D4t and ABC

BACKGROUND: Limited data are available on patterns of resistance mutations in pediatric patients in southern Africa, where HIV-1 subtype C (HIV-1C) predominates. METHODS: Retrospective chart review of pediatric patients. Nucleoside reverse transcriptase inhibitor (NRTI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations quantified from population-based sequencing genotypic resistance assay results taken at time of first-line antiretroviral therapy (ART) failure (first-line ART = stavudine [d4T] or zidovudine [ZDV] + lamivudine [3TC] + nevirapine [NVP] or efavirenz [EFV])...

INTRODUCTION: Thymidine analogs zidovudine (AZT) and stavudine (d4T) have been widely used because of their antiviral activity against HIV, but at the expense of high toxicity, mainly related to mitochondrial damage. Many studies have been performed replacing AZT or d4T with newer nucleoside analogs reverse transcriptase inhibitors (NRTIs) with less toxicity, such as tenofovir (TDF) or abacavir (ABC), maintaining virological efficacy. AREAS COVERED: Relevant literature was identified using a PubMed search of articles published up to June 2010...

BACKGROUND: recycling nucleos(t)ides (NUCs) is useful in regions where new antiretrovirals are not available. This study compares the effectiveness of NUC-containing regimens as rescue therapy in routine care. METHODS: retrospective, multicentre cohort study (January 2001 to June 2006) of patients with ≥ 1 virological failure who started therapy with 2 NUCs and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). The primary endpoint was the rate of treatment response at 6 months (intention-to-treat [ITT] analysis)...

Individual variation in response to antiretroviral therapy is well-known, but it is not clear if demographic characteristics such as gender, age, and ethnicity are responsible for the variation. To optimize anti-HIV therapy and guide antiretroviral drug discovery, determinants that cause variable responses to therapy need to be evaluated. We investigated the determinants of intracellular concentrations of nucleoside analogs using peripheral blood mononuclear cells from 40 healthy donors. We observed individual differences in the concentrations of the intracellular nucleoside analogs; the mean concentrations of the triphosphate metabolite of ethynylstavudine (4'-Ed4T), zidovudine (AZT), and lamivudine (3TC) were 0...

The objective of this study was to assess the patterns of genotypic and phenotypic resistance in a population of blood donor patients infected with HIV-1 subtype B' (Thai B', a clade of HIV-1 B) from central China, previously treated and harboring NRTI and NNRTI resistance mutations, with the purpose of designing effective therapeutic regimens. The HIV-1 pol genes from 65 patients were sequenced and estimated for drug resistance while the viruses isolated from the patients were used to analyze the phenotype based on the TZM-bl cell line...

Resistance to antiviral therapy is the limiting factor in the successful management of HIV. In general, the K65R mutation is rarely selected (1.7-4%) with tenofovir disoproxil fumarate (TDF), abacavir (ABC), didanosine (ddI), and stavudine (d4T), as compared with the high incidence (>40%) of thymidine analog mutations associated with zidovudine and d4T. The high barrier to the development of K65R may reflect a combination of factors, including the high potency of K65R-selecting drugs, including recommended TDF/emtricitabine and ABC/lamivudine (ABC/3TC) combinations; the partial (low-intermediate level) profile of cross-resistance conferred by K65R to TDF, ABC and 3TC; the favorable viral fitness constraint imposed by K65R and the 3TC/emtricitabine-associated M184V mutations; the bidirectional antagonism between the K65R and thymidine analog mutation pathways; and unique RNA structural considerations in the region surrounding codon 65...

The development and widespread clinical use of coformulated abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) as Trizivir represented an important advance in the management of HIV-infected patients, especially those with adherence challenges. With a low pill burden, no food restrictions, limited drug-drug interactions, and a favorable resistance profile, ABC/3TC/ZDV remains an alternative option in the US Department of Health and Human Services Consensus Panel Guidelines as initial treatment in antiretroviral-naive patients...

BACKGROUND AND OBJECTIVE: India has 1.1 million injecting drug users (IDUs) with an HIV prevalence rate as high as 64%. Drug resistance screening before therapy is beneficial to the individual. Here, we have studied primary drug resistance among IDUs in Chennai. METHODS: Specimens (n = 55) collected between March 2005 and April 2006 were subjected to genotyping assay. The mutations for the drug resistance were interpreted using the Stanford HIV Drug Resistance Database...

BACKGROUND: Thymidine nucleoside reverse transcriptase inhibitors (NRTIs) are associated with subcutaneous fat loss. Facial changes cannot be assessed by dual-energy X-ray absorptiometry (DEXA) scans. There are limited objective data on the reversibility of facial lipoatrophy. METHODS: We performed a facial volume substudy of a randomized thymidine NRTI replacement study carried out in HIV-infected subjects with moderate to severe lipoatrophy. Facial volume changes were assessed using validated 3D laser imaging...

Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-gamma hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-gamma) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-gamma with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations...

In this study we have developed an in vitro system to evaluate the combined effect of two NRTIs on HIV replication and to assess their antagonism or synergy. Synergy or antagonism effect was determined in peripheral blood mononuclear cells (PBMCs) to approach a more physiological model than T-cell lines. PBMCs were infected with a full-length HIV-1 clone carrying the luciferase gene as a reporter. The following combinations were investigated: zidovudine+stavudine (ZDV + d4T), lamivudine + abacavir (3TC + ABC), lamivudine + didanosine (3TC + ddI), lamivudine + stavudine (3TC + d4T), tenofovir + stavudine (TDF + d4T), tenofovir + didanosine (TDF + ddI), tenofovir + abacavir (TDF + ABC), tenofovir + lamivudine (TDF + 3TC), tenofovir + zidovudine (TDF + ZDV), stavudine + didanosine (d4T + ddI), zidovudine + lamivudine (ZDV + 3TC), abacavir + didanosine (ABC + ddI), zidovudine + didanosine (ZDV + ddI), and abacavir + stavudine (ABC + d4T)...

Recent findings suggest bidirectional antagonisms between the K65R mutation and thymidine analogue mutations in human immunodeficiency virus type 1 (HIV-1)-infected, treatment-experienced patients, yet little is known about HIV-2 in this regard. This study addressed the effects of innate polymorphisms in HIV-2 on emergent resistance to nucleoside/nucleotide analogues. Emergent drug resistance profiles in HIV-2 subtypes A (n = 3) and B (n = 1) were compared to those of HIV-1 subtypes B and C. Drug resistance was evaluated with cord blood mononuclear cells (CBMCs) and MT2 cells, using selective pressure with tenofovir (TFV), zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), or various dual-drug combinations...

OBJECTIVES: To assess long-term changes in subcutaneous tissue among antiretroviral-naive persons initiating 1 of 3 nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens. METHODS: We compared changes in 308 participants initiating stavudine plus lamivudine (d4T+3TC; N = 63), zidovudine plus lamivudine (ZDV+3TC; N = 192), and abacavir plus lamivudine (ABC+3TC; N = 53), along with protease inhibitors and/or non-NRTIs. Anthropometric measurements (skinfolds) were performed at baseline and 4-month intervals...

OBJECTIVE: To study the genotypic resistance profiles of HIV-1 children failing highly active antiretroviral therapy (HAART) so as to provide helpful information for the treatment regime of Chinese children infected with HIV-1. METHODS: Peripheral venous blood samples were collected from 20 HIV-1 infected children of Henan province, aged 9 (3 - 14). Nested RT-PCR was used to amplify part of the RT (40 -250 aa) gene. The PCR products of RT gene underwent nucleotide sequencing, the resulting nucleotide sequences were analyzed by the HIVdb data offered by the Stanford University web site to find the drug resistance mutations...

OBJECTIVE: To evaluate the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (EVG/r) and the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or abacavir (ABC) upon coadministration. METHODS: In 3 studies, healthy subjects were administered a single dose of ddI, d4T, or ABC, or multiple doses of ZDV, followed by multiple doses of EVG/r alone and together with an NRTI; pharmacokinetics (PK) of EVG and NRTIs were evaluated after individual administration and coadministration...

Experiments were performed to investigate the impact of didanosine (ddI), lamivudine (3TC), and stavudine (d4T) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using a cell cloning assay for assessing the effects of individual nucleoside analogs (NRTIs)/drug combinations in human TK6 B-lymphoblastoid cells. Three-day treatments with 0, 33, 100, or 300 microM ddI, 3TC, or ddI-3TC produced positive trends for increased HPRT and TK mutant frequencies...

OBJECTIVES: The safety and effectiveness of highly active antiretroviral therapy (HAART) is challenged by viral resistance to antiretrovirals and the frequent occurrence of drug interactions which may limit the access of these drugs to the target sites. In particular, drug distribution and elimination may be modified by active efflux transporters. While P-glycoprotein is well evaluated in this regard, the interaction of antiretrovirals with the ABC transporter BCRP (ABCG2) is far from being elucidated...

OBJECTIVES: Cipla Pharmaceuticals have developed generic fixed-dose combinations of stavudine, lamivudine and nevirapine for HIV-infected children (Pedimune Baby and Junior). We determined the pharmacokinetic profiles of stavudine, lamivudine and nevirapine in Pedimune and compared these with the branded products. METHODS: This Phase I, comparative, single-centre, open-label, three-period, single-dose study was designed as a pilot study to exclude large differences in pharmacokinetics...

BACKGROUND: Treatment simplification in antiretroviral-experienced patients receiving protease inhibitor (PI)-containing antiretroviral regimens seems safe, but randomized trials have limited power to detect differences in virological rebound (VR) between different switch strategies. METHODS: From the French Hospital Database on HIV, we selected 2462 patients with undetectable viral load (VL) who switched from a first PI-containing antiretroviral combination (cART) to a combination containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC)...

OBJECTIVE: To compare alternative class-sparing antiretroviral regimens in treatment-naive subjects. DESIGN: Open-label, multicenter, randomized trial of up to 3 consecutive treatment regimens over 96 weeks. METHODS: Two hundred ninety-one subjects received abacavir (ABC) and lamivudine and efavirenz (nonnucleoside reverse transcriptase inhibitors [NNRTIs]), ritonavir-boosted amprenavir (protease inhibitor [PI]), or stavudine (nucleoside reverse transcriptase inhibitor [NRTI]) by random assignment...