusto B; Gismondo, Maria Rita; Medaglia, Massimo; Micheli, Valeria; Vimercati, Stefania; Pallone, Enza; Esposti, Luca Degli; Clementi, Emilio

    2014-01-01

    Background Highly active antiretroviral therapy (HAART) has reduced morbidity and mortality in patients infected with human immunodeficiency virus (HIV). Studies have documented high interindividual variability in the pharmacokinetics of antiretroviral drugs, which may impair the success of HAART if not managed properly. Therapeutic drug monitoring (TDM) is a useful diagnostic tool that helps clinicians to optimize drug doses so that drug concentrations associated with the highest therapeutic efficacy are obtained with a reduced risk of concentration-dependent adverse effects. The aim of this study was to assess whether use of TDM improves clinical outcomes and cost of illness. Methods A retrospective cohort study was conducted at L Sacco University Hospital in Milan, Italy, in HIV-infected patients aged ≥18 years with at least one prescription of antiretroviral drugs for which TDM was applied. The inclusion period was from January 2010 to December 2011, with a follow-up period of up to 12 months. Laboratory and administrative databases were analyzed and matched with each other. Results The cohort consisted of 5,347 patients (3,861 males and 1,486 females) of mean age 43.9±12.5 years. We found that TDM had been used in 143 of these patients, among whom adherence with therapy was significantly higher than among those in whom TDM had not been used (94% versus 78%). In TDM-controlled patients, the mean length of HIV-related hospitalization stay and mean cost of hospitalization were significantly reduced with respect to those observed in the group in which TDM had not been used (7.21 days versus 29.47 days and €293 versus €688, respectively). Conclusion Inclusion of TDM as part of routine clinical optimization of drug dosing in HIV-infected patients is associated with higher adherence to therapy, reduced length of hospitalization stay, and reduced cost of illness. PMID:25053888

  2. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis

    OpenAIRE

    Divya Goel

    2014-01-01

    Tuberculosis (TB) is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB) and extensive drug-resistant tuberculosis (XDR-TB). Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB an...

  3. Training needs assessment for clinicians at antiretroviral therapy clinics: evidence from a national survey in Uganda

    Directory of Open Access Journals (Sweden)

    Namagala Elizabeth

    2009-08-01

    Full Text Available Abstract Background To increase access to antiretroviral therapy in resource-limited settings, several experts recommend "task shifting" from doctors to clinical officers, nurses and midwives. This study sought to identify task shifting that has already occurred and assess the antiretroviral therapy training needs among clinicians to whom tasks have shifted. Methods The Infectious Diseases Institute, in collaboration with the Ugandan Ministry of Health, surveyed health professionals and heads of antiretroviral therapy clinics at a stratified random sample of 44 health facilities accredited to provide this therapy. A sample of 265 doctors, clinical officers, nurses and midwives reported on tasks they performed, previous human immunodeficiency virus training, and self-assessment of knowledge of human immunodeficiency virus and antiretroviral therapy. Heads of the antiretroviral therapy clinics reported on clinic characteristics. Results Thirty of 33 doctors (91%, 24 of 40 clinical officers (60%, 16 of 114 nurses (14% and 13 of 54 midwives (24% who worked in accredited antiretroviral therapy clinics reported that they prescribed this therapy (p Conclusion Training initiatives should be an integral part of the support for task shifting and ensure that antiretroviral therapy is used correctly and that toxicity or drug resistance do not reverse accomplishments to date.

  4. Totally drug-resistant tuberculosis and adjunct therapies.

    Science.gov (United States)

    Parida, S K; Axelsson-Robertson, R; Rao, M V; Singh, N; Master, I; Lutckii, A; Keshavjee, S; Andersson, J; Zumla, A; Maeurer, M

    2015-04-01

    The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options. PMID:24809736

  5. Antimicrobial (Drug) Resistance: Methicillin-Resistant Staphylococcus aureus (MRSA)

    Science.gov (United States)

    ... Marketing Share this: Main Content Area Methicillin-Resistant Staphylococcus aureus (MRSA) During the past four decades, methicillin-resistant Staphylococcus aureus , or MRSA, has evolved from a controllable ...

  6. Drug-resistance mechanisms and prevalence of Enterobacter cloacae resistant to multi-antibiotics

    Institute of Scientific and Technical Information of China (English)

    张杰; 顾怡明; 俞云松; 周志慧; 杜小玲

    2004-01-01

    @@The main drug-resistance mechanism of gram-negative bacteria is producing β-lactamases. Two kinds of enzymes cause drug resistance by hydrolyzing oxyimino-cephalosporins and aztreonam: one is chromosomally encoded AmpC β-lactamases, the other is plasmid-mediated extended-spectrum β-lactamases (ESBLs). Enterobacter cloacae can produce both of them, so that these strains are seriously resistance to many antibiotics. In order to study the main drug-resistant mechanism in Enterobacter cloacae, PCR and nucleotide sequencing were performed on 58 multidrug resistant strains.

  7. Fitness of Leishmania donovani parasites resistant to drug combinations.

    Directory of Open Access Journals (Sweden)

    Raquel García-Hernández

    2015-04-01

    Full Text Available Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc line. In the absence of stress, none of the Leishmania lines showed growth advantage relative to the other when mixed at a 1:1 parasite ratio. However, when promastigotes from resistant lines and the Luc line were mixed and exposed to different stresses, we observed that the resistant lines are more tolerant of different stress conditions: nutrient starvation and heat shock-pH stress. Further to this, we observed that intracellular amastigotes from resistant lines present a higher capacity to survive inside the macrophages than those of the control line. These results suggest that resistant parasites acquire an overall fitness increase and that resistance to drug combinations presents significant differences in their fitness capacity versus single-drug resistant parasites, particularly in intracellular amastigotes. These results contribute to the assessment of the possible impact of drug resistance on leishmaniasis control programs.

  8. Defeating pathogen drug resistance: guidance from evolutionary theory.

    Science.gov (United States)

    Pepper, John W

    2008-12-01

    Many of the greatest challenges in medicine and public health involve the evolution of drug resistance by pathogens. Recent advances in the theory of natural selection suggest that there are two broad classes of pathogen traits that can be targeted by drugs or vaccines. The first class, consisting of traits that benefit the individual organisms bearing them, causes a strong evolutionary response and the rapid emergence of drug resistance. The second class, consisting of traits that benefit groups of pathogen organisms including the individual provider, causes a weaker evolutionary response and less drug resistance. Although most previous drug development has targeted the first class, it would be advantageous to focus on the second class as targets for drug and vaccine development. Specific examples and test cases are discussed.

  9. Delamanid: A new armor in combating drug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Alphienes Stanley Xavier

    2014-01-01

    Full Text Available Intense search has been made in the discovery of newer anti-TB drugs to tackle the issues such as drug resistance, HIV co-infection and risk of drug-drug interactions in the management of TB. Delamanid, a newer mycobacterial cell wall synthesis inhibitor, received a conditional approval from European medicines agency (EMA for the treatment of MDR-TB. Preclinical and clinical studies have shown that delamanid has high potency, least risk for drug-drug interactions and better tolerability.

  10. Pharmacodynamic and Antiretroviral Activities of Combination Nanoformulated Antiretrovirals in HIV-1–Infected Human Peripheral Blood Lymphocyte–Reconstituted Mice

    OpenAIRE

    Roy, Upal; McMillan, JoEllyn; Alnouti, Yazen; Gautum, Nagsen; Smith, Nathan; Balkundi, Shantanu; Dash, Prasanta; Gorantla, Santhi; Martinez-Skinner, Andrea; Meza, Jane; Kanmogne, Georgette; Swindells, Susan; Cohen, Samuel M.; Mosley, R. Lee; Poluektova, Larisa

    2012-01-01

    Lack of adherence, inaccessibility to viral reservoirs, long-term drug toxicities, and treatment failures are limitations of current antiretroviral therapy (ART). These limitations lead to increased viral loads, medicine resistance, immunocompromise, and comorbid conditions. To this end, we developed long-acting nanoformulated ART (nanoART) through modifications of existing atazanavir, ritonavir, and efavirenz suspensions in order to establish cell and tissue drug depots to achieve sustained ...

  11. Bedaquiline for the treatment of drug-resistant tuberculosis.

    Science.gov (United States)

    Bélard, Sabine; Heuvelings, Charlotte C; Janssen, Saskia; Grobusch, Martin P

    2015-05-01

    Bedaquiline is a much-needed novel drug which is highly effective against drug-resistant tuberculosis. While its clinical development has been laudably fast-tracked and the drug is now available for inclusion into treatment regimens when no suitable alternatives exist, clinical experience with bedaquiline is still limited. Phase III trial data and Phase IV studies are needed particularly to study different patient populations and to optimize treatment regimens. Drug resistance to bedaquiline needs to be monitored carefully, and full access to bedaquiline treatment where it is appropriate and needed must be promoted. PMID:25797824

  12. Drug-resistant epilepsy associated with cortical dysplasias

    Directory of Open Access Journals (Sweden)

    I. E. Poverennova

    2013-12-01

    Full Text Available Epilepsy associated with malformations of the cerebral cortex is reported in the literature to account for up to 25% of the total cases of symptomatic epilepsies. It is characterized by the most severe course and often induces drug-resistance in seizures. A group of patients with resistant seizures is singled out among the total number of patients with symptomatic epilepsy caused by cerebral cortical dysgenesis. The most important risk factors for resistance are identified in dysplasias. The prognostically unfavorable clinical features of epilepsy are described. A diagnostic algorithm is proposed to identify risk groups and to prevent drug-resistant forms of epilepsy.

  13. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Divya Goel

    2014-01-01

    Full Text Available Tuberculosis (TB is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB and extensive drug-resistant tuberculosis (XDR-TB. Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB and XDR-TB relies on the drugs, which are less potent, more toxic and more costly and have to be administered for the longer duration. No new drug had come in to market for last 40 years, but the emergence of MDR-TB and XDR-TB has spurred interest in the development of novel drugs. For the effective treatment outcome, there is a dire need of new drugs with a different mechanism of action that can tackle both drug sensitive as well as drug-resistant strains. Bedaquiline is one such new drug with unique mechanism of action. Food and Drug Administration has approved bedaquiline for MDR-TB in December 2012. This article reviews the available evidence of efficacy and safety of bedaquiline.

  14. Cost analysis of antiretroviral agents available in India

    OpenAIRE

    Sagar S. Panchal; Prasad R. Pandit; Abhishek M. Phatak; Komal M. Lohi

    2015-01-01

    Background: AIDS is one of the most prevalent causes of death due to infectious origin which requires a lifelong therapy. There is variation in prices of antiretroviral drugs available in Indian market. Thus, a study was planned to find out variation in prices of antiretroviral drugs either as a single drug or in combination and to evaluate the difference in cost of various brands of the same antiretroviral drugs by calculating percentage variation in cost in Indian rupees. Methods: Cost o...

  15. Resistance profiles and adherence at primary virological failure in three different highly active antiretroviral therapy regimens: analysis of failure rates in a randomized study

    DEFF Research Database (Denmark)

    Røge, B T; Barfod, T S; Kirk, O;

    2004-01-01

    OBJECTIVES: To investigate the interplay between resistance and adherence in the virological failure of three fundamentally different highly active antiretroviral therapy (HAART) regimens. METHODS: We retrospectively identified 56 verified primary virological failures (viral load >400 HIV-1 RNA...... copies/mL) among 293 patients randomized to two nucleoside reverse transcriptase inhibitors (NRTIs)+ritonavir+saquinavir (RS-arm) (n=115), two NRTIs+nevirapine+nelfinavir (NN-arm) (n=118), or abacavir+stavudine+didanosine (ASD-arm) (n=60) followed up for a median of 90 weeks. Data on adherence were...... collected from patient files, and genotyping was performed on plasma samples collected at time of failure. RESULTS: Treatment interruption or poor adherence was mainly caused by side effects and accounted for 74% of failures, and was associated with absence of resistance mutations. In the 30 failing...

  16. The evolution of drug-resistant malaria

    OpenAIRE

    Plowe, Christopher V.

    2008-01-01

    Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted f...

  17. Antibiotics in Animal Feed Contribute to Drug-Resistant Germs

    Science.gov (United States)

    ... medlineplus/news/fullstory_158316.html Antibiotics in Animal Feed Contribute to Drug-Resistant Germs: Study Individual farm ... HealthDay News) -- Use of antibiotics in farm animal feed is helping drive the worldwide increase in antibiotic- ...

  18. Aggressive chemotherapy and the selection of drug resistant pathogens.

    Directory of Open Access Journals (Sweden)

    Silvie Huijben

    2013-09-01

    Full Text Available Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold, without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.

  19. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.

    NARCIS (Netherlands)

    Gandhi, N.R.; Nunn, P.; Dheda, K.; Schaaf, H.S.; Zignol, M.; Soolingen, D. van; Jensen, P.; Bayona, J.

    2010-01-01

    Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of

  20. Highly active ozonides selected against drug resistant malaria

    Science.gov (United States)

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  1. Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

    Directory of Open Access Journals (Sweden)

    Regina Joice

    Full Text Available The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8% against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains. Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak.

  2. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

    Institute of Scientific and Technical Information of China (English)

    REBECCA L DUNNE; LINDA A DUNN; PETER UPCROFT; PETER J O'DONOGHUE; JACQUELINE A UPCROFT

    2003-01-01

    Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved,effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and crossresistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

  3. Fitness of Leishmania donovani parasites resistant to drug combinations.

    OpenAIRE

    Raquel García-Hernández; Verónica Gómez-Pérez; Santiago Castanys; Francisco Gamarro

    2015-01-01

    Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc lin...

  4. Tiagabine add-on for drug-resistant partial epilepsy

    OpenAIRE

    Pereira, J; Marson, A G; Hutton, J L

    2012-01-01

    Cochrane Database Syst Rev. 2002;(3):CD001908. Tiagabine add-on for drug-resistant partial epilepsy. Pereira J, Marson AG, Hutton JL. Servico de Neurologia, Hospital de Santo Antonio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal. Abstract BACKGROUND: Epilepsy is a common neurological condition, affecting almost 0.5 to 1 per cent of the population. Nearly 30 per cent of people with epilepsy are resistant to currently available drugs. Tiagabine...

  5. Nanodrug Formed by Coassembly of Dual Anticancer Drugs to Inhibit Cancer Cell Drug Resistance.

    Science.gov (United States)

    Zhao, Yuanyuan; Chen, Fei; Pan, Yuanming; Li, Zhipeng; Xue, Xiangdong; Okeke, Chukwunweike Ikechukwu; Wang, Yifeng; Li, Chan; Peng, Ling; Wang, Paul C; Ma, Xiaowei; Liang, Xing-Jie

    2015-09-01

    Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a "green" and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs. PMID:26270258

  6. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  7. New antiretrovirals and new combinations.

    Science.gov (United States)

    Havlir, D V; Lange, J M

    1998-01-01

    The appearance in the clinic of two to three new antiretroviral agents yearly since 1995 has permitted unprecedented advances in HIV treatment. This remarkable pace of drug development is a testimony to an extraordinary international effort involving scientists, clinicians, governments, community activists and industry dedicated to the rapid and safe development of novel therapies. New drugs present the opportunity to improve HIV therapy. They also create an enormous challenge to the clinician, who must constantly assimilate data on new drugs and incorporate this information into practical management strategies. Combination therapy has proven the most effective approach to treat HIV disease. The profound and sustained viral suppression achievable with combinations such as indinavir (IDV), lamivudine (3TC) and zidovudine (ZDV) have resulted in a dramatic shift in HIV treatment paradigms over the last year. The full potential of combination therapy with available drugs has yet to be realized as only a limited number of the possible combinations incorporating new drugs have been fully tested. Even drugs available for many years may have untapped potential. Didanosine (ddI) and stavudine (d4T), once thought to be contraindicated in combination because of their overlapping peripheral neuropathy toxicity, have proven well tolerated and effective. Combination therapy can increase antiviral suppression, prevent drug resistance, optimize drug exposure and simplify dosing, but it can also result in pharmacologic antagonism, subtherapeutic drug concentrations and unexpected toxicities. Clinical studies have confirmed in vitro studies showing pharmacologic antagonism for the combination of ZDV and d4T. Combining protease inhibitors with each other or with non-nucleoside reverse transcriptase inhibitors is complicated by effects both classes of drugs have on drug metabolism and clearance. These observations underline the importance of carefully conducted clinical studies to

  8. Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors

    Science.gov (United States)

    Sarkar, S.; Cohen, N.; Sabhachandani, P.; Konry, T.

    2015-01-01

    Acquired drug resistance is a key factor in the failure of chemotherapy. Due to intratumoral heterogeneity, cancer cells depict variations in intracellular drug uptake and efflux at the single cell level, which may not be detectable in bulk assays. In this study we present a droplet microfluidics-based approach to assess the dynamics of drug uptake, efflux and cytotoxicity in drug-sensitive and drug-resistant breast cancer cells. An integrated droplet generation and docking microarray was utilized to encapsulate single cells as well as homotypic cell aggregates. Drug-sensitive cells showed greater death in the presence or absence of Doxorubicin (Dox) compared to the drug-resistant cells. We observed heterogeneous Dox uptake in individual drug-sensitive cells while the drug-resistant cells showed uniformly low uptake and retention. Dox-resistant cells were classified into distinct subsets based on their efflux properties. Cells that showed longer retention of extracellular reagents also demonstrated maximal death. We further observed homotypic fusion of both cell types in droplets, which resulted in increased cell survival in the presence of high doses of Dox. Our results establish the applicability of this microfluidic platform for quantitative drug screening in single cells and multicellular interactions. PMID:26456240

  9. Sphingolipids in neuroblastoma : Their role in drug resistance mechanisms

    NARCIS (Netherlands)

    Sietsma, H; Dijkhuis, AJ; Kamps, W; Kok, JW

    2002-01-01

    Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g.,

  10. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    OpenAIRE

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen recept...

  11. (Post-)genomic approaches to tackle drug resistance in Leishmania

    OpenAIRE

    Berg, Maya; Mannaert, An; Vanaerschot, Manu; Van Der Auwera, Gert; Dujardin, Jean-Claude

    2013-01-01

    Abstract: Leishmaniasis, like other neglected diseases is characterized by a small arsenal of drugs for its control. To safeguard the efficacy of current drugs and guide the development of new ones it is thus of utmost importance to acquire a deep understanding of the phenomenon of drug resistance and its link with treatment outcome. We discuss here how (post-) genomic approaches may contribute to this purpose. We highlight the need for a clear definition of the phenotypes under consideration...

  12. Study on Drug Resistance and Relative Mechanisms of Chlamydia Trachomatis

    Institute of Scientific and Technical Information of China (English)

    侯淑萍; 刘全忠

    2004-01-01

    Abstract: Chlamydia Trachomatis (C.T.) is one of the most common pathogens of human sexually transmitted diseases. Treatment of C.T. infection primarily depends on Tetracyclines, Macrolides and Quinolones, but with the wide use of antibiotics an increasing number of drug-resistant Chlamydia trachomatis cases have been reported. This review summarizes the resistant conditions and the possible resistance mechanisms of C.T..

  13. Troglitazone reverses the multiple drug resistance phenotype in cancer cells

    Directory of Open Access Journals (Sweden)

    Gerald F Davies

    2009-03-01

    Full Text Available Gerald F Davies1, Bernhard HJ Juurlink2, Troy AA Harkness11Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Canada; 2College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi ArabiaAbstract: A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1 and histone H3 expression. The thiazolidinedione troglitazone (TRG downregulated GLO-1 expression and further upregulated histone H3 expression and post-translational modifications in these cells, leading to a regained sensitivity to DOX. Given the pleiotropic effects of epigenetic changes in cancer development, we hypothesized that TRG may downregulate the multiple drug resistance (MDR phenotype in a variety of cancer cells. To test this, MCF7 human breast cancer cells and K562 cells were cultured in the presence of low-dose DOX to establish DOX-resistant cell lines (K562/DOX and MCF7/DOX. The MDR phenotype was confirmed by Western blot analysis of the 170 kDa P-glycoprotein (Pgp drug efflux pump multiple drug resistance protein 1 (MDR-1, and the breast cancer resistance protein (BCRP. TRG markedly decreased expression of both MDR-1 and BCRP in these cells, resulting in sensitivity to DOX. Silencing of MDR-1 expression also sensitized MCF7/DOX cells to DOX. Use of the specific and irreversible peroxisome proliferator-activated receptor gamma (PPARγ inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPARγ-independent, but indicated that PPARγ may play a role in the MDR phenotype, which is antagonized by TRG. We conclude that TRG is potentially a useful adjunct therapy in chemoresistant cancers. Keywords: chemotherapy, doxorubicin, breast cancer resistance protein-1, multiple drug resistance, multiple drug resistance protein 1

  14. Extensively Drug-Resistant Tuberculosis (XDR TB)

    Science.gov (United States)

    ... American Community Summit Background Slideset Children Correctional Facilities Homelessness International Travelers Pregnancy Health Disparities Laboratory Information Model Performance Evaluation Program (MPEP) Drug Susceptibility Testing The Uses of Nucleic Acid Amplification ...

  15. The Need for Development of New HIV-1 Reverse Transcriptase and Integrase Inhibitors in the Aftermath of Antiviral Drug Resistance

    Directory of Open Access Journals (Sweden)

    Mark A. Wainberg

    2012-01-01

    Full Text Available The use of highly active antiretroviral therapy (HAART involves combinations of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. There are two broad classes of reverse transcriptase inhibitors, the nucleoside reverse transcriptase inhibitors (NRTIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs. Since the first classes of such compounds were developed, viral resistance against them has necessitated the continuous development of novel compounds within each class. This paper considers the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second line therapy and describes the patterns of resistance associated with their use, as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with low genetic barrier are more commonly used in resource-limited settings. Their use results to the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings. More recently, the advent of integrase strand transfer inhibitors represents another major step forward toward control of HIV infection, but these compounds are also susceptible to problems of HIV drug resistance.

  16. Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance

    Science.gov (United States)

    Power, Robert A.; Davaniah, Siva; Derache, Anne; Wilkinson, Eduan; Tanser, Frank; Pillay, Deenan; de Oliveira, Tulio

    2016-01-01

    Background Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics. Method We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naïve to the respective treatment. Results GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we highlighted the ability of GWAS to identify epistatic effects, identifying two replicable variants within amino acid 68 of the reverse transcriptase protein previously described as potential fitness compensatory mutations. A possible additional DR variant within amino acid 91 of the matrix region of the Gag protein was associated with tenofovir failure, highlighting GWAS’s ability to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR. Conclusions These results validate the applicability of GWAS to HIV WGS data even in relative small samples, and emphasise how high throughput sequencing can provide novel and clinically relevant insights. Further they suggested that for viruses like HIV, population structure was only minor concern compared to that seen in bacteria or parasite GWAS. Given the small genome length and reduced burden for multiple testing, this makes HIV an ideal candidate for GWAS. PMID:27677172

  17. Estimation of the standardized risk difference and ratio in a competing risks framework: application to injection drug use and progression to AIDS after initiation of antiretroviral therapy.

    Science.gov (United States)

    Cole, Stephen R; Lau, Bryan; Eron, Joseph J; Brookhart, M Alan; Kitahata, Mari M; Martin, Jeffrey N; Mathews, William C; Mugavero, Michael J

    2015-02-15

    There are few published examples of absolute risk estimated from epidemiologic data subject to censoring and competing risks with adjustment for multiple confounders. We present an example estimating the effect of injection drug use on 6-year risk of acquired immunodeficiency syndrome (AIDS) after initiation of combination antiretroviral therapy between 1998 and 2012 in an 8-site US cohort study with death before AIDS as a competing risk. We estimate the risk standardized to the total study sample by combining inverse probability weights with the cumulative incidence function; estimates of precision are obtained by bootstrap. In 7,182 patients (83% male, 33% African American, median age of 38 years), we observed 6-year standardized AIDS risks of 16.75% among 1,143 injection drug users and 12.08% among 6,039 nonusers, yielding a standardized risk difference of 4.68 (95% confidence interval: 1.27, 8.08) and a standardized risk ratio of 1.39 (95% confidence interval: 1.12, 1.72). Results may be sensitive to the assumptions of exposure-version irrelevance, no measurement bias, and no unmeasured confounding. These limitations suggest that results be replicated with refined measurements of injection drug use. Nevertheless, estimating the standardized risk difference and ratio is straightforward, and injection drug use appears to increase the risk of AIDS. PMID:24966220

  18. INDUCTION OF DRUG RESISTANCE IN PLASMODIUM FALCIPARUM: AN INTERMITTENT DRUG EXPOSURE METHOD

    Directory of Open Access Journals (Sweden)

    M.Nateghpour

    1998-03-01

    Full Text Available The production of experimentally induced drug resistance in the laboratory provides valuable opportunities for investigators to study the nature and genetics of drug resistance mechanisms to a given agent, patterns of cross resistance and the mode of action of drugs. At the beginning the continuous drug exposure was chosen as a standard procedure to produce drug— resistant strains of P. falciparum,.but later on some other methods were also applied. An intermittent drug exposure method as a novel procedure has been introduced in this study. Intermittent exposure of chloroquine resistant Kl and chloroquine sensitive T9.96 strains of P. falciparum to halofantrine culminated in a relatively rapid reduction in sensitivity to the drug. The response of halofantrifle - resistnat K1HF and T9.96 strains and parent parasites to halofantrifle, inefloquine, quinine and chloroquine was determined. The results indicated that the effectiveness of halofantrine to K1HF and T9.96HF strains decreased 9 and 3 folds respectively, compared to the parent parasites. Cross -resistance occurred among halofantrine. mefloquine and quinine. Halofantrine resistance was associated with enhanced chloroquine sensitivity in the strain derived from chloroquine - resistant K1 strain, hut not in the strain derived from chloroquine - sensitive T9.96 parasites.

  19. Update on antifungal drug resistance mechanisms of Aspergillus fumigatus.

    Science.gov (United States)

    Chamilos, G; Kontoyiannis, D P

    2005-12-01

    Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis (IA) remains unacceptably high. Aspergillus fumigatus still accounts for the majority of cases of IA; however less susceptible to antifungals non-fumigatus aspergilli began to emerge. Antifungal drug resistance of Aspergillus might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, has brought resistance testing to the forefront of clinical mycology. In addition, molecular biology has started to shed light on the mechanisms of resistance of A. fumigatus to azoles and the echinocandins, while genome-based assays show promise for high-throughput screening for genotypic antifungal resistance. Several problems remain, however, in the study of this complex area. Large multicenter clinical studies--point prevalence or longitudinal--to capture the incidence and prevalence of antifungal resistance in A. fumigatus isolates are lacking. Correlation of in vitro susceptibility with clinical outcome and susceptibility breakpoints has not been established. In addition, the issue of cross-resistance between the newer triazoles is of concern. Furthermore, in vitro resistance testing for polyenes and echinocandins is difficult, and their mechanisms of resistance are largely unknown. This review examines challenges in the diagnosis, epidemiology, and mechanisms of antifungal drug resistance in A. fumigatus. PMID:16488654

  20. Drug resistance pattern among afb smear positive retreatment completed cases

    International Nuclear Information System (INIS)

    Worldwide, multidrug resistance (MDR TB) is a serious issue. It has increased over the last decade. Re-treatment completed sputum smear positive cases have much higher incidence of MDR- TB as compared to primary MDR - TB. Objective: To estimate the incidence of drug resistance pattern among AFB smear positive re-treatment completed cases. Study Design: Evidence based prospective study. Study Setting: Institute of Chest Medicine, Mayo Hospital Lahore, Tertiary care hospital affiliated with King Edward Medical University, Lahore, Pakistan. Methodology: A total 50 (Male 22, Female 28) pulmonary TB patients who had completed Re- treatment regimen in the past and are still sputum smear positive for acid fast Bacilli were included in the study. Three consecutive sputum specimens were collected at Aga Khan University collection center at Lahore. The specimen were sent to Aga Khan University Lab Karachi for AFB smear, culture and drug sensitivity both for essential and reserve drugs. Reports for AFB smear were received within a week, while culture and drug sensitivity' reports after 6 weeks. Reports data was analyzed for essential and reserve anti tuberculous drug sensitivity for mycobacterium tuberculosis. Results: Data Analysis revealed MDR TB in 31(62%) patients which include 11 males and 23 females. Individual drug resistance to essential drugs was INH - 62%, Rifampicin - 68%, Ethambutol - 24%, PZA - 25% and Streptomycin - 21 %. Poly drug resistance was determined in' 38% cases. Individual drug resistance to reserve drugs - kanamycin, Amikacin, ofloxacin, Ethionamide and PAS was 4%, 4%, 36%, 10% and 2% respectively. Conclusion: There is a very high proportion of MDR TB in sputum smear AFB positive retreatment cases. Suggestion: Comprehensive measures including DO- TS PLUS are needed to control MDR TB in Pakistan. (author)

  1. Modeling and predicting drug resistance rate and strength.

    Science.gov (United States)

    Fullybright, R; Dwivedi, A; Mallawaarachchi, I; Sinsin, B

    2016-08-01

    Drug resistance has been worsening in human infectious diseases medicine over the past several decades. Our ability to successfully control resistance depends to a large extent on our understanding of the features characterizing the process. Part of that understanding includes the rate at which new resistance has been emerging in pathogens. Along that line, resistance data covering 90 infectious diseases, 118 pathogens, and 337 molecules, from 1921 through 2007, are modeled using various statistical tools to generate regression models for the rate of new resistance emergence and for cumulative resistance build-up in pathogens. Thereafter, the strength of the association between the number of molecules put on the market and the number of resulting cases of resistance is statistically tested. Predictive models are presented for the rate at which new resistance has been emerging in infectious diseases medicine, along with predictive models for the rate of cumulative resistance build-up in the aggregate of 118 pathogens as well as in ten individual pathogens. The models are expressed as a function of time and/or as a function of the number of molecules put on the market by the pharmaceutical industry. It is found that molecules significantly induce resistance in pathogens and that new or cumulative drug resistance across infectious diseases medicine has been arising at exponential rates. PMID:27209288

  2. Supramolecular Antibiotic Switches: A Potential Strategy for Combating Drug Resistance.

    Science.gov (United States)

    Bai, Haotian; Lv, Fengting; Liu, Libing; Wang, Shu

    2016-08-01

    Bacterial infectious disease is a serious public health concern throughout the world. Pathogen drug resistance, arising from both rational use and abuse/misuse of germicides, complicates the situation. Aside from developing novel antibiotics and antimicrobial agents, molecular approaches have become another significant method to overcome the problem of pathogen drug resistance. Established supramolecular systems, the antibiotic properties of which can be switched "on" and "off" through host-guest interactions, show great potential in combating issues regarding antibiotic resistance in the long term, as indicated by several recent studies. In this Concept, recently developed strategies for antibacterial regulation are summarized and further directions for research into antibiotic switches are proposed. PMID:27312106

  3. Allele-specific real-time PCR testing for minor HIV-1 drug resistance mutations: assay preparation and application to reveal dynamic of mutations in vivo

    Institute of Scientific and Technical Information of China (English)

    GUO Dong-xing; LI Jing-yun; LI Han-ping; LI Lin; ZHUANG Dao-min; JIAO Li-yan; WANG Zheng; BAO Zuo-yi; LIU Si-yang; LIU Yong-jian

    2010-01-01

    Background It is very important for the clinical management to test for minor HIV-1 resistance mutations accurately and sensitively. The conventional genotypic assays of HIV drug resistance detection based on sequencing can only discriminate the mutations which present in more than 20%-30%. The aim of this study was to evaluate allele-specific real-time PCR (ASPCR) to detect the resistance-related mutations located at positions 103, 184 and 215.Methods We developed the allele-specific PCR assay, using the most common drug resistance mutations in Chinese AIDS patients, K103N, M184V/I, T215F/Y as a model system. The standards were constructed by cloning the wild-type and mutant DNA fragments into the T-vector. We designed specific primers to discriminate mutant templates in the real-time PCR using SYBR green as a fluorescence reporter. And then we evaluated the ASPCR assay and tested 140clinical samples using this method.Results The sensitivities of ASPCR assay were 0.04% for K103N, 0.30% for M1841, 0.40% for M184V, 0.03% for T215F and 0.02% for T215Y. The intra-assay and inter-assay coefficients of variation were less than 0.42. One hundred and forty plasma samples were tested by ASPCR and dynamic resistance curves of ten patients were obtained.Conclusions Drug resistance emerged half a year after the start of antiretroviral therapy. The mutation of T215Yemerged 1 to 1.5 years after starting treatment and then increased rapidly. The ASPCR assay we developed was a sensitive, accurate and rapid method to detect the minor HIV-1 variants and it can provide earlier and more drug-resistance information for HIV research and AIDS antiretroviral therapy.

  4. High frequency of antiviral drug resistance and non-b subtypes in HIV-1 patients failing antiviral therapy in Cuba

    Directory of Open Access Journals (Sweden)

    Vivian Kouri

    2014-11-01

    Full Text Available Introduction: Emergence of HIV-1 drug resistance may limit the sustained benefits of antiretroviral therapy (ART in settings with limited laboratory monitoring and drug options. The objective is to implement the surveillance of drug resistance and subtypes in HIV-1 patients failing ART in Cuba. Methods: This study compiled clinical and genotypic drug resistance data 588 ART-experienced HIV-1 patients attending a clinical center in Havana in 2009–2013. Drug resistance testing was performed as part of routine clinical care. Drug resistance mutations and levels were determined using Rega version 8.0.2. Results: Eighty-three percent received solely ART containing at least three drugs. Patients from 2009 to 2010 were longer treated (median: 4.9 vs 2.7 years and exposed to more ART regimens (median: 4 vs 2 regimens compared to patients from 2011–2013. Nucleoside reverse transcriptase inhibitor (NRTI, non-nucleoside RTI (NNRTI and PI mutations were present in 83.5, 77.4 and 52.0%. Full-class resistance (FCR to NRTI, NNRTI, PI and multidrug resistance (MDR were detected in 25.0, 33.7, 11.4 and 6.3%. FCR to NRTI, NNRTI, PI and MDR were present in 12.8, 28.7, 0 and 0% after first-line failure (164 patients and in 23.1, 34.6, 3.8 and 3.1% after second-line failure (130 patients. Subtype B (32.5%, BG recombinants (19.6% and CRF19_cpx (16.2% were the most prevalent genetic forms. Subtype distribution did not change significantly between 2009–2010 and 2011–2013, except for BG recombinants that increased from 12.2 to 21.3% (p=0.002. Conclusions: Our study found a high prevalence of drug resistance and supports the need for appropriate laboratory monitoring in clinical practice and access to drug options in case of virological failure.

  5. High frequency of antiviral drug resistance and non-b subtypes in HIV-1 patients failing antiviral therapy in Cuba

    Science.gov (United States)

    Kouri, Vivian; Alemán, Yoan; Pérez, Lissette; Pérez, Jorge; Fonseca, Carlos; Correa, Consuelo; Aragonés, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Vinken, Lore; Limia, Celia; Soto, Yudira; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2014-01-01

    Introduction Emergence of HIV-1 drug resistance may limit the sustained benefits of antiretroviral therapy (ART) in settings with limited laboratory monitoring and drug options. The objective is to implement the surveillance of drug resistance and subtypes in HIV-1 patients failing ART in Cuba. Methods This study compiled clinical and genotypic drug resistance data 588 ART-experienced HIV-1 patients attending a clinical center in Havana in 2009–2013. Drug resistance testing was performed as part of routine clinical care. Drug resistance mutations and levels were determined using Rega version 8.0.2. Results Eighty-three percent received solely ART containing at least three drugs. Patients from 2009 to 2010 were longer treated (median: 4.9 vs 2.7 years) and exposed to more ART regimens (median: 4 vs 2 regimens) compared to patients from 2011–2013. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside RTI (NNRTI) and PI mutations were present in 83.5, 77.4 and 52.0%. Full-class resistance (FCR) to NRTI, NNRTI, PI and multidrug resistance (MDR) were detected in 25.0, 33.7, 11.4 and 6.3%. FCR to NRTI, NNRTI, PI and MDR were present in 12.8, 28.7, 0 and 0% after first-line failure (164 patients) and in 23.1, 34.6, 3.8 and 3.1% after second-line failure (130 patients). Subtype B (32.5%), BG recombinants (19.6%) and CRF19_cpx (16.2%) were the most prevalent genetic forms. Subtype distribution did not change significantly between 2009–2010 and 2011–2013, except for BG recombinants that increased from 12.2 to 21.3% (p=0.002). Conclusions Our study found a high prevalence of drug resistance and supports the need for appropriate laboratory monitoring in clinical practice and access to drug options in case of virological failure. PMID:25397499

  6. The prevalence of drug resistance in patients with HIV/AIDS attending to Imam Khomeini Hospital in Tehran, Iran during 2008-2009: letter to editor

    Directory of Open Access Journals (Sweden)

    Hajabdulbaghy M

    2011-07-01

    Full Text Available "nThe combinations of antiretroviral (ARV drugs have proven effective in controlling the progression of AIDS, but these benefits can be compromised by drug resistance. Thus, drug-resistance testing has become an important tool in the management of HIV-infected individuals.1 Drug resistance develops when mutations in the HIV virus proteins occur due to amino acid substitutions.2 Drug resistance testing is done in two ways: phenotypic test and genotypic test.3 In the first method, virus proliferation is measured in the presence of different concentrations of the drugs. In the second, the genetic structure of viral genome sequences are investigated.4 Although, the first case of HIV infection in Iran was identified 23 years ago (1988, there is still no study published on its drug resistance. The main purpose of this study was to determine the prevalence of drug resistance mutations in patients with HIV/AIDS attending Imam Khomeini Hospital in Tehran. The secondary objectives of the study were to determine the frequency of drug resistance to specific drugs such as nucleoside reverse transcriptase inhibitors (NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs and protease inhibitors (PI. We collected plasma samples from 25 patients with HIV/AIDS and immunological failure. After the extraction of the viral RNA from plasma, genomic sequencing was performed. Finally, the data for determining drug resistance were analyzed by the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu software. Out of the 25 patients under study, 20 were male (80% and five were female (20%. Routes of HIV transmission were: 56% by needle sharing among injecting drug users (IDUs, 20% through sexual contact, 12% through blood transfusions and 12% by unknown routes. High-level drug resistance for ARV drugs included: 24% to NRTIs, 28% to NNRTIs and zero percent to PI drugs. In addition, 15 patients had been infected with genotype A and 10 patients with

  7. Determinants of immunological failure among clients on the first line treatment with highly active antiretroviral drugs in Dar es Salaam, Tanzania

    Institute of Scientific and Technical Information of China (English)

    Anthony Kapesa; Daniel Magesa; Alexander William; John Kaswija; Jeremiah Seni; Cyprian Makwaya

    2014-01-01

    Objective:To determine socio-cultural, demographic and highly active antiretroviral therapy (HAART) program-related factors associated with immunological failure (IF) among clients on HAART in Dar es Salaam care and treatment clinics. Methods:A 1:2 matched case control study was done from February to April 2012 in HIV/AIDS care and treatment clinics in Dar es Salaam. Data were collected from National AIDS Control Program (NACP) data base and patient’s charts to obtain 60 sets of study participants who were interviewed using the structured questionnaire. Data analysis was done by using EPI Info 3.5.1 version. Results:The mean age of all study participants was (42.00±9.07) years with 35% (63) being males. History of poor antiretroviral therapy (ART) adherence due to exposure to drug holiday with loss to follow up (OR=11.96;95%CI=2.07-69.26), history of changing care and treatment clinics (OR=12.07;95%CI=2.10-69.27) and the lack of treatment supporter (OR=23.26;95%CI=1.85-291.66) were found to be strongly associated with the occurrence of first line HAART-IF. Conclusions:HAART-IF in Dar es Salaam is associated with ART programmatic and patients’ centered challenges. There is a need to review the approaches on ensuring ART adherence, clients follow up and referral system so as to reduce the incidence of IF as we move to a more decentralized peripheral drug picks clinical initiative.

  8. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes.

    Science.gov (United States)

    Rudramurthy, Gudepalya Renukaiah; Swamy, Mallappa Kumara; Sinniah, Uma Rani; Ghasemzadeh, Ali

    2016-01-01

    Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals). Antimicrobials are considered "miracle drugs" and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs) depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future. PMID:27355939

  9. Anti tuberculosis drug resistance in west of Iran

    Directory of Open Access Journals (Sweden)

    Parviz Mohajeri

    2014-01-01

    Full Text Available Background and Objective: Mycobacterium tuberculosis has developed resistance to antituberculosis drugs and becoming a major and alarming public health problem in worldwide. This study was aimed to determine antituberculosis drug resistance rate and to identify multidrug resistant tuberculosis (MDR-TB in West of Iran. Materials and Methods: Of 130 samples were included between December 2011 and July 2012 in the study from that 112 cases were M. tuberculosis. The proportional method was carried out according to the Clinical and Laboratory Standards Institute on Lowenstein-Jensen against isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, para aminosalicylic acid, ethionamide, cycloserine (CYC. The microdilution method was carried out using 7H9 broth with 96 well-plates. Results: From 112 isolates, resistance was observed to isoniazid 18 (16.07%, rifampicin 16 (14.28%, streptomycin 25 (22.32%, ethambutol 15 (13.39%, pyrazinamide 27 (24.10%, para aminosalicylic acid 19 (16.96%, CYC 4 (3.57%, and ethionamide 14 (12.5% cases. 16 isolates were MDR. Conclusion: The high prevalence of MDR-TB in our study is assumed to be due to recent transmission of drug-resistant strains. Overall, the rate of drug resistance in our study was high, which is in line with findings of some high-burden countries. Hence that early case detection, rapid drug susceptibility testing, and effective anti-TB treatment is necessary.

  10. Analysis of Antiretrovirals in Single Hair Strands for Evaluation of Drug Adherence with Infrared-Matrix-Assisted Laser Desorption Electrospray Ionization Mass Spectrometry Imaging.

    Science.gov (United States)

    Rosen, Elias P; Thompson, Corbin G; Bokhart, Mark T; Prince, Heather M A; Sykes, Craig; Muddiman, David C; Kashuba, Angela D M

    2016-01-19

    Adherence to a drug regimen can be a strong predictor of health outcomes, and validated measures of adherence are necessary at all stages of therapy from drug development to prescription. Many of the existing metrics of drug adherence (e.g., self-report, pill counts, blood monitoring) have limitations, and analysis of hair strands has recently emerged as an objective alternative. Traditional methods of hair analysis based on LC-MS/MS (segmenting strands at ≥1 cm length) are not capable of preserving a temporal record of drug intake at higher resolution than approximately 1 month. Here, we evaluated the detectability of HIV antiretrovirals (ARVs) in hair from a range of drug classes using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) with 100 μm resolution. Infrared laser desorption of hair strands was shown to penetrate into the strand cortex, allowing direct measurement by MSI without analyte extraction. Using optimized desorption conditions, a linear correlation between IR-MALDESI ion abundance and LC-MS/MS response was observed for six common ARVs with estimated limits of detection less than or equal to 1.6 ng/mg hair. The distribution of efavirenz (EFV) was then monitored in a series of hair strands collected from HIV infected, virologically suppressed patients. Because of the role hair melanin plays in accumulation of basic drugs (like most ARVs), an MSI method to quantify the melanin biomarker pyrrole-2,3,5-tricarboxylic acid (PTCA) was evaluated as a means of normalizing drug response between patients to develop broadly applicable adherence criteria.

  11. Analysis of Antiretrovirals in Single Hair Strands for Evaluation of Drug Adherence with Infrared-Matrix-Assisted Laser Desorption Electrospray Ionization Mass Spectrometry Imaging.

    Science.gov (United States)

    Rosen, Elias P; Thompson, Corbin G; Bokhart, Mark T; Prince, Heather M A; Sykes, Craig; Muddiman, David C; Kashuba, Angela D M

    2016-01-19

    Adherence to a drug regimen can be a strong predictor of health outcomes, and validated measures of adherence are necessary at all stages of therapy from drug development to prescription. Many of the existing metrics of drug adherence (e.g., self-report, pill counts, blood monitoring) have limitations, and analysis of hair strands has recently emerged as an objective alternative. Traditional methods of hair analysis based on LC-MS/MS (segmenting strands at ≥1 cm length) are not capable of preserving a temporal record of drug intake at higher resolution than approximately 1 month. Here, we evaluated the detectability of HIV antiretrovirals (ARVs) in hair from a range of drug classes using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) with 100 μm resolution. Infrared laser desorption of hair strands was shown to penetrate into the strand cortex, allowing direct measurement by MSI without analyte extraction. Using optimized desorption conditions, a linear correlation between IR-MALDESI ion abundance and LC-MS/MS response was observed for six common ARVs with estimated limits of detection less than or equal to 1.6 ng/mg hair. The distribution of efavirenz (EFV) was then monitored in a series of hair strands collected from HIV infected, virologically suppressed patients. Because of the role hair melanin plays in accumulation of basic drugs (like most ARVs), an MSI method to quantify the melanin biomarker pyrrole-2,3,5-tricarboxylic acid (PTCA) was evaluated as a means of normalizing drug response between patients to develop broadly applicable adherence criteria. PMID:26688545

  12. Challenges of drug resistance in the management of pancreatic cancer.

    LENUS (Irish Health Repository)

    Sheikh, Rizwan

    2012-02-01

    The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and\\/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

  13. Epidemiological Surveillance of HIV-1 Transmitted Drug Resistance in Spain in 2004-2012: Relevance of Transmission Clusters in the Propagation of Resistance Mutations.

    Directory of Open Access Journals (Sweden)

    Yolanda Vega

    Full Text Available Our objectives were to carry out an epidemiological surveillance study on transmitted drug resistance (TDR among individuals newly diagnosed of HIV-1 infection during a nine year period in Spain and to assess the role of transmission clusters (TC in the propagation of resistant strains. An overall of 1614 newly diagnosed individuals were included in the study from January 2004 through December 2012. Individuals come from two different Spanish regions: Galicia and the Basque Country. Resistance mutations to reverse transcriptase inhibitors (RTI and protease inhibitors (PI were analyzed according to mutations included in the surveillance drug-resistance mutations list updated in 2009. TC were defined as those comprising viruses from five or more individuals whose sequences clustered in maximum likelihood phylogenetic trees with a bootstrap value ≥90%. The overall prevalence of TDR to any drug was 9.9%: 4.9% to nucleoside RTIs (NRTIs, 3.6% to non-nucleoside RTIs (NNRTIs, and 2.7% to PIs. A significant decrease of TDR to NRTIs over time was observed [from 10% in 2004 to 2% in 2012 (p=0.01]. Sixty eight (42.2% of 161 sequences with TDR were included in 25 TC composed of 5 or more individuals. Of them, 9 clusters harbored TDR associated with high level resistance to antiretroviral drugs. T215D revertant mutation was transmitted in a large cluster comprising 25 individuals. The impact of epidemiological networks on TDR frequency may explain its persistence in newly diagnosed individuals. The knowledge of the populations involved in TC would facilitate the design of prevention programs and public health interventions.

  14. Long non-coding RNAs in cancer drug resistance development.

    Science.gov (United States)

    Majidinia, Maryam; Yousefi, Bahman

    2016-09-01

    The presence or emergence of chemoresistance in tumor cells is a major burden in cancer therapy. While drug resistance is a multifactorial phenomenon arising from altered membrane transport of drugs, altered drug metabolism, altered DNA repair, reduced apoptosis rate and alterations of drug metabolism, it can also be linked to genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) have important regulatory roles in many aspects of genome function including gene transcription, splicing, and epigenetics as well as biological processes involved in cell cycle, cell differentiation, development, and pluripotency. As such, it may not be surprising that some lncRNAs have been recently linked to carcinogenesis and drug resistance/sensitivity. Research is accelerating to decipher the exact molecular mechanism of lncRNA-regulated drug resistance and its therapeutic implications. In this article, we will review the structure, biogenesis, and mode of action of lncRNAs. Then, the involvement of lncRNAs in drug resistance will be discussed in detail. PMID:27427176

  15. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  16. Hsp90 governs dispersion and drug resistance of fungal biofilms.

    Directory of Open Access Journals (Sweden)

    Nicole Robbins

    2011-09-01

    Full Text Available Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving

  17. Impact of therapeutic drug monitoring of antiretroviral drugs in routine clinical management of patients infected with human immunodeficiency virus and related health care costs: a real-life study in a large cohort of patients

    Directory of Open Access Journals (Sweden)

    Perrone V

    2014-07-01

    Full Text Available Valentina Perrone,1 Dario Cattaneo,1 Sonia Radice,1 Diego Sangiorgi,2 Augusto B Federici,3 Maria Rita Gismondo,4 Massimo Medaglia,5 Valeria Micheli,4 Stefania Vimercati,5 Enza Pallone,6 Luca Degli Esposti,2 Emilio Clementi1,71Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, L Sacco University Hospital, University of Milan, Milan, 2CliCon Srl, Health, Economics and Outcomes Research, Ravenna, 3Hematology and Transfusion Medicine, Department of Clinical Sciences and Community Health, 4Clinical Microbiology Virology and Diagnosis of Bioemergency, 5Pharmaceutical Department, 6Quality Clinical Risk and Accreditation Unit, L Sacco University Hospital, Milan, 7Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, ItalyBackground: Highly active antiretroviral therapy (HAART has reduced morbidity and mortality in patients infected with human immunodeficiency virus (HIV. Studies have documented high interindividual variability in the pharmacokinetics of antiretroviral drugs, which may impair the success of HAART if not managed properly. Therapeutic drug monitoring (TDM is a useful diagnostic tool that helps clinicians to optimize drug doses so that drug concentrations associated with the highest therapeutic efficacy are obtained with a reduced risk of concentration-dependent adverse effects. The aim of this study was to assess whether use of TDM improves clinical outcomes and cost of illness.Methods: A retrospective cohort study was conducted at L Sacco University Hospital in Milan, Italy, in HIV-infected patients aged ≥18 years with at least one prescription of antiretroviral drugs for which TDM was applied. The inclusion period was from January 2010 to December 2011, with a follow-up period of up to 12 months. Laboratory and administrative databases were analyzed and matched with each other.Results: The cohort consisted of 5,347 patients (3,861 males and 1,486 females of mean age 43.9±12.5 years. We found

  18. Dynamics of immune response and drug resistance in malaria infection

    Directory of Open Access Journals (Sweden)

    Gurarie David

    2006-10-01

    Full Text Available Abstract Background Malaria parasites that concurrently infect a host compete on the basis of their intrinsic growth rates and by stimulating cross-reactive immune responses that inhibit each others' growth. If the phenotypes also show different drug sensitivities ('sensitive' vs. 'resistant' strains, drug treatment can change their joint dynamics and the long-term outcome of the infection: most obviously, persistent drug pressure can permit the more resistant, but otherwise competitively-inferior, strains to dominate. Methods Here a mathematical model is developed to analyse how these and more subtle effects of antimalarial drug use are modulated by immune response, repeated re-inoculation of parasites, drug pharmacokinetic parameters, dose and treatment frequency. Results The model quantifies possible effects of single and multiple (periodic treatment on the outcome of parasite competition. In the absence of further inoculation, the dosage and/or treatment frequency required for complete clearance can be estimated. With persistent superinfection, time-average parasite densities can be derived in terms of the basic immune-regulating parameters, the drug efficacy and treatment regimen. Conclusion The functional relations in the model are applicable to a wide range of conditions and transmission environments, allowing predictions to be made on both the individual and the community levels, and, in particular, transitions from drug-sensitive to drug-resistant parasite dominance to be projected on both levels.

  19. HIV resistance testing and detected drug resistance in Europe

    DEFF Research Database (Denmark)

    Schultze, Anna; Phillips, Andrew N; Paredes, Roger;

    2015-01-01

    calculated using logistic regression with generalized estimating equations. RESULTS: Compared to 74.2% of ART-experienced individuals in 1997, only 5.1% showed evidence of virological failure in 2012. The odds of resistance testing declined after 2004 (global P 

  20. The action of Pseudomonas aeruginosa biofilms in intrinsic drug resistance

    Institute of Scientific and Technical Information of China (English)

    XIE Yi; JIA Wen-xiang; ZENG Wei; YANG Wei-qing; CHENG Xi; LI Xue-ru; WANG Lan-lan; KANG Mei; ZHANG Zai-rong

    2005-01-01

    Background There is a growing interest in studying the relationship between intrinsic resistance and biofilms resistance to drugs. However, the relationship still remains unclear in the macroscopic bacterial growth. Our study is to illuminate the change of bacterial drug resistance of gyrA mutant and active efflux pump during the development of Pseudomonas aeruginosa (P. aeruginosa) biofilms. Methods The strains of type Ⅱ topoisomerase gene mutant (gyrA mutant) and multidrug resistance (MDR) efflux pump were clinical isolates and detected by polymerase chain reaction (PCR). The process of bacterial biofilms development was observed by scanning electron microscope. Triparental mating experiments were performed to transfer report gene of green fluorescent protein (GFP) into P. aeruginosa biofilms strains and followed by analysis of bacterial survival rate between intrinsic resistance and biofilms resistance.Results The fluorescent strains with pGFPuv could develop mature biofilms on Teflon surface. Before a period of 72 hours, the survival rate of biofilms bacteria and intrinsic resistance strains in ciprofloxacin solution was significantly different (P0.05). The carbonyl cyanide m-chlorophenylhydrazone and azithromycin could significantly reduce the drug resistance of biofilm strains and efflux pump strains.Conclusions In the development of P. aeruginosa biofilms, the strains of gyrA mutation and MDR efflux could be conferred with new level of drug resistance. When co-cultured mutated strains with biofilm strains, biofilms may play a major role in bacterial resistance. But after 72 hours incubation (a mature biofilms had been developed), there was no clearly difference between the number of mutant strains and biofilm strains.

  1. Efflux Pump-mediated Drug Resistance in Burkholderia

    Directory of Open Access Journals (Sweden)

    Nicole L Podnecky

    2015-04-01

    Full Text Available Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in B. cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance.

  2. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    1997-01-01

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  3. Potential risk for drug resistance globalization at the Hajj.

    Science.gov (United States)

    Al-Tawfiq, J A; Memish, Z A

    2015-02-01

    Antibiotics were once considered the miracle cure for infectious diseases. The tragedy would be the loss of these miracles as we witness increased antibiotic resistance throughout the world. One of the concerns during mass gatherings is the transmission of antibiotic resistance. Hajj is one of the most common recurring mass gatherings, attracting millions of people from around the world. The transmission of drug-resistant organisms during the Hajj is not well described. In the current review, we summarize the available literature on the transmission and acquisition of antibiotic resistance during the Hajj and present possible solutions.

  4. TWO OPTIMAL CONTROL PROBLEMS IN CANCER CHEMOTHERAPY WITH DRUG RESISTANCE

    Directory of Open Access Journals (Sweden)

    Werner Krabs

    2012-01-01

    Full Text Available We investigate two well-known basic optimal control problems forchemotherapeutic cancer treatment modified by introducing a timedependent “resistance factor”. This factor should be responsible for the effect of the drug resistance of tumor cells on the dynamical growth for the tumor. Both optimal control problems have common pointwise but different integral constraints on the control. We show that in both models the usually practised bang-bang control is optimal if the resistance is sufficiently strong. Further, we discuss different optimal strategies in both models for general resistance.

  5. Declining trend in transmitted drug resistance detected in a prospective cohort study of acute HIV infection in Bangkok, Thailand

    Science.gov (United States)

    Colby, Donn J; Crowell, Trevor A; Sirivichayakul, Sunee; Pinyakorn, Suteeraporn; Kroon, Eugene; Benjapornpong, Khunthalee; Intasan, Jintana; Trichavaroj, Rapee; Tovanabutra, Sodsai; Robb, Merlin; Phanuphak, Praphan; Ananworanich, Jintanat; Phanuphak, Nittaya

    2016-01-01

    Introduction As availability of antiretroviral therapy expands in developing countries, the risk for transmission of drug-resistant HIV also increases. Patients with acute HIV infection (AHI) provide an opportunity for real-time monitoring of transmitted drug resistance (TDR). SEARCH 010/RV 254 study is a prospective, longitudinal study of AHI. This analysis was performed to characterize changes in TDR over time in persons enrolled in the AHI cohort. Methods Genotype testing for TDR mutations was performed on 229 subjects enrolled from 2009 to 2014. Results The cohort was predominantly male (95%) and men who have sex with men (92%). TDR prevalence was 7.0%, declining from 12.5% in 2009–2010 to 4.8% in 2013–2014 (p=0.08). By drug class, resistance prevalence was 3.6% for proteases inhibitors, 2.6% for nucleoside/nucleotide reverse transcriptase inhibitors and 2.2% for non-nucleoside reverse transcriptase inhibitors. The greatest decline in prevalence was seen in the non-nucleoside reverses transcriptase inhibitors, from 9.4% in 2009–2010 to 0.7% in 2013–2014 (p=0.005). Conclusions TDR appears to be declining among individuals with AHI in Bangkok and in 2013 to 2014 met the World Health Organization definition for low prevalence. Continued surveillance is necessary to determine if this trend persists. PMID:27802846

  6. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study

    NARCIS (Netherlands)

    Nieuwkerk, PT; Sprangers, MAG; Burger, DM; Hoetelmans, RMW; Hugen, PWH; Danner, SA; van der Ende, Marchina E.; Schneider, MME; Schrey, G; Meenhorst, PL; Sprenger, HG; Kauffmann, RH; Jambroes, M; Chesney, MA; de Wolf, F; Lange, JMA

    2001-01-01

    Background: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. Methods: Patients re

  7. Drug Repurposing Identifies Inhibitors of Oseltamivir-Resistant Influenza Viruses.

    Science.gov (United States)

    Bao, Ju; Marathe, Bindumadhav; Govorkova, Elena A; Zheng, Jie J

    2016-03-01

    The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti-influenza drug. However, oseltamivir-resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir-resistant, alternative therapy options are needed. Herein, we show that a structure-based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir-resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild-type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir-resistance mutation itself caused susceptibility to these drugs. PMID:26833677

  8. Antiretrovirals for developing world.

    Science.gov (United States)

    Adler, M W

    1998-01-24

    The most recent UNAIDS figures indicate that approximately 30 million people are infected with HIV worldwide, 5.8 million of whom were newly infected during 1997. At the 10th International Conference on AIDS and Sexually Transmitted Diseases in Africa, the President and Secretary of Health of France called upon developed countries to establish a Therapeutic Assistance Fund to make antiretrovirals available to people with HIV/AIDS in sub-Saharan Africa. While the annual per capita health budget in most African countries is less than US$10, triple antiretroviral therapy against AIDS in the developed world costs $12,000-14,000 per patient per year. Calculations based upon a lower per patient cost of $7000, and treating all 1.4 million African AIDS cases, would cost US$10 billion per year for drugs alone, more than 30 times the amount currently spent annually by international donors for AIDS programs in the entire developing world. Basic infrastructural requirements would have to be met were antiretrovirals made widely available, ranging from HIV screening and counseling to the provision of clean water with which to consume the required 20-30 tablets per day. High program costs will challenge long-term sustainability. Universal access to care and treatment for HIV infection and AIDS is not a reality in the developed world, let alone feasible in developing countries. Given the competing health care priorities in developing countries, the high costs of antiretroviral agents, poor infrastructure, and inability to sustain such a program, the French initiative is ill-advised and foolish public health practice.

  9. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes

    Directory of Open Access Journals (Sweden)

    Gudepalya Renukaiah Rudramurthy

    2016-06-01

    Full Text Available Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals. Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future.

  10. Extensively Drug-Resistant Tuberculosis: Principles of Resistance, Diagnosis, and Management.

    Science.gov (United States)

    Wilson, John W; Tsukayama, Dean T

    2016-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed.

  11. Efeito das drogas anti-retrovirais sobre as taxas de fertilidade de ratas Wistar Effects of antiretroviral drugs on fertility of Wistar rats

    Directory of Open Access Journals (Sweden)

    Ernesto Antonio Figueiró Filho

    2002-12-01

    írus da imunodeficiência humana.PURPOSE: to evaluate experimentally the effects of antiretroviral drugs used alone and in association upon the fertility of pregnant Wistar rats and the perinatal effects on the offspring. METHODS: adult female pregnant Wistar rats weighing 200-230 g were used. The antiretroviral drugs zidovudine (AZT, lamivudine (3TC and nelfinavir (NFV were used alone and in association at daily doses of ten times the dose normally used in pregnant women, proportionally to the animal's body weight. Seven groups were studied, including the control one. The experiment started on day 0 and the pregnant animals were sacrificed on day 21. The alive and dead fetuses, the total implantation sites and the total numbers of corporea lutea were used to calculate the fertility values. The statistical analysis was performed by Student's t test and by the Mann-Whitney test. RESULTS: there were no significant statistical differences regarding preimplantation loss and implantation efficiency values of the rats treated with isolated and associated antiretroviral drugs. There was a significant increase in the postimplantation loss values (control group: 7.6%; drug groups variation: 20.2-26.7%, a decrease in the fetal viability values (control group: 92.4%, drug groups variation: 73.3-79.8%, and a decreasing number of fetuses per animal (control group: 14.7; drug groups variation: 11.1-12.7. There was a significant weight reduction of the female rats and of the offspring of animals treated with 3TC, AZT + 3TC and AZT + 3TC + NFV. CONCLUSION: with the administration of high antiretroviral doses, important fertility effects could be observed, which showed that less histotoxic antiretroviral drugs must be studied in order to warrant the safety of using these medicines in pregnant HIV-1 - infected women.

  12. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  13. Evolution of drug resistance in HIV infected patients remaining on a virologically failing cART regimen

    DEFF Research Database (Denmark)

    Cozzi-Lepri, A; Phillips, AN; Ruiz, L;

    2007-01-01

    OBJECTIVE: To estimate the extent of drug resistance accumulation in patients kept on a virologically failing regimen and its determinants in the clinical setting. DESIGN: The study focused on 110 patients of EuroSIDA on an unchanged regimen who had two genotypic tests performed at two time points...... January 2006. Patients were grouped according to the number of active drugs in the failing regimen at t0 (GSS_f-t0). RESULTS: At t0, patients had been on the failing combination antiretroviral therapy (cART) for a median of 11 months (range, 6-50 months). Even patients with extensive resistance...... to the failing regimen were still receiving benefit from treatment. An overall 6-monthly increase of 1.96 (SD, 2.23) International Aids Society-mutations and an average loss of 1.25 (SD, 1.81) active drugs were estimated. In comparison with patients with GSS_f-t0 = 0, the number of active drugs lost was -1...

  14. Molecular and biochemical mechanisms of drug resistance in fungi.

    Science.gov (United States)

    Yamaguchi, H

    1999-01-01

    This paper reviews the current status of our understanding of resistance mechanisms of three major classes of antifungal drugs for systemic use, amphotericin B (AMPH), flucytosine (5-FC) and several azole antifungals, in particular fluconazole (FLCZ), at the molecular and cellular levels. Although the number of reports of AMPH- or 5-FC-resistant fungal species and strains is limited, several mechanisms of resistance have been described. AMPH-resistant Candida have a marked decrease in ergosterol content compared with AMPH-susceptible control isolates. A lesion in the UMP-pyrophosphorylase is the most frequent determinant of 5-FC resistance in C. albicans. Recently resistance of C. albicans to azoles has become an increasing problem. Extensive biochemical studies have highlighted a significant diversity in mechanisms conferring resistance to FLCZ and other azoles, which include alterations in sterol biosynthesis, target site, uptake and efflux. Among them, the most important mechanism clinically is reduced access of the drug to the intracellular P450 14 DM target, probably because of the action of a multidrug resistance efflux pump, and overproduction of that target. However, other possible resistance mechanisms for azoles remain to be identified.

  15. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study.

    Science.gov (United States)

    Kovari, Helen; Sabin, Caroline A; Ledergerber, Bruno; Ryom, Lene; Reiss, Peter; Law, Matthew; Pradier, Christian; Dabis, Francois; d'Arminio Monforte, Antonella; Smith, Colette; de Wit, Stephane; Kirk, Ole; Lundgren, Jens D; Weber, Rainer

    2016-01-01

    Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (2 years RR = 1.26, 95% CI, 1.13-1.41); stavudine (2 years RR = 1.17, 95% CI, 1.03-1.32), and tenofovir disoproxil fumarate (2 years RR = 1.18, 95% CI, 1.05-1.32), but only short-term exposure to nevirapine (abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions.  Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated. PMID:26925429

  16. Drug resistance mechanisms of fungal biofilms

    OpenAIRE

    Seneviratne, CJ; Samaranayake, LP

    2011-01-01

    Fungi are ubiquitous in nature and exist in soil, water, plants, and in animals and humans. Similar to bacteria, fungi also form confluent biofilms either singly (mono-species) or with other microbial species (mixed-species). Fungal biofilms are known to be highly resistant to the adverse environmental conditions including antimicrobials and biocide compared to its planktonic (free-floating) counterparts. Although bacterial biofilms have been studied in detail, relatively little is known of f...

  17. Drugs that target pathogen public goods are robust against evolved drug resistance.

    Science.gov (United States)

    Pepper, John W

    2012-11-01

    Pathogen drug resistance is a central problem in medicine and public health. It arises through somatic evolution, by mutation and selection among pathogen cells within a host. Here, we examine the hypothesis that evolution of drug resistance could be reduced by developing drugs that target the secreted metabolites produced by pathogen cells instead of directly targeting the cells themselves. Using an agent-based computational model of an evolving population of pathogen cells, we test this hypothesis and find support for it. We also use our model to explain this effect within the framework of standard evolutionary theory. We find that in our model, the drugs most robust against evolved drug resistance are those that target the most widely shared external products, or 'public goods', of pathogen cells. We also show that these drugs exert a weak selective pressure for resistance because they create only a weak correlation between drug resistance and cell fitness. The same principles apply to design of vaccines that are robust against vaccine escape. Because our theoretical results have crucial practical implications, they should be tested by empirical experiments.

  18. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

    Directory of Open Access Journals (Sweden)

    Andrew S Bell

    Full Text Available The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

  19. New strategies against drug resistance to herpes simplex virus

    Institute of Scientific and Technical Information of China (English)

    Yu-Chen Jiang; Hui Feng; Yu-Chun Lin; Xiu-Rong Guo

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV.

  20. HIV Drug-resistant Strains as Epidemiologic Sentinels

    Science.gov (United States)

    Grant, Robert M.; Porco, Travis C.; Getz, Wayne M.

    2006-01-01

    Observed declines in drug resistance to nucleoside reverse transcriptase inhibitors among persons recently infected with HIV-1 in monitored subpopulations can be interpreted as a positive sign and lead public health officials to decrease efforts towards HIV prevention. By means of a mathematical model, we identified 3 processes that can account for the observed decline: increase in high-risk behavior, decrease in proportion of acutely infected persons whose conditions are treated, and change in treatment efficacy. These processes, singly or in combination, can lead to increases or decreases in disease and drug-resistance prevalence in the general population. We discuss the most appropriate public health response under each scenario and emphasize how further data collection and analyses are required to more reliably evaluate the observed time trends and the relative importance of forces shaping the epidemic. Our study highlights how drug resistance markers can be used as epidemiologic sentinels to devise public health solutions. PMID:16494741

  1. New strategies against drug resistance to herpes simplex virus

    Science.gov (United States)

    Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

  2. Antimicrobial drug resistance ofStaphylococcus aureus in dairy products

    Institute of Scientific and Technical Information of China (English)

    Sasidharan S; Prema B; Yoga Latha L

    2011-01-01

    Objective:To evaluate the prevalence of multidrug resistantStaphylococcus aureus(S. aureus) in dairy products.Methods:Isolation and identification ofS. aureus were performed in3 dairy-based food products. The isolates were tested for their susceptibility to5 different common antimicrobial drugs.Results:Of50 samples examined,5 (10%) were contaminated with S. aureus. Subsequently, the5 isolates were subjected to antimicrobial resistance pattern using five antibiotic discs (methicillin, vancomycin, kanamycin, chloramphenicol and tetracycline). Sample 29 showed resistance to methicillin and vancomycin. Sample18 showed intermediate response to tetracycline. The other samples were susceptible to all the antibiotics tested.Conclusions:The results provide preliminary data on sources of food contamination which may act as vehicles for the transmission of antimicrobial-resistantStaphylococcus.Therefore, it enables us to develop preventive strategies to avoid the emergence of new strains of resistantS. aureus.

  3. Multidrug resistance in oncology and beyond : from imaging of drug efflux pumps to cellular drug targets

    NARCIS (Netherlands)

    Nagengast, Wouter B; Oude Munnink, Thijs H; Dijkers, Eli; Hospers, Geesiena; Brouwers, Adrienne H; Schröder, Carolien P; Lub-de Hooge, Marjolijn; de Vries, Elisabeth G E

    2010-01-01

    Resistance of tumor cells to several structurally unrelated classes of natural products, including anthracyclines, taxanes, and epipodophyllotoxines, is often referred as multidrug resistance (MDR). This is associated with ATP-binding cassette transporters, which function as drug efflux pumps such a

  4. Prediction of resistance development against drug combinations by collateral responses to component drugs

    DEFF Research Database (Denmark)

    Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika;

    2014-01-01

    to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing...

  5. HIV behind bars: human immunodeficiency virus cluster analysis and drug resistance in a reference correctional unit from southern Brazil.

    Directory of Open Access Journals (Sweden)

    Isabel M Prellwitz

    Full Text Available People deprived of liberty in prisons are at higher risk of infection by the human immunodeficiency virus (HIV due to their increased exposure through intravenous drug use, unprotected sexual activity, tattooing in prison and blood exposure in fights and rebellions. Yet, the contribution of intramural HIV transmission to the epidemic is scarcely known, especially in low- and middle-income settings. In this study, we surveyed 1,667 inmates incarcerated at Presídio Central de Porto Alegre, located in southern Brazil, for HIV infection and molecular characterization. The HIV seroprevalence was 6.6% (110/1,667. Further analyses were carried out on 40 HIV-seropositive inmates to assess HIV transmission clusters and drug resistance within the facility with the use of molecular and phylogenetic techniques. The molecular epidemiology of HIV-1 subtypes observed was similar to the one reported for the general population in southern Brazil, with the predominance of HIV-1 subtypes C, B, CRF31_BC and unique BC recombinants. In particular, the high rate (24% of URF_BC found here may reflect multiple exposures of the population investigated to HIV infection. We failed to find HIV-infected inmates sharing transmission clusters with each other. Importantly, the analysis of HIV-1 pol genomic fragments evidenced high rates of HIV primary and secondary (acquired drug resistance and an alarming proportion of virologic failure among patients under treatment, unveiling suboptimal access to antiretroviral therapy (ARV, low ARV adherence and dissemination of drug resistant HIV strains in primary infections. Our results call for immediate actions of public authority to implement preventive measures, serological screening and, for HIV-seropositive subjects, clinical and treatment follow-up in order to control HIV infection and limit the spread of drug resistance strains in Brazilian prisons.

  6. Reverse Transcriptase drug resistance mutations in HIV-1 Subtype C infected patients on ART in Karonga District, Malawi

    LENUS (Irish Health Repository)

    Bansode, Vijay B

    2011-10-13

    Abstract Background Drug resistance testing before initiation of, or during, antiretroviral therapy (ART) is not routinely performed in resource-limited settings. High levels of viral resistance circulating within the population will have impact on treatment programs by increasing the chances of transmission of resistant strains and treatment failure. Here, we investigate Drug Resistance Mutations (DRMs) from blood samples obtained at regular intervals from patients on ART (Baseline-22 months) in Karonga District, Malawi. One hundred and forty nine reverse transcriptase (RT) consensus sequences were obtained via nested PCR and automated sequencing from blood samples collected at three-month intervals from 75 HIV-1 subtype C infected individuals in the ART programme. Results Fifteen individuals showed DRMs, and in ten individuals DRMs were seen from baseline samples (reported to be ART naïve). Three individuals in whom no DRMs were observed at baseline showed the emergence of DRMs during ART exposure. Four individuals who did show DRMs at baseline showed additional DRMs at subsequent time points, while two individuals showed evidence of DRMs at baseline and either no DRMs, or different DRMs, at later timepoints. Three individuals had immune failure but none appeared to be failing clinically. Conclusion Despite the presence of DRMs to drugs included in the current regimen in some individuals, and immune failure in three, no signs of clinical failure were seen during this study. This cohort will continue to be monitored as part of the Karonga Prevention Study so that the long-term impact of these mutations can be assessed. Documenting proviral population is also important in monitoring the emergence of drug resistance as selective pressure provided by ART compromises the current plasma population, archived viruses can re-emerge

  7. Drug Resistance and Cancer Stem Cells

    OpenAIRE

    Fonseca, João Pedro Couto

    2012-01-01

    O cancro do pulmão é a principal causa de morte por cancro a nível mundial. Apesar do crescente conhecimento sobre os mecanismos subjacentes ao processo tumorigénico não se tem observado alteração significativa na sobrevivência dos pacientes. É, por isso, urgente encontrar novas estratégias terapêuticas que visem superar a resistência, tanto intrínseca como extrínseca, observada com a quimioterapia corrente. Os tumores são caracterizados pela sua heterogeneidade celular, devido à coexistên...

  8. A new antihypertensive drug ameliorates insulin resistance

    Institute of Scientific and Technical Information of China (English)

    Yan-xia LIU

    2012-01-01

    Insulin resistance (IR)is defined as decreased sensitivity and/or responsiveness to insulin that promote glucose disposal.A growing body of clinical and epidemiologic evidence indicates that essential hypertension and IR often coexist[1].Approximately 50 percent of patients with hypertension can be considered to have IR and hyperinsulinemia[1].This inextricable linkage between hypertension and IR has been identified to increase the prevalence of cardiovascular disease (CVD)and new onset of type Ⅱ diabetes that is the major cause of morbidity and mortality in this clinical syndrome[2].However,the driving force linking IR and hypertension remains to be fully elucidated.

  9. Antiviral Resistance and Correlates of Virologic Failure in the first Cohort of HIV-Infected Children Gaining Access to Structured Antiretroviral Therapy in Lima, Peru: A Cross-Sectional Analysis

    Directory of Open Access Journals (Sweden)

    Rath Barbara A

    2013-01-01

    Full Text Available Abstract Background The impact of extended use of ART in developing countries has been enormous. A thorough understanding of all factors contributing to the success of antiretroviral therapy is required. The current study aims to investigate the value of cross-sectional drug resistance monitoring using DNA and RNA oligonucleotide ligation assays (OLA in treatment cohorts in low-resource settings. The study was conducted in the first cohort of children gaining access to structured ART in Peru. Methods Between 2002–5, 46 eligible children started the standard regimen of AZT, 3TC and NFV Patients had a median age of 5.6 years (range: 0.7-14y, a median viral load of 1.7·105 RNA/ml (range: 2.1·103 – 1.2·106, and a median CD4-count of 232 cells/μL (range: 1–1591. Of these, 20 patients were classified as CDC clinical category C and 31/46 as CDC immune category 3. At the time of cross-sectional analysis in 2005, adherence questionnaires were administered. DNA OLAs and RNA OLAs were performed from frozen PBMC and plasma, RNA genotyping from dried blood spots. Results During the first year of ART, 44% of children experienced virologic failure, with an additional 9% failing by the end of the second year. Virologic failure was significantly associated with the number of resistance mutations detected by DNA-OLA (p Conclusions Advanced immunosuppression at baseline and previous exposures to unsupervised brief cycles of ART significantly impaired treatment outcomes at a time when structured ART was finally introduced in his cohort. Brief maternal exposures to with AZT +/− NVP for the prevention of mother-to-child transmission did not affect treatment outcomes in this group of children. DNA-OLA from frozen PBMC provided a highly specific tool to detect archived drug resistance. RNA consensus genotyping from dried blood spots and RNA-OLA from plasma consistently detected drug resistance mutations, but merely in association with virologic failure.

  10. (Post-) Genomic approaches to tackle drug resistance in Leishmania.

    Science.gov (United States)

    Berg, Maya; Mannaert, An; Vanaerschot, Manu; Van Der Auwera, Gert; Dujardin, Jean-Claude

    2013-10-01

    Leishmaniasis, like other neglected diseases is characterized by a small arsenal of drugs for its control. To safeguard the efficacy of current drugs and guide the development of new ones it is thus of utmost importance to acquire a deep understanding of the phenomenon of drug resistance and its link with treatment outcome. We discuss here how (post-)genomic approaches may contribute to this purpose. We highlight the need for a clear definition of the phenotypes under consideration: innate and acquired resistance versus treatment failure. We provide a recent update of our knowledge on the Leishmania genome structure and dynamics, and compare the contribution of targeted and untargeted methods for the understanding of drug resistance and show their limits. We also present the main assays allowing the experimental validation of the genes putatively involved in drug resistance. The importance of analysing information downstream of the genome is stressed and further illustrated by recent metabolomics findings. Finally, the attention is called onto the challenges for implementing the acquired knowledge to the benefit of the patients and the population at risk. PMID:23480865

  11. Multi drug resistance to cancer chemotherapy: Genes involved and blockers

    International Nuclear Information System (INIS)

    During the last three decades, important and considerable research efforts had been performed to investigate the mechanism through which cancer cells overcome the cytotoxic effects of a variety of chemotherapeutic drugs. Most of the previously published work has been focused on the resistance of tumor cells to those anticancer drugs of natural source. Multidrug resistance (MDR) is a cellular cross-resistance to a broad spectrum of natural products used in cancer chemotherapy and is believed to be the major cause of the therapeutic failures of the drugs belonging to different naturally obtained or semisynthetic groups including vinca alkaloids, taxans, epipodophyllotoxins and certain antibiotics. This phenomenon results from overexpression of four MDR genes and their corresponding proteins that act as membrane-bound ATP consuming pumps. These proteins mediate the efflux of many structurally and functionally unrelated anticancer drugs of natural source. MDR may be intrinsic or acquired following exposure to chemotherapy. The existence of intrinsically resistant tumor cell clone before and following chemotherapeutic treatment has been associated with a worse final outcome because of increased incidence of distant metasis. In view of irreplaceability of natural product anticancer drugs as effective chemotherapeutic agents, and in view of MDR as a major obstacle to successful chemotherapy, this review is aimed to highlight the genes involved in MDR, classical MDR blockers and gene therapy approaches to overcome MDR. (author)

  12. Live-cell luciferase assay of drug resistant cells

    OpenAIRE

    sprotocols

    2015-01-01

    To date, multiplexing cell-based assay is essential for high-throughput screening of molecular targets. Measuring multiple parameters of a single sample increases consistency and decrease time and cost of assay. Functional assay of living cell is useful as a first step of multiplexing assay, because live-cell assay allows following second assay using cell lysate or stained cell. However, live-cell assay of drug resistant cells that are highly activated of drug efflux mechanisms is sometimes u...

  13. HIV Drug-Resistant Patient Information Management, Analysis, and Interpretation

    OpenAIRE

    Singh, Yashik; Mars, Maurice

    2012-01-01

    Introduction The science of information systems, management, and interpretation plays an important part in the continuity of care of patients. This is becoming more evident in the treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), the leading cause of death in sub-Saharan Africa. The high replication rates, selective pressure, and initial infection by resistant strains of HIV infer that drug resistance will inevitably become an important health car...

  14. Antibiotic residues and drug resistance in human intestinal flora.

    OpenAIRE

    Corpet, D. E.

    1987-01-01

    The effect of residual levels of ampicillin on the drug resistance of fecal flora was studied in human volunteers given 1.5 mg of ampicillin orally per day for 21 days. This treatment failed to have any significant reproducible effect on the number of resistant Escherichia coli in their feces. The effect of continuous administration of small doses of ampicillin, chlortetracycline, or streptomycin in the drinking water was studied in gnotobiotic mice inoculated with a human fecal flora. In thi...

  15. Extensively drug-resistant tuberculosis: epidemiology and management

    Directory of Open Access Journals (Sweden)

    Matteelli A

    2014-04-01

    Full Text Available Alberto Matteelli,1 Alberto Roggi,1 Anna CC Carvalho21Institute of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/HIV Co-Infection, University of Brescia, Brescia, Italy; 2Laboratory of Innovations in Therapies, Education and Bioproducts (LITEB, Oswaldo Cruz Institute (IOC, Oswaldo Cruz Foundation (Fiocruz, Rio de Janeiro, BrazilAbstract: The advent of antibiotics for the treatment of tuberculosis (TB represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR strains (ie, strains resistant to both isoniazid and rifampicin has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB. The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR

  16. Clinical Correlates and Drug Resistance in HIV-Infected and -Uninfected Pulmonary Tuberculosis Patients in South India

    Science.gov (United States)

    Sara, Chandy; Elsa, Heylen; Baijayanti, Mishra; Lennartsdotter, Ekstrand Maria

    2016-01-01

    Objectives To examine demographics, clinical correlates, sputum AFB (acid fast bacilli) smear grading DOTS (Directly Observed Therapy Short Course) uptake, and drug resistance in a cohort of newly-diagnosed, smear positive pulmonary tuberculosis (TB) patients with respect to HIV status at baseline, and compare smear conversion rates, side effects and mortality after two months. Design A prospective study among 54 HIV positive and 41 HIV negative pulmonary TB patients. Data were collected via face-to-face interviews, review of medical records, and lab tests. Results HIVTB co-infected patients, though more symptomatic at baseline, showed more improvement in their symptoms compared to HIV-uninfected TB patients at follow-up. The HIV co-infected group had more prevalent perceived side effects, and sputum smear positivity was marginally higher compared to the HIV negative group at follow-up. Mortality was higher among the HIV-infected group. Both groups had high rates of resistance to first-line anti-tubercular drugs, particularly isoniazid. There was no significant difference in the drug resistance patterns between the groups. Conclusions Prompt initiation and provision of daily regimens of ATT (Anti-Tubercular treatment) along with ART (Anti-Retroviral treatment) via ART centers is urgently needed in India. As resistance to ART and/or ATT is directly linked to medication non-adherence, the use of counseling, regular reinforcement, early detection and appropriate intervention strategies to tackle this complex issue could help prevent premature mortality and development of resistance in HIV-TB co-infected patients. The high rate of isoniazid resistance might preclude its use in India as prophylaxis for latent TB in HIV infected persons as per the World Health Organization (WHO) guideline.

  17. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy.

    Science.gov (United States)

    Lee, Jinsoo; Son, Kwanghyun; Hwang, Gwiseo; Kim, Moonju

    2016-01-01

    Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT) has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p = 0.0284, Fisher's exact test). Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children. PMID:27047568

  18. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

    Directory of Open Access Journals (Sweden)

    Jinsoo Lee

    2016-01-01

    Full Text Available Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p=0.0284, Fisher’s exact test. Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children.

  19. Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria.

    Science.gov (United States)

    Couce, Alejandro; Rodríguez-Rojas, Alexandro; Blázquez, Jesús

    2016-07-01

    Any pathogen population sufficiently large is expected to harbor spontaneous drug-resistant mutants, often responsible for disease relapse after antibiotic therapy. It is seldom appreciated, however, that while larger populations harbor more mutants, the abundance distribution of these mutants is expected to be markedly uneven. This is because a larger population size allows early mutants to expand for longer, exacerbating their predominance in the final mutant subpopulation. Here, we investigate the extent to which this reduction in evenness can constrain the genetic diversity of spontaneous drug resistance in bacteria. Combining theory and experiments, we show that even small variations in growth rate between resistant mutants and the wild type result in orders-of-magnitude differences in genetic diversity. Indeed, only a slight fitness advantage for the mutant is enough to keep diversity low and independent of population size. These results have important clinical implications. Genetic diversity at antibiotic resistance loci can determine a population's capacity to cope with future challenges (i.e., second-line therapy). We thus revealed an unanticipated way in which the fitness effects of antibiotic resistance can affect the evolvability of pathogens surviving a drug-induced bottleneck. This insight will assist in the fight against multidrug-resistant microbes, as well as contribute to theories aimed at predicting cancer evolution.

  20. Evidence for epistatic interactions in antiepileptic drug resistance.

    Science.gov (United States)

    Kim, Myeong-Kyu; Moore, Jason H; Kim, Jong-Ki; Cho, Ki-Hyun; Cho, Yong-Won; Kim, Yo-Sik; Lee, Min-Cheol; Kim, Young-Ok; Shin, Min-Ho

    2011-01-01

    To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene-gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (P < 0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32-5.85 (P < 0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene-gene interactions underlying AED resistance. PMID:21124337

  1. Transmitted Drug Resistance among People Living with HIV/Aids at Major Cities of Sao Paulo State, Brazil

    Directory of Open Access Journals (Sweden)

    Joao Leandro Paula Ferreira

    2013-01-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 transmitted drug resistance (TDR is an important public health issue. In Brazil, low to intermediate resistance levels have been described. We assessed 225 HIV-1 infected, antiretroviral naïve individuals, from HIV Reference Centers at two major metropolitan areas of Sao Paulo (Sao Paulo and Campinas, the state that concentrates most of the Brazilian Aids cases. TDR was analyzed by Stanford Calibrated Population Resistance criteria (CPR, and mutations were observed in 17 individuals (7.6%, 95% CI: 4.5%–11.9%. Seventy-six percent of genomes (13/17 with TDR carried a nonnucleoside reverse transcriptase inhibitor (NNRTI resistance mutation, mostly K103N/S (9/13, 69%, potentially compromising the preferential first-line therapy suggested by the Brazilian HIV Treatment Guideline that recommends efavirenz-based combinations. Moreover, 6/17 (35% had multiple mutations associated with resistance to one or more classes. HIV-1 B was the prevalent subtype (80%; other subtypes include HIV-1 F and C, mosaics BC, BF, and single cases of subtype A1 and CRF02_AG. The HIV Reference Center of Campinas presented more cases with TDR, with a significant association of TDR with clade B infection (P<0.05.

  2. Hepatitis C Virus and Antiviral Drug Resistance

    Science.gov (United States)

    Kim, Seungtaek; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-01-01

    Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens. PMID:27784846

  3. Additional drug resistance of multidrug-resistant tuberculosis in patients in 9 countries.

    Science.gov (United States)

    Kurbatova, Ekaterina V; Dalton, Tracy; Ershova, Julia; Tupasi, Thelma; Caoili, Janice Campos; Van Der Walt, Martie; Kvasnovsky, Charlotte; Yagui, Martin; Bayona, Jaime; Contreras, Carmen; Leimane, Vaira; Via, Laura E; Kim, HeeJin; Akksilp, Somsak; Kazennyy, Boris Y; Volchenkov, Grigory V; Jou, Ruwen; Kliiman, Kai; Demikhova, Olga V; Cegielski, J Peter

    2015-06-01

    Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line injectable drug would qualify as candidates for a bedaquiline-containing regimen in accordance with published guidelines. Among candidates for the 9-month regimen, standardized drug-susceptibility tests demonstrated susceptibility to a median of 5 (interquartile range 5-6) drugs. Among candidates for bedaquiline, drug-susceptibility tests demonstrated susceptibility to a median of 3 (interquartile range 2-4) drugs; 26% retained susceptibility to <2 drugs. These data may assist national TB programs in planning to implement new drugs and drug regimens. PMID:25988299

  4. Biophysical principles predict fitness landscapes of drug resistance.

    Science.gov (United States)

    Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I

    2016-03-15

    Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

  5. Biophysical principles predict fitness landscapes of drug resistance.

    Science.gov (United States)

    Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I

    2016-03-15

    Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies. PMID:26929328

  6. "Applied" Aspects of the Drug Resistance Strategies Project

    Science.gov (United States)

    Hecht, Michael L.; Miller-Day, Michelle A.

    2010-01-01

    This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of "applied" from the traditional notion of utilizing theory, which we call "applied.1," in order to consider theory-grounded, theory testing and theory developing applied research. We…

  7. P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Andrea Picchianti-Diamanti

    2014-03-01

    Full Text Available Autoimmune diseases such as systemic lupus erythematosus (SLE, rheumatoid arthritis (RA and psoriatic arthritis (PsA are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS, synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

  8. Flu Resistance to Antiviral Drug in North Carolina

    Centers for Disease Control (CDC) Podcasts

    2011-12-19

    Dr. Katrina Sleeman, Associate Service Fellow at CDC, discusses resistance to an antiviral flu drug in North Carolina.  Created: 12/19/2011 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/19/2011.

  9. Leukemia stem cells in drug resistance and metastasis

    Institute of Scientific and Technical Information of China (English)

    DENG Chao-hua; ZHANG Qiu-ping

    2010-01-01

    Objective To review the central role of leukemia stem cells (LSCs) in drug resistance and metastasis, aiming to provide key insights into leukemogenic pathology and developing novel therapeutic strategies against the relapse of leukemia.Data sources The data used in this review were obtained mainly from the studies reported in PubMed using the key terms "tumor-initiating cells", "leukemia stem cells", "drug resistance" and "metastasis".Study selection Relevant articles on studies of leukemia stem cells were selected.Results Increasing numbers of studies have suggested the importance of cancer stem cells (CSCs) in the initiation and maintenance of cancer, especially in leukemia. This review has summarized the origin, characteristics, isolation and identification of LSCs. It highlights the crucial role of LSCs in drug resistance and metastasis of leukemia by illustrating possible mechanisms and aims to provide novel therapeutic strategies for LSCs-targeted treatment.Conclusion LSCs play a crucial role in drug resistance and metastasis of leukemia and new promising LSCs-targeted therapies warrant investigation in both experimental models and clinical practice.

  10. Mechanisms of antifungal drug resistance in Candida dubliniensis.

    LENUS (Irish Health Repository)

    Coleman, David C

    2010-06-01

    Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.

  11. Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report

    Directory of Open Access Journals (Sweden)

    A. Despotovic

    2016-01-01

    Full Text Available Non-tuberculous mycobacteria are rare but important causes of infection in HIV-positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti-TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS. The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment.

  12. Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report.

    Science.gov (United States)

    Despotovic, A; Savic, B; Salemovic, D; Ranin, J; Jevtovic, Dj

    2016-01-01

    Non-tuberculous mycobacteria are rare but important causes of infection in HIV-positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB) was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti-TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART) was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS). The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment. PMID:26603644

  13. Drug Resistance Characteristics and Macrolide-Resistant Mechanisms of Streptococcus pneumoniae in Wenzhou City, China.

    Science.gov (United States)

    Hu, Dakang; Sun, Zheng; Luo, Xinhua; Liu, Shuangchun; Yu, Lianhua; Qu, Ying; Yang, Jinhong; Yu, Jian; Li, Xiangyang; Zhang, Jin

    2016-01-01

    BACKGROUND Streptococcus pneumoniae (SP) is a Gram-positive, alpha-hemolytic, facultative anaerobic member of the genus Streptococcus. The erythromycin-resistant methylase (erm) gene and macrolide efflux (mef) gene are the 2 main genes that can mediate SP. Transposon (Tn) also plays an important role in the collection and metastasis of the gene. In the present study we investigated the drug resistance characteristics and the macrolide-resistant mechanisms of SP in Wenzhou City, China. MATERIAL AND METHODS Sixty-eight strains of SP were isolated from sputum samples of hospitalized children in the Second Affiliated Hospital of Wenzhou Medical University. These strains were analyzed using antimicrobial susceptibility tests to determine their drug resistance to 10 kinds of antibacterials. Macrolide-resistant phenotypes were identified using K-B method. PCR method was used to analyze the erm B gene, mef A gene, and int Tn gene. RESULTS Drug resistance rates of 68 strains of SP were 98.5%, 100.0%, 63.2%, 52.9%, 94.1%, 89.7%, 0.0%, 0.0%, 16.2%, and 14.7% for clindamycin, erythromycin, penicillin G, cefotaxime, tetracycline, sulfamethoxazole/trimethoprim, levofloxacin, vancomycin, chloramphenicol, and amoxicillin, respectively. Total detection rates of the erm B gene, mef A gene, and int Tn gene were 98.5%, 91.2%, and 100.0%, respectively. CONCLUSIONS SP shows significant multi-drug resistance in Wenzhou City, whereas there is no clinical value of macrolides antibiotics for SP. cMLSB mediated by erm B gene is the most predominant phenotype among macrolide-resistant SP. The int Tn gene may play an important role in horizontal transfer and clonal dissemination of SP drug resistance genes in Wenzhou City. PMID:27483416

  14. Increasing HIV-1 Drug Resistance Between 2010 and 2012 in Adults Participating in Population-Based HIV Surveillance in Rural KwaZulu-Natal, South Africa.

    Science.gov (United States)

    Manasa, Justen; Danaviah, Siva; Lessells, Richard; Elshareef, Muna; Tanser, Frank; Wilkinson, Eduan; Pillay, Sureshnee; Mthiyane, Hloniphile; Mwambi, Henry; Pillay, Deenan; de Oliveira, Tulio

    2016-08-01

    As more human immunodeficiency virus (HIV)-infected patients access combination antiretroviral therapy (cART), higher proportions of newly infected patients may be infected with drug-resistant viruses. Regular surveillance of transmitted drug resistance (TDR) is required in southern Africa where high rates of transmission persist despite rapid expansion of ART. Dried blood spot samples from cART-naive participants from two rounds of an annual population-based HIV surveillance program in rural KwaZulu-Natal were tested for HIV RNA, and samples with HIV RNA >10,000 copies/ml were genotyped for drug resistance. The 2009 surveillance of drug resistance mutation (SDRM) list was used for drug resistance interpretation. The data were added to previously published data from the same program, and the χ(2) test for trend was used to test for trend in estimated prevalence of any TDR. Seven hundred and one participants' data were analyzed: 67 (2010), 381 (2011), and 253 (2012). No TDR was detected in 2010. Years 2011 and 2012 had 18 participants with SDRMs 4.7% and 7.1%, respectively (p = .02, χ(2) test for trend). The nonnucleoside reverse transcriptase inhibitor mutation, K103N, was the most common mutation, occurring in 27 (3.8%) of the participants, while nucleoside reverse transcriptase inhibitor (NRTI) SDRMs were detected in 10 (1.4%) of the participants, of whom eight had only a single NRTI SDRM. The increase in levels of drug resistance observed in this population could be a signal of increasing transmission of drug-resistant HIV. Thus, continued surveillance is critical to inform public health policies around HIV treatment and prevention. PMID:27002368

  15. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    Science.gov (United States)

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

  16. HIV2EU: supporting standardized HIV-2 drug resistance interpretation in Europe

    Directory of Open Access Journals (Sweden)

    F Brun-Vezinet

    2012-11-01

    Full Text Available Various items are complicating the treatment of HIV-2 infected patients. Compared to HIV-1 there is much less treatment experience, no evidence from randomized control trials, a reduced number of effective drugs and no broadly available test for viral load monitoring. In case of treatment failure there is only limited guidance and presently no easy accessible tool for nucleic acid sequence interpretation available. To solve this problem, we initiated an expert workshop to address some of these problems. A panel of experts from four different European countries voted on a rule set for interpretation of mutations in the HIV-2 protease, reverse transcriptase and integrase. Rules were proposed by each member and were then modified during discussion by considering data gained from HIV-1 and accumulated experience of the follow up of HIV-2-infected patients. Based on the HIV-GRADE internet-tool an online tool was developed to make the rule set easily accessible and usable. Rules were laid down for the interpretation of HIV-2 drug resistance to NRTIs, PIs and INIs (integrase inhibitors. Due to natural resistance of HIV-2, usage of NNRTIs and T-20 was not recommended as part of an antiretroviral regimen for HIV-2. These rules were then translated in a machine interpretable format (algorithm specification interface, ASI and the HIV-GRADE tool was extended for usage of HIV-2 sequences. Further consensus sequences were generated from the reference sequence data set provided by Los Alamos National Laboratories. In contrast to HIV-1, mutations were compared to a group specific consensus sequence (Group A or Group B and not to a consensus sequence from the most predominant HIV-2 Group A. This change was necessary due to significant differences between the various HIV-2 strains. We developed a rule set and an automated tool for HIV-2 drug resistance analyses. This tool and the rules will be freely available on the internet. Access to the pre

  17. Presence of key drug resistance mutations in isolates from untreated patients of Abidjan, Côte d'Ivoire: ANRS 1257 study.

    Science.gov (United States)

    Toni, Thomas D'Aquin; Recordon-Pinson, Patricia; Minga, Albert; Ekouevi, Didier; Bonard, Dominique; Bequet, Laurence; Huet, Charlotte; Chenal, Henri; Rouet, François; Dabis, François; Lafon, Marie-Edith; Salamon, Roger; Masquelier, Bernard; Fleury, Herve J

    2003-08-01

    A total of 107 HIV-1 isolates from untreated adult patients recruited in Abidjan, CMte d'Ivoire, in 2001 and 2002 were sequenced in the env, reverse transcriptase (RT), and protease genes. The results show that CRF02_AG is still predominant in this west African population; key mutations of resistance to antiretroviral drugs (NRTI, NNRTI, and PIs) were detected in 5.6% of the patients. We hypothesize that these resistant mutants have been acquired through horizontal transmission. Compared to a previous study carried out by our group in 1997-2000 in a similar population of Abidjan, it seems that there is a dynamic process of resistance and that a survey will be necessary.

  18. The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens.

    Science.gov (United States)

    Wilson, Benjamin A; Garud, Nandita R; Feder, Alison F; Assaf, Zoe J; Pennings, Pleuni S

    2016-01-01

    Drug resistance is a costly consequence of pathogen evolution and a major concern in public health. In this review, we show how population genetics can be used to study the evolution of drug resistance and also how drug resistance evolution is informative as an evolutionary model system. We highlight five examples from diverse organisms with particular focus on: (i) identifying drug resistance loci in the malaria parasite Plasmodium falciparum using the genomic signatures of selective sweeps, (ii) determining the role of epistasis in drug resistance evolution in influenza, (iii) quantifying the role of standing genetic variation in the evolution of drug resistance in HIV, (iv) using drug resistance mutations to study clonal interference dynamics in tuberculosis and (v) analysing the population structure of the core and accessory genome of Staphylococcus aureus to understand the spread of methicillin resistance. Throughout this review, we discuss the uses of sequence data and population genetic theory in studying the evolution of drug resistance.

  19. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis

    Science.gov (United States)

    Yu, Caitong; Zhou, Mengjiao; Zhang, Xiujuan; Wei, Weijia; Chen, Xianfeng; Zhang, Xiaohong

    2015-03-01

    Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in

  20. Individualization of antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Pavlos R

    2011-12-01

    Full Text Available Rebecca Pavlos, Elizabeth J PhillipsInstitute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AustraliaAbstract: Antiretroviral therapy (ART has evolved considerably over the last three decades. From the early days of monotherapy with high toxicities and pill burdens, through to larger pill burdens and more potent combination therapies, and finally, from 2005 and beyond where we now have the choice of low pill burdens and once-daily therapies. More convenient and less toxic regimens are also becoming available, even in resource-poor settings. An understanding of the individual variation in response to ART, both efficacy and toxicity, has evolved over this time. The strong association of the major histocompatibility class I allele HLA-B*5701 and abacavir hypersensitivity, and its translation and use in routine HIV clinical practice as a predictive marker with 100% negative predictive value, has been a success story and a notable example of the challenges and triumphs in bringing pharmacogenetics to the clinic. In real clinical practice, however, it is going to be the exception rather than the rule that individual biomarkers will definitively guide patient therapy. The need for individualized approaches to ART has been further increased by the importance of non-AIDS comorbidities in HIV clinical practice. In the future, the ideal utilization of the individualized approach to ART will likely consist of a combined approach using a combination of knowledge of drug, virus, and host (pharmacogenetic and pharmacoecologic [factors in the individual's environment that may be dynamic over time] information to guide the truly personalized prescription. This review will focus on our knowledge of the pharmacogenetics of the efficacy and toxicity of currently available antiretroviral agents and the current and potential utility of such information and approaches in present and future HIV clinical care.Keywords: HIV

  1. Drug resistance of bacteria——present situation and treatment

    Directory of Open Access Journals (Sweden)

    Min ZHAO

    2011-02-01

    Full Text Available Antimicrobial resistance of bacteria is a serious problem worldwide.It has become the difficulty of anti-infection that multidrug-resistance(MDR and drug wide-resistance(DWR gram-negative bacteria are increasing year and year.Alarm has been knolled again on the emerging of Gram-negative pathogens producing the NDM-1 worldwide in 2010.NDM-1 is a new metallo-carbapenemase which is highly resistant to all antibiotics,and has been mostly found among Escherichia coli and Klebsiella pneumoniae.Infections of MDR and DWR Enterobacteriaceae can be effectively treated with tigecycline,polymyxin and fosfomycin on clinic trail.Prevention is very important for reducing the occurring and spreading of MDR and DWR bacteria.

  2. Microsocial environmental influences on highly active antiretroviral therapy outcomes among active injection drug users: the role of informal caregiving and household factors.

    Science.gov (United States)

    Knowlton, Amy R; Arnsten, Julia H; Gourevitch, Marc N; Eldred, Lois; Wilkinson, James D; Rose, Carol Dawson; Buchanan, Amy; Purcell, David W

    2007-11-01

    Active injection drug users (IDUs) are at high risk of unsuccessful highly active antiretroviral therapy (HAART). We sought to identify baseline factors differentiating IDUs' treatment success versus treatment failure over time among those taking HAART. Interventions for Seropositive Injectors-Research and Evaluation (INSPIRE) study participants were assessed at baseline and at 6- and 12-month follow-ups. Multinominal regression determined baseline predictors of achieving or maintaining viral suppression relative to maintaining detectable viral loads over 12 months. Of 199 participants who were retained and remained on HAART, 133 (67%) had viral load change patterns included in the analysis. At follow-up, 66% maintained detectable viral loads and 15% achieved and 19% maintained viral suppression. Results indicated that those having informal care (instrumental or emotional support) were 4.6 times more likely to achieve or maintain viral suppression relative to experiencing treatment failure. Those who maintained viral suppression were 3.5 times less likely to live alone or to report social discomfort in taking HAART. Study results underscore the importance of microsocial factors of social network support, social isolation, and social stigma for successful HAART outcomes among IDUs. The findings suggest that adherence interventions for IDUs should promote existing informal HIV caregiving, living with supportive others, and positive medication-taking norms among social networks. PMID:18089980

  3. Antimalarial drug resistance in Bangladesh, 1996-2012.

    Science.gov (United States)

    Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald

    2013-12-01

    Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh.

  4. Experience with pulmonary resection for extensively drug-resistant tuberculosis.

    Science.gov (United States)

    Shiraishi, Yuji; Katsuragi, Naoya; Kita, Hidefumi; Toishi, Masayuki; Onda, Takahito

    2008-12-01

    Extensively drug-resistant tuberculosis is becoming a global threat. It is a relatively new phenomenon, and its optimal management remains undetermined. We report our experience in using pulmonary resection for treating patients with this disease. Records were reviewed of 54 consecutive patients undergoing a pulmonary resection for multidrug-resistant tuberculosis at Fukujuji Hospital between 2000 and 2006. These patients were identified using the definition approved by the World Health Organization Global Task Force on extensively drug-resistant tuberculosis in October 2006. Five (9%) patients (3 men and 2 women) aged 31-60 years met the definition. None of the patients was HIV-positive. Although the best available multidrug regimens were initiated, no patient could achieve sputum conversion. Adjuvant resectional surgery was considered because the patients had localized disease. Procedures performed included pneumonectomy (2) and upper lobectomy (3). There was no operative mortality or morbidity. All patients attained sputum-negative status after the operation, and they were maintained on multidrug regimens for 12-25 months postoperatively. All patients remained free from disease at the time of follow-up. Pulmonary resection under cover of state-of-the-art chemotherapy is safe and effective for patients with localized extensively drug-resistant tuberculosis.

  5. Systematic review of the performance of rapid rifampicin resistance testing for drug-resistant tuberculosis.

    Directory of Open Access Journals (Sweden)

    Matthew Arentz

    Full Text Available INTRODUCTION: Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB. However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. METHODS: We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. RESULTS: We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI assay, Nitrate Reductase Assay (NRA and MODS tests: for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. LIMITATIONS: In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. DISCUSSION: Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

  6. Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

    Science.gov (United States)

    Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu

    2007-04-01

    Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. PMID:17425594

  7. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

    Science.gov (United States)

    Kovari, Helen; Sabin, Caroline A.; Ledergerber, Bruno; Ryom, Lene; Reiss, Peter; Law, Matthew; Pradier, Christian; Dabis, Francois; d'Arminio Monforte, Antonella; Smith, Colette; de Wit, Stephane; Kirk, Ole; Lundgren, Jens D.; Weber, Rainer

    2016-01-01

    Background. Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions. Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated. PMID:26925429

  8. Antiviral drug resistance in Cuban children infected with HIV-1

    Directory of Open Access Journals (Sweden)

    L Pérez

    2012-11-01

    Full Text Available Between 1986 and 2011, 100 children have been diagnosed with HIV-1 in Cuba. 38 have acquired HIV-1 by vertical transmission, 6 by blood transfusion and 56 by sexual contacts (teenager. Currently, AZT/D4T + 3TC + NVP/KALETRA are available for the treatment of pediatric patients. The aim of the study was to monitor the subtype distribution and emergence of drug resistance in pediatric HIV-1 infections. Plasma from 46 HIV-1-infected children were collected from November 2005 to November 2011, subsequently extracted, amplified and sequenced. Phylogenetic analysis was performed using Mega 4 (Neighbour joining, Kimura 2. The CPR tool v6.0 (WHO list 2009 was used to interpret transmitted drug resistance (TDR. In addition, acquired drug resistance was interpreted according to HIVdb v6.1.1. Experiments were successful for 28 samples from 20 patients (5 patients with multiple samples. At the moment of analysis, 17 children were receiving ART. The median age at diagnosis was 1.9 years, whereas the median age at sampling was 4.5 years. Ten children were male (50%, 16 (80% were infected by vertical transmission, 1 by blood transfusion (5% and 3 by sexual route (15%. The subtypes were CRF18_cpx (25%, CRF19_cpx (25%, B (20%, CRF20_BG (10%, G (10%, CRF24_BG (5% and C (5%. 82.3% of the children who were receiving ART at sampling (14/17 displayed at least one drug resistance mutation. The most common NRTI and NNRT mutations were: M184V (55.5%, T215FY (16.6% and K70R (16.6%; and K103NS (61.1% and G190A (22.0%. In contrast, only one PI mutation, L90M (5.5%, was observed. 5.8% of these children displayed single NRTI class resistance, 17.4% single NNRTI class resistance, 59% double NRTI + NNRTI class resistance and 5.8% triple NRTI + NNRTI + PI class resistance. According to HIVdb, NRTI, NNRTI and PI resistance was present in respectively 42.8%, 58.7% and 8.08% of the treated children. High-level NVP and EFV resistance was observed in 76.5% and 58

  9. Sensitive, resistant and multi-drug resistant Acinetobacter baumanii at Saudi Arabia hospital eastern region.

    Science.gov (United States)

    Ahmed, Mughis Uddin; Farooq, Reshma; Al-Hawashim, Nadia; Ahmed, Motasim; Yiannakou, Nearchos; Sayeed, Fatima; Sayed, Ali Rifat; Lutfullah, Sualiha

    2015-05-01

    Since the Physicians start use of antibiotics long ago with un-notice drug resistance. However actual problem was recognized about 85 years ago. Antibiotic resistant and Multi-drug resistant bacterial strains are at rise throughout the world. It is physicians and researchers to take scientific research based appropriate action to overcome this ever-spreading problem. This study is designed to find out sensitive (S), resistant (R) and multi-drug resistant (MDR) Acinetobacter baumanii strain along with other isolates in the resident patients of Eastern Region of Saudi Arabia. Pseudomonas aeruginosa is excluded from other gram-negative organisms isolated from different sites as it will be dealt separately. This study is based in was retrospective observations designed to collect data of different stains of Acinetobacter baumanii with reference to their Sensitivity (S), Resistance (R), Multi-Drug Resistance (MDR) along with other Gram negative isolated from different sites (from 1st January 2004 to 31st December 2011) at King Abdulaziz Hospital located Eastern Region of Kingdom of Saudi Arabia (KSA). All necessary techniques were used to culture and perform sensitivity of these isolates. There were 4532 isolates out of which 3018 (67%) were from patients. Out of Acinetobacter baumanii infected were 906 (20%) while other 3626 (80%) isolates were miscellaneous. Numbers of patients or cases were 480 (53%) out of 906 isolates and numbers of patients or cases in other organisms were 2538 (70%) out of 3626 isolates. Acinetobacter baumanii infected patients 221 (46%) were male and 259 (54%) were female and the male and female ratio of 1:1.2. In other organisms this male female ratio was almost same. There was steady rise in number of patients and the hence the isolates from 2004 to 2011. Majority of the bacterial strains were isolated as single organism but some were isolated as double or triple or quadruple or more organisms from different sites. Sensitive, Resistant and

  10. Drug resistance profiles of Mycobacterium tuberculosis isolates to first line anti-tuberculous drugs: A five years study

    Directory of Open Access Journals (Sweden)

    Sarala Menon

    2012-01-01

    Full Text Available Background: Drug resistance is a major problem in the treatment of tuberculosis (TB. An estimate of drug resistance is extremely important in the epidemiology and control of TB. However, an assessment of the magnitude of drug resistance in TB is not very well described globally and data remains scantier for India. In view of this, we reviewed our data over last five years. Materials and Methods: Six hundred and seventy-three Mycobacterium tuberculosis isolates were subjected to drug susceptibility against primary anti-tuberculosis drugs by economic variant proportion method. All isolates resistant to isoniazid and rifampicin were taken as multi-drug resistant (MDR. Results: Out of the 673 strains tested, 95 (14.11% showed monoresistance, 365 (54.23% strains were found to be resistant to more than one drug. A total of 118 (17.53% strains were found to be resistant to all the four drugs tested. MDR was seen with 320 (47.54% isolates. This study observed maximum resistance with rifampicin (74.4% followed by streptomycin (70.0%, isoniazid (53.2%, and ethambutol (21.7%. Conclusion: While this information may not reflect true prevalence of drug resistance in the region, this may help in further planning long term surveillance studies to know the trend of drug resistance in this area.

  11. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection

    DEFF Research Database (Denmark)

    Cooper, David A; Steigbigel, Roy T; Gatell, Jose M;

    2008-01-01

    BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS: We c...

  12. Elaboration of a global strategy for containing microbial drug resistance.

    Science.gov (United States)

    Zabicki, W

    2001-01-01

    The World Health Organization is engaged in developing the Global Strategy for Containment of Antimicrobial Resistance. The preliminary document WHO/CDC/CSR/DRS/2000.I Draft has already been distributed, and remarks have been solicited. The World Health Assembly Resolution of 1998 urged Member States to encourage the appropriate and cost-effective use of antimicrobials. Member States were requested to implement effective systems of microbial resistance surveillance and to monitor volumes and patterns of antimicrobial drug use. The phenomenon of antimicrobial resistance is rising rapidly and causing growing international concern. Many countries have undertaken their own national plans to address the problem. The overall aim of the strategy being developed is to find the most effective forms and to prevent the spread of antimicrobial resistance and resistant microbes. The strategy covers the following topics: patients and general community, prescribers, hospitals, veterinarians, manufacturers and drug dispensers, and international aspects. The strategy is being developed on the basis of expert opinions, published reports, reviews of specific topics specially commissioned by various international and national bodies, and a large body of literature with a list of publications containing over 100 items. PMID:17986973

  13. [MOLECULAR MECHANISMS OF DRUG RESISTANCE NEISSERIA GONORRHOEAE HISTORY AND PROSPECTS].

    Science.gov (United States)

    Bodoev, I N; Il'ina, E N

    2015-01-01

    Neisseria gonorrhoeae (gonococcus) is a strict human pathogen, which causes gonorrhea--an infectious disease, whose origin dates back to more than two thousand years. Due to the unique plasticity of the genetic material, these bacteria have acquired the capacity to adapt to the host immune system, cause repeated infections, as well as withstand antimicrobials. Since the introduction of antibiotics in 1930s, gonococcus has displayed its propensity to develop resistance to all clinically useful antibiotics. It is important to note that the known resistance determinants of N. gonorrhoeae were acquired through horizontal gene transfer, recombination and spontaneous mutagenesis, and may be located both in the chromosome and on the plasmid. After introduction of a new antimicrobial drug, gonococcus becomes resistant within two decades and replaces sensitive bacterial population. Currently Ceftriaxone is the last remaining antibiotic for first-line treatment of gonorrhea. However, the first gonococcus displaying high-level resistance to Ceftriaxone was isolated in Japan a few years ago. Therefore, in the near future, gonorrhea may become untreatable. In the present review, we discuss the chronology of the anti-gonorrhea drugs (antibiotics) replacement, the evolution of resistance mechanisms emergence and future perspectives of N. gonorrhoeae treatment.

  14. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance.

    Science.gov (United States)

    Wongsrichanalai, C; Sibley, C H

    2013-10-01

    Following a decade-long scale up of malaria control through vector control interventions, the introduction of rapid diagnostic tests and highly efficacious Artemisinin-based Combination Therapy (ACT) along with other measures, global malaria incidence declined significantly. The recent development of artemisinin resistance on the Cambodia-Thailand border, however, is of great concern. This review encompasses the background of artemisinin resistance in Plasmodium falciparum, its situation, especially in the Greater Mekong Sub-region (GMS), and the responses taken to overcome this resistance. The difficulties in defining resistance are presented, particularly the necessity of measuring the clinical response to artemisinins using the slow parasite-clearance phenotype. Efforts to understand the molecular basis of artemisinin resistance and the search for molecular markers are reviewed. The markers, once identified, can be applied as an efficient tool for resistance surveillance. Despite the limitation of current surveillance methods, it is important to continue vigilance for artemisinin resistance. The therapeutic efficacy "in vivo study" network for monitoring antimalarial resistance in the GMS has been strengthened. GMS countries are working together in response to artemisinin resistance and aim to eliminate all P. falciparum parasites. These efforts are crucial since a resurgence of malaria due to drug and/or insecticide resistance, program cuts, lack of political support and donor fatigue could set back malaria control success in the sub-region and threaten malaria control and elimination if resistance spreads to other regions.

  15. Detection of HIV drug resistance mutations in pregnant women receiving single dose Nevirapine in south India

    Directory of Open Access Journals (Sweden)

    Mini S Jacob

    2011-01-01

    Full Text Available Background: Single dose of Nevirapine to prevent mother to child transmission of HIV is the commonest preventive regimen in resource-limited countries. Objectives: The objective of this study was to detect drug-resistant virus after single dose of Nevirapine (sdNVP provided to delivering HIV seropositive (HIV+ve women and to evaluate the time taken for its decay. Results: Of the 36 consenting HIV+ve pregnant women enrolled into the study, the mean hemoglobin and total lymphocyte counts were 10.8 g/dl and 1843 cells/mm 3 , respectively. Mean CD4 counts in 64% of women was 363 cells/mm 3 and mean viral load for 16/36 women was 28,143 copies/ml of plasma. Nevirapine-resistance mutations were detected in 28% of women at delivery; using OLA (Oligonucleotide Ligation Assay. K103N mutations were seen in 19.4% of women while the Y181C mutation was seen in 5%. Both the mutations were detected in 2.7% of women. Sequential blood samples collected at delivery, 7-10 days, 6 weeks, 4 months, 6 months and one year postpartum showed that 81% of K103N mutations and 66.7% of Y181C mutations were detected at 6 weeks postpartum . Wild-type virus had replaced the mutants by one year postpartum in all women except one. Conclusion : These observations are relevant for future treatment with antiretroviral therapy in these women for their HIV disease.

  16. The management of drug resistant seizures in tuberous sclerosis

    Directory of Open Access Journals (Sweden)

    Romina MOAVERO

    2009-12-01

    Full Text Available Tuberous Sclerosis Complex (TSC is a multisystem autosomal dominant genetic disorder resulting from mutations in one of two genes, TSC1 and TSC2. Pathologically TSC is characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. The majority of patients with TSC have epilepsy, although the mechanisms underlying epileptogenesis remain unknown. Seizures onset is frequently during the first year of life, and in a sizable proportion of individuals tend to be refractory to antiepileptic drug treatment. This article reviews the progress in understanding drug resistant seizures in TSC, from molecular pathogenesis to the pathophysiological mechanisms of epileptogenesis, and the rationale for appropriate medical and surgical treatment.

  17. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  18. Multi drug resistant tuberculosis presenting as anterior mediastinal mass

    Directory of Open Access Journals (Sweden)

    Parmarth Chandane

    2016-01-01

    Full Text Available Enlargement of the mediastinal lymphatic glands is a common presentation of intrathoracic tuberculosis (TB in children. However, usually, the mediastinal TB nodes enlarge to 2.8 ± 1.0 cm. In this report, we describe a case of anterior mediastinal lymphnode TB seen as huge mass (7 cm on computed tomography (CT thorax without respiratory or food pipe compromise despite anterior mediastinum being an enclosed space. CT guided biopsy of the mass cultured Mycobacterium TB complex which was resistant to isoniazide, rifampicin, streptomycin ofloxacin, moxifloxacin, and pyrazinamide. Hence, we report primary multi drug resistant TB presenting as anterior mediastinal mass as a rare case report.

  19. HIV quasispecies dynamics during pro-active treatment switching: impact on multi-drug resistance and resistance archiving in latent reservoirs.

    Directory of Open Access Journals (Sweden)

    Max von Kleist

    Full Text Available The human immunodeficiency virus (HIV can be suppressed by highly active anti-retroviral therapy (HAART in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after

  20. Prevalence of drug resistance mutations and HIV type 1 subtypes in an HIV type 1-infected cohort in rural Tanzania.

    Science.gov (United States)

    Masimba, Pax; Kituma, Elimsaada; Klimkait, Thomas; Horvath, Edit; Stoeckle, Marcel; Hatz, Christoph; Mossdorf, Erick; Mwaigomole, Emmanuel; Khamis, Salim; Jullu, Boniphace; Abdulla, Salim; Tanner, Marcel; Felger, Ingrid

    2013-09-01

    The development of resistance mutations in drug-targeted HIV-1 genes compromises the success of antiretroviral