didanosine and abacavir

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Delayed-Action Preparations; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Monitoring; Emtricitabine; Furans; HIV Infections; Humans; Lamivudine; Nevirapine; Oligopeptides; Organophosphates; Organophosphonates; Organophosphorus Compounds; Oxazines; Pyridines; Randomized Controlled Trials as Topic; Stavudine; Sulfonamides; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine

Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells.. A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays.. No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus.. An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug.

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA, Mitochondrial; Drug Administration Schedule; Female; HIV; HIV Infections; Humans; Lamivudine; Male; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; RNA; RNA, Mitochondrial; Tenofovir

Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs)--abacavir and didanosine--may each be associated with excess risk of myocardial infarction. The reproducibility of this finding in an independent dataset was explored and plausible biological mechanisms were sought.. Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N = 2752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included.. Current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical myocardial infarction (n = 19), major CVD (myocardial infarction, stroke, surgery for coronary artery disease, and CVD death; n = 70), expanded CVD (major CVD plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed deaths; n = 112) were 4.3 [95% confidence interval (CI): 1.4-13.0], 1.8 (1.0-3.1), and 1.9 (1.3-2.9). At baseline in a subset of patients with biomarker data, high sensitivity-C-reactive protein and interleukin-6 were 27% (P = 0.02) and 16% (P = 0.02) higher for patients receiving abacavir (N = 175) compared with those receiving other NRTIs (N = 500). Didanosine was associated neither with altered risk of CVD nor with altered levels of biomarkers.. Abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event.

Topics: Adult; Anti-Retroviral Agents; Biomarkers; C-Reactive Protein; Didanosine; Dideoxynucleosides; Electrocardiography; Female; HIV Infections; HIV-1; Humans; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Risk; Serum Amyloid A Protein; Serum Amyloid P-Component

Prior abacavir (ABC) or didanosine (ddI) therapy can result in the L74V/I or K65R mutation in HIV-1 reverse transcriptase. Preexisting K65R may have an impact on the treatment response to tenofovir disoproxil fumarate (TDF).. An allele-specific polymerase chain reaction (AS-PCR) assay was developed to detect K65R with a lower limit of quantitation of 0.5%.. Among baseline plasma samples from 63 treatment-naive patients, no K65R was detected by AS-PCR. Among baseline samples from 154 treatment-experienced patients, 8 had K65R and 44 had L74V/I by population sequencing. Low-level K65R was detected in an additional 11 patients by AS-PCR, 3 of whom subsequently developed full K65R. Baseline K65R correlated with absence of thymidine analog mutations (TAMs; P = 0.003) and use of ABC or ddI (P = 0.004). Patients with full or low-level K65R at baseline or with L74V/I showed a diminished TDF response. Multivariate analyses confirmed that multiple TAMs, K65R, and L74V/I were independent predictors of diminished TDF response.. Prior therapy with ABC or ddI can result in a population genotype that shows K65R or L74V/I but does not reveal low-level K65R present in some patients. Subsequent treatment intensification with TDF resulted in a poor virologic response and may result in expansion of the preexisting K65R mutant.

Topics: Adenine; Alleles; Didanosine; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Organophosphonates; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI+d4T) vs. abacavir and lamivudine- (ABC+3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI+d4T- and 50 received ABC+3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI+d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC+3TC, with the 2 arms being significantly different (P<0.05). For high-density lipoprotein cholesterol rates of change, ddI+d4T decreased, while ABC+3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI+d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI+d4T or ABC+3TC.

Topics: Adult; Anti-HIV Agents; Body Composition; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Male; Middle Aged; Prospective Studies; Stavudine

Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy.. A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA < or = 400 copies/mL after > or = 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24).. Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (< 400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; < 50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed.. ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Hydroxyurea; Male; Middle Aged; Oxazines; RNA, Viral; Time Factors; Treatment Failure

We compared the long-term immunologic and virologic efficacy of the dual- and triple-nucleoside therapy for HIV infection. This was a retrospective analysis of 2 randomized clinical trials in antiretroviral-naive patients. In the dual-nucleoside group, 15 started with didanosine (ddI) monotherapy and then added stavudine (d4T) after 24 weeks, 63 started with various doses of d4T and ddI, and 53 started with zidovudine (ZDV) and lamivudine (3TC). In the triple-nucleoside group, 53 started with ZDV, 3TC, and ddI. After 48 weeks, patients who were not failing were randomized to immediate (before treatment failure) versus delayed (at the time of virologic failure) switching from ddI and d4T to ZDV and 3TC or vice versa and from ZDV, 3TC, and ddI to d4T, 3TC, and abacavir (ABC). Failure was defined as a plasma HIV-1 RNA level>or=1 log10 above nadir or >or=10,000 copies/mL when nadir was <500 copies/mL. Patients failing therapy before week 48 received the new treatment as in the immediate switching group. Hydroxyurea was added to the last treatment regimen if patients failed after week 96. CD4 count and plasma HIV-1 RNA level (branched DNA assay with a cutoff point of 50 copies/mL) at week 144 were analyzed by intention to treat. Compared with the dual-nucleoside group, the triple-nucleoside group had a higher proportion of patients with <50 copies/mL at 144 weeks (60% vs. 18%; P<0.001), higher median CD4 count (388 cells/microL vs. 346 cells/microL; P=0.018), and longer duration of response, defined as the time from onset of viral suppression (<500 copies/mL) to the time of treatment failure (the first of 2 consecutive HIV-1 RNA measurements >500 copies/mL never followed by 2 consecutive visits showing suppressible viremia to <500 copies/mL) or discontinuation from the study (144 weeks vs. 104 weeks; P=0.002). Multivariate regression analyses showed that significant predictors for treatment success, defined as a plasma viral load <50 copies/mL at week 144, were asymptomatic clinical status at enrollment, a baseline plasma viral load

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Retrospective Studies; RNA, Viral; Stavudine; Thailand; Time Factors; Zidovudine

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Denmark; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Genome, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutation; Phenotype; Reverse Transcriptase Inhibitors; Salvage Therapy; Stavudine; Time Factors; Treatment Failure

Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear.. Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks.. At baseline, the median CD4 cell count was 161 x 106 cells/l (range, 0-920) and the HIV RNA was 5.0 log10 copies/ml (range, 2.7-6.7). At 48 weeks, 43% in the A/S/D arm had a HIV RNA < or = 20 copies/ml, compared with 69% in the N/N arm (P < 0.01) and 62% in the R/S arm (P < 0.05). In a multivariate analysis, the A/S/D arm had an odds ratio of obtaining a viral load of < or = 20 copies/ml at week 48 of 0.25 [95% confidence interval (CI) 0.10-0.59] versus N/N and 0.53 (95% CI, 0.33-0.83) versus R/S. The A/S/D arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms 8%.. The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Male; Middle Aged; Nelfinavir; Nervous System Diseases; Nevirapine; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Treatment Outcome

Highly active antiretroviral therapy (HAART) of HIV disease is associated with effective virologic control, immune reconstitution, and clinical improvements. This study addresses the potential for improvements in lymphocyte phenotype and virologic responses of HIV-infected persons with extensive experience with dual nucleoside reverse transcriptase (NRTI) treatment and advanced HIV disease after a change to a potent antiretroviral therapy (NRTI + protease inhibitor). The majority of participants achieved virologic success. There was a median rise in CD4+ lymphocytes of 99 cells/mm(3) by 48 weeks, because of an increase in memory CD4+ cells at 4 and 16 weeks, followed by a later increase in naive CD4+ cells between weeks 16 and 48. The proportion of activated, DR+ CD38+ CD8+ lymphocytes decreased during the 48 weeks of follow-up. The immunologic findings (increased memory and naive T cells and reduced activation levels) were significantly improved in participants with persistent suppression of viral replication over the 48 weeks of the study. Baseline HIV RNA copy number was lower (median, 14,784 copies/ml) in persons who responded virologically than in those not suppressing viral replication (median, 49,454 copies/ml). CD4+ cell counts above the median (125/mm(3)) at time 0 for the participants, was the only baseline immunologic marker significantly associated with viral suppression at week 48. Participants older than 40 years of age demonstrated less immunologic recovery. The results of the study show that patients with extensive experience with NRTIs respond both virologically and immunologically during the first 48 weeks of therapy with a potent antiretroviral regimen.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cyclopropanes; Didanosine; Dideoxynucleosides; Double-Blind Method; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine

This article discusses the design of an ongoing open-label, randomized trial comparing three strategies of initial and subsequent HIV therapy in terms of long-term immunological and virological effect. The three treatment arms are (1) didanosine (ddI) plus stavudine (d4T) plus efavirenz (EFV) followed by zidovudine (ZDV) plus lamivudine (3TC) plus abacavir (ABC) plus nelfinavir (NFV); (2) ddI plus d4T plus NFV followed by ZDV plus 3TC plus ABC plus EFV; (3) ddI plus d4T plus EFV plus NFV followed by ZDV plus 3TC plus ABC plus saquinavir plus ritonavir. The primary objective is to determine whether it is best to start with a protease inhibitor (PI)-containing regimen, a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI)-containing regimen, or with a regimen containing both a PI and an NNRTI. The aim is to recruit over 1000 patients followed for at least 3 years. The entry criteria are broad with no restriction on stage of disease, CD4 count, or HIV viral load. The criteria for therapeutic failure determining change of treatment are not defined and are left to the clinicians, but randomization is stratified by country and by the current criteria used for changing treatment. We describe the rationale behind various aspects of the design and discuss the complexities involved in undertaking such a large trial in HIV-infected patients from 180 clinical sites in 17 countries. Control Clin Trials 2001;22:160-175

Topics: Adult; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Patient Selection; Randomized Controlled Trials as Topic; Research Design; Ritonavir; Sample Size; Saquinavir; Stavudine; Zidovudine

Sequencing of reverse-transcriptase genes and recombinant virus assays were performed on paired isolates from antiretroviral drug-naive patients randomized to stavudine and didanosine (group 1; n = 21) or zidovudine and lamivudine (group 2; n = 21) at baseline and after > or = 12 months of follow-up. The T215Y mutation emerged in 13 (61.9%) and 2 (9.5%) isolates in groups 1 and 2, respectively (P < .0001). Furthermore, in group 1, mutations associated with multidideoxynucleoside resistance were selected in 3 isolates. In group 2, all isolates carried the M184V mutation. The median fold changes in susceptibilities to zidovudine, stavudine, and lamivudine were 16.4 and 1, 2.2 and 0.6, and 4.5 and > 38 in groups 1 and 2, respectively (P < .0001, all comparisons). These results suggest that the combination of stavudine and didanosine is associated more frequently with the emergence of zidovudine resistance and a decrease in susceptibility to stavudine than the combination of zidovudine and lamivudine.

Topics: Adult; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Microbial Sensitivity Tests; Phenotype; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5'-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients.. ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity <4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94C>A (rs1127354) and c.124 + 21A>C (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs.. In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34-7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype.. This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism.

Topics: Adult; Aged; Diabetes Mellitus; Didanosine; Dideoxynucleosides; Erythrocytes; Female; Genotype; HIV Infections; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Pyrophosphatases; Reverse Transcriptase Inhibitors; Tenofovir

HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis.. We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs.. Subtype B patients ( n  =   3410) were mostly MSM (78%) and those with subtype C ( n  =   810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P  <   0.001).. Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Genetic Association Studies; Genotype; HIV Infections; HIV-1; Humans; Male; Multivariate Analysis; Mutation; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Stavudine; Tenofovir

Treatment of HIV has reduced HIV/AIDS-related mortality. Sustaining >90% virologic suppression in sub-Saharan Africa requires decentralized care and prevention services to rural communities. In Zimbabwe, the number of people receiving antiretroviral treatment (ART) has increased rapidly. However, access to treatment monitoring tools such as viral load and drug resistance testing is limited. We assessed virologic treatment outcomes among ART recipients in Nyamutora, a rural community receiving bimonthly ART and prevention services. We enrolled all ART recipients (143) at 6-monthly visits in the Nyamutora community in 2014 and 2015. Whole blood samples were collected in K-EDTA tubes, transported to Harare for CD4 counts and viral load testing, and genotype was obtained in participants with viral loads >1,000 copies/ml. Ages ranged from 2 to 75 years (median 43 years) with a median 42 months on ART at follow-up. Eight of 143 (6%) had viral loads >1,000 copies/ml at one of the 3 visits, 7 on first-line nevirapine (NVP)-based ART and 1 on second-line LPV/r-based ART. Seven participants had sequence data available, and five had drug resistance mutations, K65R, T69N, K101E, K103N, Y181C/I, M184V, and G190A. Virologic failure (p = .001) and drug resistance mutations (p = .01) on first-line NVP-based ART were associated with younger age by univariate exact logistic regression. The participants had high viral suppression (94%) despite less than optimal (NVP based) ART regimens without laboratory monitoring. Virologic failure and drug resistance were higher among children and adolescents. Effective ART delivery to the community achieved high rates of virologic suppression and minimal drug resistance.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Community Health Centers; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nevirapine; Ritonavir; Rural Population; Treatment Failure; Viral Load; Young Adult; Zimbabwe

HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] + zidovudine [ZDV] vs. EFV + 3TC + ddI) among the HIV-1 CRF06_cpx infected subjects in Estonia. HIV-1 genomic RNA was sequenced; DRMs and amino acid substitutions were compared in 44 treatment naïve and 45 first-line NNRTI + 2 NRTI treatment failed patients consisting of EFV + 3TC + ZDV (n = 17) and EFV + 3TC + didanosine[ddI] (n = 21) therapy failed sub-populations. At least one DRM was found in 78% of treatment experienced patients. The most common NRTI mutations were M184V (80%), L74V (31%), L74I (17%), K219E (9%), and M184I (9%), NNRTI mutations were K103N (83%), P225H (14%), L100I (11%), and Y188L (11%), reflecting generally the similar pattern of DRMs to that seen in treatment failed subtype B viruses. Sub-population analysis revealed that EFV + 3TC + ddI failed patients had more DRMs compared to EFV + 3TC + ZDV failed patients, especially the ddI DRM L74IV and several additional NNRTI DRMs. Additionally, CRF06_cpx specific mutation E179V and substitutions R32K, K122E, and V200AE were also detected in treatment experienced population. After the failure of the first-line EFV + 3TC + ddI therapy HIV-1 CRF06_cpx viruses develop additional NRTI and NNRTI mutations compared to EFV + 3TC + ZDV regimen. Therefore the usage of EFV + 3TC + ddI in this subtype decreases the options for next regimens containing abacavir, and NNRTI class agents.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Estonia; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Prevalence; Reverse Transcriptase Inhibitors; Zidovudine

NRTIs are essential components of HIV therapy with well-documented, long-term mitochondrial toxicity in hepatic cells, but whose acute effects on mitochondria are unclear. As acetaminophen-induced hepatotoxicity also involves mitochondrial interference, we hypothesized that it would be exacerbated in the context of ART.. We evaluated the acute effects of clinically relevant concentrations of the most widely used NRTIs, alone or combined with acetaminophen, on mitochondrial function and cellular viability.. The purine analogues abacavir and didanosine produced an immediate and concentration-dependent inhibition of oxygen consumption and complex I and III activity. This inhibition was accompanied by an undermining of mitochondrial function, with increased production of reactive oxygen species and reduction of mitochondrial membrane potential and intracellular ATP levels. However, this interference did not compromise cell survival. Co-administration with concentrations of acetaminophen below those considered hepatotoxic exacerbated the deleterious effects of both compounds on mitochondrial function and compromised cellular viability, showing a clear correlation with diminished glutathione levels.. The simultaneous presence of purine analogues and low concentrations of acetaminophen significantly potentiates mitochondrial dysfunction, increasing the risk of liver injury. This new mechanism is relevant given the liver's susceptibility to mitochondrial dysfunction-related toxicity and the tendency of the HIV infection to increase oxidative stress.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Anti-HIV Agents; Cell Line; Chemical and Drug Induced Liver Injury; Didanosine; Dideoxynucleosides; Electron Transport Chain Complex Proteins; Glutathione; Humans; Mitochondria, Liver; Mitochondrial Diseases; Oxygen Consumption; Reactive Nitrogen Species

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.. A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.. Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).. Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

Topics: Anti-HIV Agents; Base Sequence; Child; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; pol Gene Products, Human Immunodeficiency Virus; Sequence Analysis, DNA; South Africa; Statistics, Nonparametric; Stavudine

To report a case of blepharoptosis in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) with biopsy confirmed mitochondrial deletions consistent with HAART related myopathy.. A 51-year-old man with HIV demonstrated visually significant ptosis after being on HAART therapy for over 20 years.. Muscle tissue biopsy following blepharoplasty was analyzed and found to have significant mitochondrial deletions.. This patient represents a case of isolated ptosis consistent with acquired myopathy secondary to mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blepharoptosis; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA, Mitochondrial; HIV Infections; Humans; Male; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Oculomotor Muscles

There is controversy regarding cardiovascular (CV) toxicity of the nucleoside reverse-transcriptase inhibitors used to treat human immunodeficiency virus infection.. We evaluated the effects of nucleoside reverse-transcriptase inhibitors on leukocyte-endothelium interactions, a hallmark of CV diseases, in rat mesenteric vessels using intravital microscopy and in human arterial cells using a flow chamber system.. Abacavir and didanosine increased rolling, adhesion and emigration in rat vessels. These effects were reversed with antibodies against Macrophage-1 antigen (Mac-1) or intercellular adhesion molecule 1 and were reproduced in human cells. Lamivudine, zidovudine, emtricitabine, and tenofovir had no effects.. Our results support the association of abacavir and didanosine with CV diseases.

Topics: Animals; Anti-HIV Agents; Arterioles; CD11b Antigen; CD18 Antigens; Cell Adhesion; Cell Communication; Cells, Cultured; Didanosine; Dideoxynucleosides; Endothelial Cells; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Leukocyte Rolling; Leukocytes, Mononuclear; Neutrophils; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors; Venules

Telomerase is a specialized reverse transcriptase responsible for the de novo synthesis of telomeric DNA repeats. In addition to its established reverse transcriptase and terminal transferase activities, recent reports have revealed unexpected cellular activities of telomerase, including RNA-dependent RNA polymerization. This telomerase characteristic, distinct from other reverse transcriptases, indicates that clinically relevant reverse transcriptase inhibitors might have unexpected telomerase inhibition profiles. This is particularly important for the newer generation of RT inhibitors designed for anti-HIV therapy, which have reported higher safety margins than older agents. Using an in vitro primer extension assay, we tested the effects of clinically relevant HIV reverse transcriptase inhibitors on cellular telomerase activity. We observed that all commonly used nucleoside reverse transcriptase inhibitors (NRTIs), including zidovudine, stavudine, tenofovir, didanosine and abacavir, inhibit telomerase effectively in vitro. Truncated telomere synthesis was consistent with the expected mode of inhibition by all tested NRTIs. Through dose-response experiments, we established relative inhibitory potencies of NRTIs on in vitro telomerase activity as compared to the inhibitory potencies of the corresponding dideoxynucleotide triphosphates. In contrast to NRTIs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and efavirenz did not inhibit the primer extension activity of telomerase, even at millimolar concentrations. Long-term, continuous treatment of human HT29 cells with select NRTIs resulted in an accelerated loss of telomere repeats. All tested NRTIs exhibited the same rank order of inhibitory potencies on telomerase and HIV RT, which, according to published data, were orders-of-magnitude more sensitive than other DNA polymerases, including the susceptible mitochondria-specific DNA polymerase gamma. We concluded that telomerase activity could be inhibited by common NRTIs, including currently recommended RTI agents tenofovir and abacavir, which warrants large-scale clinical and epidemiological investigation of the off-target effects of long-term highly active antiretroviral therapy (HAART) with these agents.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cell Line; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA Primers; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Nevirapine; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Telomerase; Tenofovir; Zidovudine

Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Developing Countries; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Health Planning; Health Services; HIV Infections; Humans; Lamivudine; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome

The use of abacavir and didanosine in HAART has been associated with an increased risk of myocardial infarction in HIV-infected patients. The aim of this study was to address the development of endothelial dysfunction in cultivated coronary artery endothelial cells (HCAECs) in response to abacavir, didanosine and tenofovir. We examined the impact of these drugs on the expression levels of the proinflammatory, oxidative stress and apoptosis regulating genes in HCAECs.. We tested gene and protein expression changes in HCAECs in response to abacavir, didanosine and tenofovir using quantitative real-time reverse transciptase PCR, FACS and ELISA. The assessed genes/proteins included the proinflammatory molecules VCAM-1, ICAM-1, MCP-1, RANTES and IL-6. In addition, we assessed the gene expression of the intracellular reactive oxygen producing NADPH oxidase subunit gp91(PHOX) and the apoptosis regulating molecules Bcl-2 and BAD.. Exposure of HCAECs to abacavir, didanosine and tenofovir resulted in no statistically significant changes in any of the tested genes/proteins at any time point or at any concentration.. We found no evidence that abacavir, didanosine or tenofovir had direct in vitro effects on coronary endothelial cell gene transcription and protein expression of the selected mediators. If abacavir or didanosine increase cardiovascular risk, it is likely not through the direct endothelial activation pathways tested in these experiments. However, further studies are needed to completely exclude the toxicity of abacavir or didanosine on endothelial cells.

Topics: Adenine; Anti-HIV Agents; Apoptosis; Cardiovascular Diseases; Cell Adhesion Molecules; Coronary Vessels; Cytokines; Didanosine; Dideoxynucleosides; Endothelial Cells; Gene Expression; Gene Expression Profiling; HIV Infections; HIV-1; Humans; Inflammation; NADPH Oxidases; Organophosphonates; Oxidative Stress; Primary Cell Culture; Proto-Oncogene Proteins; Tenofovir

Abacavir and didanosine are nucleoside reverse transcriptase inhibitors (NRTI) widely used in therapy for HIV-infection but which have been linked to cardiovascular complications. The objective of this study was to analyze the effects of clinically relevant doses of abacavir and didanosine on human leukocyte-endothelium interactions and to compare them with those of other NRTIs.. The interactions between human leukocytes - specifically peripheral blood polymorphonuclear (PMN) or mononuclear (PBMC) cells - and human umbilical vein endothelial cells were evaluated in a flow chamber system that reproduces conditions in vivo. The expression of adhesion molecules was analyzed by flow cytometry.. Abacavir induced a dose-dependent increase in PMN and PBMC rolling and adhesion. This was reproduced by didanosine but not by lamivudine or zidovudine. Both abacavir and didanosine increased Mac-1 expression in neutrophils and monocytes, but produced no effects on either lymphocytes or the expression of endothelial adhesion molecules. The PMN/PBMC rolling and adhesion induced by abacavir or didanosine did not occur when antibodies against Mac-1 or its ligand ICAM-1 were blocked.. Abacavir induces significant human leukocyte accumulation through the activation of Mac-1, which in turn interacts with its endothelial ligand ICAM-1. The fact that didanosine exhibits similar effects and that lamivudine and zidovudine do not points to a relationship between the chemical structure of NRTIs and the induction of leukocyte/endothelial cell interactions. This mechanism may be especially relevant to the progression of the vascular damage associated with atherosclerosis and myocardial infarction in abacavir and didanosine-treated patients.

Topics: Analysis of Variance; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Didanosine; Dideoxynucleosides; Endothelial Cells; Endothelium, Vascular; Humans; Leukocytes; Macrophage-1 Antigen; Reverse Transcriptase Inhibitors; Up-Regulation

Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques.

Topics: Adenine; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Organophosphonates; Phenotype; Plasmids; Tenofovir; Viral Load

The new non-reversed transcriptase inhibitor (NRTI) drugs for treatment of acquired immunodeficiency syndrome (AIDS) are reported. An improvement in the sensitivity and selectivity of high-performance liquid chromatography was obtained by diamond electrode-electrochemical detector and fluorescence detector owing to different structural information. The four anti-retroviral NRTI drugs (abacavir, didanosine, lamivudine and zidovudine) were separated on a CapcellPak C18 UG120 column (250 mm x 4.6 mm I.D., 5 microm) with an acetonitrile-25 mM potassium dihydrogenphosphate buffer (pH 8.0; 1:9, v/v) as the mobile phase. We applied dual detection (electrochemical detection and florescence detection) for improving the peak identification and also for improved selectivity, which assisted monitoring by trace-volume samples (e.g., plasma). The electrochemical detector, equipped with a diamond electrode, was set at 2000 mV (applied voltage) and the fluorescence detector was set at excitation wavelength 275 nm and emission wavelength 315 nm. The detection limits of the four NRTIs in spiked plasma were 1-100 ng/ml by electrochemical detection and 5-10 pg/ml by fluorescence detection. The calibration graphs were linear up to 20 microg/ml by electrochemical detection and 10 microg/ml by fluorescence detection. This is the first report of LC analysis of NRTIs by electrochemical detection, also combined with fluorescence detection. The detection limits of didanosine, lamivudine and zidovudine were improved 20-fold by electrochemical detection and 500-fold by fluorescence detection compared to previous reports on UV detection. The selectivity was also improved by dual detection. The proposed method was applied to the preliminary monitoring of NRTIs in plasma.

Topics: Anti-Retroviral Agents; Chromatography, High Pressure Liquid; Didanosine; Dideoxynucleosides; Electrochemical Techniques; Fluorescence; Humans; Lamivudine; Linear Models; Reproducibility of Results; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Water; Zidovudine

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blepharoptosis; Carbamates; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Oculomotor Muscles; Organophosphates; Organophosphonates; Sulfonamides; Tenofovir

We previously reported that 2',3'-dideoxyinosine (didanosine, or ddI) significantly altered mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells in human immunodeficiency virus type 1 (HIV-1)-infected children who had undetectable plasma HIV-1 RNA for more than 2 years while receiving highly active antiretroviral therapy. This research examines the in vitro effects of nucleoside reverse transcriptase inhibitors (NRTIs) on mitochondria of human skeletal muscle cells (HSMCs), including myoblasts and differentiated myotubes. mtDNA, mitochondrial RNA (mtRNA), and mRNA levels for nuclear mitochondrial regulatory factors were quantified in vitro using HSMCs, including myoblasts and differentiated myotubes, treated with NRTIs singly and in combination. After 5 days of treatment, mtDNA was significantly decreased in myoblasts and myotubes treated with ddI (P < 0.001 and P = 0.01, respectively) and ddI-containing regimens (P < 0.001 and P < 0.001, respectively) compared to levels in untreated cells. mtRNA (MTCYB) was also significantly decreased in the myoblasts and myotubes treated with ddI (P = 0.004) and ddI-containing regimens (P < 0.001). Regardless of the NRTI regimens examined, NRTI combinations significantly decreased mtRNA (MTCO3) in myoblasts and myotubes (P = 0.02 and P = 0.01, respectively). No significant differences were observed for nuclear mitochondrial regulatory factor mRNA in myoblasts or myotubes when treated with NRTIs (P > 0.07). ddI and ddI-containing regimens significantly decrease mtDNA and mtRNA in HSMCs, most notably in myoblasts. These findings may be of particular importance in developing countries, where ddI is widely used for first-line treatment of HIV-infected children.

Topics: Cell Proliferation; Cells, Cultured; Dideoxynucleosides; DNA, Mitochondrial; Humans; Lamivudine; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts; Nucleosides; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Mitochondrial; Stavudine; Zidovudine

Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug-Related Side Effects and Adverse Reactions; Humans; Myocardial Ischemia; Risk Factors; United States; United States Food and Drug Administration

The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase can be selected by abacavir, didanosine, tenofovir, and stavudine in vivo resulting in reduced susceptibility to these drugs and decreased viral replication capacity. In clinical isolates, K65R is frequently accompanied by the A62V and S68G reverse transcriptase mutations.. The role of A62V and S68G in combination with K65R was investigated using phenotypic, viral growth competition, pre-steady-state kinetic, and excision analyses.. Addition of A62V and S68G to K65R caused no significant change in human immunodeficiency virus type 1 resistance to abacavir, didanosine, tenofovir, or stavudine but partially restored the replication defect of virus containing K65R. The triple mutant K65R+A62V+S68G still showed some replication defect compared with wild-type virus. Pre-steady-state kinetic analysis demonstrated that K65R resulted in a decreased rate of incorporation (kpol) for all natural dNTPs, which were partially restored to wild-type levels by addition of A62V and S68G. When added to K65R and S68G, the A62V mutation seemed to restore adenosine triphosphate-mediated excision of tenofovir to wild-type levels.. A62V and S68G serve as partial compensatory mutations for the K65R mutation in reverse transcriptase by improving the viral replication capacity, which is likely due to increased incorporation efficiency of the natural substrates.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Organophosphonates; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Virus Replication

Topics: Didanosine; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Endothelium, Vascular; HIV Infections; Humans; Myocardial Infarction; Nucleotidases

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. TDM is useful to determine the best dosage regimen adapted to each patient. Here, we apply MALDI-TOF/TOF technology to quantify abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine in the plasma of HIV-infected patients, by standard additions analysis. Regression of standard additions was linear over the whole anti-HIV concentration range explored (1.00 x 10(-2)-1.00 pmol/microL). The absolute recovery ranged between 80% and 110%. Values of the drug concentration determined by MALDI-TOF/TOF were in the range of 1.00 x 10(-2)-1.00 pmol/microL. The limit of quantification value was 1.00 x 10(-2)pmol/microL for abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Monitoring; Feasibility Studies; Furans; Humans; Molecular Structure; Nevirapine; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrophotometry, Ultraviolet; Stavudine; Sulfonamides

Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Dideoxynucleosides; Heart Diseases; Humans; Multicenter Studies as Topic; Risk Factors

Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients.. We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals.. Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir).. There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.

Topics: Adult; Aged; Aged, 80 and over; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Poisson Distribution; Reverse Transcriptase Inhibitors; Risk Factors

Topics: Anti-HIV Agents; Australia; Didanosine; Dideoxynucleosides; Europe; Heart Diseases; HIV Infections; HIV-1; Humans; Myocardial Infarction; North America; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors

We describe an unusual pathway of human immunodeficiency virus type 1 reverse transcriptase resistance during therapy with tenofovir-emtricitabine, characterized initially by the mutations K70E and M184V and later by K70G and M184V, with the two mutations coexisting on the same viral genome. Phenotypic resistance to lamivudine, emtricitabine, abacavir, didanosine, and tenofovir was observed, whereas susceptibility to zidovudine and stavudine was preserved.

Topics: Adenine; Amino Acid Substitution; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Emtricitabine; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Molecular Sequence Data; Mutation; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Zidovudine

To improve adherence and virologic suppression, we assessed the feasibility and effectiveness of a once-daily regimen of efavirenz with 3 nucleoside reverse transcriptase inhibitors as first-line or second-line highly active antiretroviral therapy in a cohort of HIV-1-infected children.. HIV-1-infected children naive to efavirenz were treated with a combination of efavirenz, abacavir, didanosine, and lamivudine in an observational, prospective, single-center study. Virologic failure-free survival was assessed with Kaplan-Meier analysis. The CD4+ T-cell increase was estimated by using a generalized linear model incorporating repeated measurements.. Thirty-six children received the study medication for a median of 69 weeks. Virologic failure-free survival rates were 76% and 67% after 48 weeks and 96 weeks, respectively. No significant difference was found in efficacy between first-line and second-line highly active antiretroviral therapy. All children receiving highly active antiretroviral therapy showed a sustained CD4+ T-cell increase, irrespective of virologic suppression. Growth rates improved with highly active antiretroviral therapy. Study medication administration was stopped for 14 children, mostly because of nonadherence (4 cases) or virologic rebound (5 cases) and because of adverse events (unrelated death and grade 2 liver toxicity) in 2 cases. Lipid abnormalities and abacavir-related hypersensitivity were not observed.. For the first time, once-daily highly active antiretroviral therapy is demonstrated to be a safe, convenient, and potent antiretroviral regimen for HIV-1-infected children.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child Development; Child, Preschool; Cholesterol; Cohort Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Oxazines; Patient Compliance; Prospective Studies; Treatment Outcome

The effects of HIV infection, highly active antiretroviral therapy (HAART), and specific antiretroviral agents on lipoproteins in women are not well described.. In a cross-sectional substudy of the Women's Interagency HIV Study with 623 HIV-negative and 1556 HIV-positive women (636 untreated, 419 on non-protease inhibitor [PI] HAART, and 501 on PI-containing HAART), we performed multivariate analyses of associations among fasting lipoprotein levels, HIV infection, and HAART.. Untreated HIV-positive women had lower high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TGs) but not lower low-density lipoprotein cholesterol (LDL-C) than HIV-negative women and were the most likely to have unfavorable HDL-C by National Cholesterol Education Program (NCEP) guidelines. PI HAART users had higher LDL-C than untreated HIV-infected women (107 vs. 100 mg/dL, P = 0.0006) and were the most likely to have unfavorable LDL-C and TGs by NCEP guidelines. HIV-negative women and non-PI HAART users had similar HDL-C levels (55 and 53 mg/dL, respectively), which were higher than those in untreated HIV-infected women and PI HAART users (42 and 49 mg/dL, respectively; P < 0.001 for all). Lamivudine, didanosine, nevirapine, and efavirenz were independently associated with higher HDL-C (P < 0.001 for all). Ritonavir, indinavir/ritonavir, and nelfinavir were associated with higher LDL-C (P < 0.01 for all). Stavudine, abacavir, and all ritonavir-containing regimens were associated with higher TGs (P < 0.05 for all), and tenofovir was associated with lower TGs (P = 0.009).. A dyslipidemic pattern was associated with HIV infection itself, was more severe in users of PI-containing HAART, but was not present in women taking non-PI HAART.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Black People; Cholesterol; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Fasting; Female; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV Seropositivity; HIV-1; Humans; Indinavir; Lamivudine; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Multivariate Analysis; Nelfinavir; Nevirapine; Organophosphonates; Ritonavir; Stavudine; Tenofovir; Triglycerides; United States; White People

We identified a deletion at codon 70 (Delta70) of HIV-1 reverse transcriptase (RT) occurring together with L74V and Q151M mutations in a sample from a tenofovir (TFV)- and abacavir (ABC)-treated patient with extensive prior antiretroviral treatment. To investigate the characteristics of this mutant, we studied the drug susceptibility, relative infectivity, and fitness of viruses carrying Delta70 and associated RT mutations. The Delta70, L74V, and Q151M mutations were introduced into Hxb2 RT by site-directed mutagenesis and expressed in HIV-1 recombinants. The Delta70 mutation increased resistance to lamivudine and emtricitabine alone and in combination with various resistance mutations and augmented resistance to ABC and didanosine when present together with L74V. A recombinant virus expressing RT from the original clinical viral sample (Delta70-PRT) exhibited greater fitness than one in which the deletion had been repaired (K70-PRT). The Delta70 mutation also increased fitness of Hxb2 wild-type and 74V and Q151M mutants. Recombinants carrying Delta70-PRT showed greater relative infectivity in the presence of ABC (but not TFV) compared with K70-PRT recombinants. These results show that Delta70 enhances resistance to certain purine and pyrimidine analogues and contributes to multinucleoside resistance in the appropriate viral genetic background.

Topics: Adenine; Antiviral Agents; Cell Line, Transformed; Codon; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Emtricitabine; HeLa Cells; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Organophosphonates; Point Mutation; Reassortant Viruses; Reverse Transcriptase Inhibitors; Tenofovir

Topics: Administration, Oral; Didanosine; Dideoxynucleosides; Drugs, Generic; HIV Infections; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

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.. 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. Lack of PK alteration bounds (90% confidence intervals [CI]) for the NRTIs were based on the lack of PK-based dose adjustments per prescribing information.. Twenty-four of 28, 32/32, and 24/26 subjects completed the ZDV-EVG/r, ddI/d4T-EVG/r, and ABC-EVG/r studies, respectively. All study drugs were well tolerated and no serious adverse events were noted. The PK of ZDV, its glucuronide (G-ZDV), d4T, ABC, and EVG were within the lack of PK alteration 90% CI bounds upon coadministration. Exposures of ddI were modestly (approximately 15%) lower, but these changes are unlikely to be clinically meaningful.. There are no clinically relevant drug interactions between EVG/r and the NRTIs zidovudine, didanosine, stavudine, or abacavir. These agents can be coadministered without dose adjustment.

Topics: Adolescent; Adult; Confidence Intervals; Cross-Over Studies; Didanosine; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Stavudine; Zidovudine

HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTI)-only based, comprising tenofovir DF(TDF) have been shown to lead to high rates of virological failures (VF), mainly in patients on first-line combination therapy. We wished to investigate the virological response to these regimens in a large cohort of antiretroviral (ARV)-treated patients.. Patients followed-up in the Aquitaine Cohort in 2001-2003 and who had received NRTI-based, TDF-including regimens for at least 3 months were included. The VF was defined as: (i) a decrease in plasma HIV-1 RNA <0.5 log(10)copies/ml between M0 and M3; or (ii) a plasma HIV-1 RNA >50 copies/ml at M3 in patients with plasma HIV-1 RNA <50 copies/ml at M0. The baseline RT genotype was determined in a subgroup of patients.. Within 121 patients (95% ARV-experienced) who received either lamivudine (3TC)/didanosine (DDI)/TDF (n=48), or abacavir (ABC)/3TC/TDF (n=14), or 3TC/zidovudine (ZDV)/TDF (n=27), or 3TC/ZDV/ABC/TDF (n=20), or DDI/ABC/TDF (n=12), the ABC/3TC/TDF and DDI/ABC/TDF combinations were associated with the highest frequencies of VF. In contrast the use of ZDV was related to a better virological response. The baseline RT genotype was also predictive of the virological outcome.. NRTI-based, TDF-including therapies can lead to high rates of VF both in ARV-naïve and in ARV-experienced patients. Our data strongly suggest the interest of associating ZDV and TDF in these regimens.

Topics: Adenine; Cohort Studies; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; France; HIV Infections; HIV Reverse Transcriptase; HIV-1; Hospitals, University; Humans; Lamivudine; Mutation; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Species Specificity; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

The K65R mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is selected in vitro by many D-nucleoside analog RT inhibitors (NRTI) but has been rarely detected in treated patients. In recent clinical trials, the K65R mutation has emerged frequently in patients experiencing virologic failure on antiretroviral combinations that do not include 3'-azidothymidine (AZT). The reason for this change is uncertain. To gain insight, we examined trends in the frequency of K65R in a large genotype database, the association of K65R with thymidine analog mutations (TAMs) and other NRTI mutations, and the viral susceptibility profile of HIV-1 with K65R alone and in combination with TAMs. Among >60,000 clinical samples submitted for genotype analysis that contained one or more NRTI resistance mutations, the frequency of K65R increased from 0.4% in 1998 to 3.6% in 2003. Among samples with K65R, a strong negative association was evident with the TAMs M41L, D67N, L210W, T215Y/F, and K219Q/E (P<0.005) but not with other NRTI mutations, including the Q151M complex. This suggested that K65R and TAMs are antagonistic. To test this possibility, we generated recombinant HIV-1 encoding K65R in two different TAM backgrounds: M41L/L210W/T215Y and D67N/K70R/T215F/K219Q. K65R reduced AZT resistance from >50-fold to <2.5-fold in both backgrounds. In addition, TAMs antagonized the phenotypic effect of K65R, reducing resistance to tenofovir, abacavir, 2',3'-dideoxycytidine, dideoxyinosine, and stavudine. In conclusion, K65R and TAMs exhibit bidirectional phenotypic antagonism. This antagonism likely explains the negative association of these mutations in genotype databases, the rare emergence of K65R with antiretroviral therapies that contain AZT, and its more frequent emergence with combinations that exclude AZT.

Topics: Adenine; Amino Acid Substitution; Anti-HIV Agents; Arginine; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Genotype; HIV Reverse Transcriptase; HIV-1; Humans; Lysine; Organophosphonates; Phenotype; Point Mutation; Reverse Transcriptase Inhibitors; Tenofovir; Thymidine; Zalcitabine; Zidovudine

A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength of 260 nm. The assay was validated over the concentration range of 0.015-5 mg/l for all five NRTIs. The average accuracies for the assay were 92-102%, inter- and intra-day coefficients of variation (CV) were <2.5% and extraction recoveries were higher than 97%. This method proved to be simple, accurate and precise, and is currently in use in our laboratory for the quantitative analysis of NRTIs in plasma.

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Didanosine; Dideoxynucleosides; Drug Stability; HIV; HIV Infections; Humans; Lamivudine; Quality Control; Reproducibility of Results; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Stavudine; Zidovudine

The human immunodeficiency virus type 1 (HIV-1) resistance profile, K65R, K70E and M184V, on reverse transcriptase gene was associated with the virologic rebound consecutively to the switch of lopinavir/r to tenofovir DF in a stable regimen with nucleoside backbone of abacavir, lamivudine and didanosine. The high selective pressure on the same resistance pathway was probably associated with the loss of antiviral potency, even in well-controlled patient.

Topics: Adenine; Adult; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Gabon; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lopinavir; Microbial Sensitivity Tests; Mutation; Organophosphonates; Pyrimidinones; Tenofovir; Viral Load

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Stevens-Johnson Syndrome

In patients coinfected and treated for both HIV-1 and hepatitis C virus (HCV), administration of ribavirin (RBV) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5'-monophosphate dehydrogenase. Drug interactions between tenofovir and RBV were studied in vitro in order to provide insights into the safety of co-administration of tenofovir disoproxil fumarate (DF) and RBV in HCV/HIV-1-coinfected patients. In accordance with previous in vitro studies, strongly increased anti-HIV activity was observed when RBV was combined with didanosine (ddl). In contrast, low-level anti-HIV antagonism was observed when RBV was combined with either tenofovir or abacavir. Significantly stronger anti-HIV antagonism was observed when RBV was combined with either zidovudine, stavudine, emtricitabine or lamivudine. Thus, although tenofovir and ddl are both adenosine analogues, their in vitro interactions with RBV are markedly different. These results suggest a low potential for increased toxicity upon co-administration of tenofovir DF with RBV in patients.

Topics: Adenine; Antiviral Agents; Cell Line; Cytopathogenic Effect, Viral; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Synergism; HIV-1; Humans; Organophosphonates; Reverse Transcriptase Inhibitors; Ribavirin; Tenofovir

We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed

Topics: Adenine; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Nucleosides; Nucleotides; Organophosphonates; Organophosphorus Compounds; Prevalence; Tenofovir

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; European Union; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Patient Selection; Pilot Projects; Safety; Tenofovir; Treatment Failure; Viral Load

To analyse the impact of the M184I/V mutation and individual thymidine-associated mutations (TAM) on nucleoside reverse transcriptase inhibitor (NRTI) phenotypic susceptibility and compare these results with those obtained using commercial and public algorithms.. An HIV genotypic/phenotypic database with over 27 000 samples was used to obtain the median fold change (5-95th percentile) in NRTI phenotypic susceptibility for viruses from patients containing individual TAM with or without the M184I or V mutation and for wild-type patient viruses.. The resulting data indicated that in vitro, individual TAM do not have an equivalent impact on NRTI resistance, with some individual TAM having little or no impact on NRTI resistance (e.g. M41L or K219Q/E/H/R). In the presence of the M184I/V mutation, re-sensitization to some drugs, including zidovudine, stavudine and tenofovir was observed despite the presence of a TAM. For didanosine and abacavir, the presence of the M184V mutation and a single TAM did not result in a fold-change increase associated with decreased drug susceptibility. Analysis of public and commercial algorithms revealed a lack of concordance regarding the impact of these mutations, and with the observed phenotypic data.. These analyses should assist in the creation of rules for genotypic drug resistance algorithms for a better reflection of the impact of individual TAM and also the impact of M184I/V on resistance. These data provide additional evidence that retaining lamivudine in those treatment regimens in which TAM can be selected may provide some therapeutic benefit by maintaining the M184V mutation.

Topics: Adenine; Algorithms; Anti-HIV Agents; Databases, Genetic; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV; HIV Infections; Humans; Mutation; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Thymidine; Zalcitabine; Zidovudine

Drug resistance testing provides useful information for managing HIV-infected patients. Phenotyping could add complementary information to genotyping and occasionally be more useful, although is less available to clinicians. Large paired geno-pheno databases have allowed the prediction of phenotypes from genotypes. However, the accuracy of these virtual phenotypes (vPT) in a clinical setting has not been well assessed yet. We analyzed the concordance between vPT and interpreted genotype (GT) in 105 samples belonging to treatment-experienced HIV-infected patients. A high concordance was seen when examining both non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) (r = 0.95 either), while it was lower for nucleoside analogs (r = 0.79). The drugs with lower concordance were abacavir (71.1%), tenofovir (71.5%) and didanosine (71.9%). In 20% of specimens (21/105), the vPT did not provide results for all approved drugs. These were mainly samples with a high number of drug resistance mutations or rare genotypes, which seem to be underepresented in the VircoNET database. Overall, there is good correlation between vPT/GT, especially for PI and NNRTI. The inclusion of additional sequences in the VircoNET database, mainly those derived from heavily treatment-experienced patients and/or from patients failing the most recently approved drugs might improve its performance.

Topics: Adenine; Amino Acid Substitution; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; Nucleosides; Organophosphonates; Phenotype; Protease Inhibitors; Reverse Transcriptase Inhibitors; Tenofovir

Nucleoside analogues are suspected of playing a role in peripheral fat loss in patients during long-term treatment with antiretroviral drugs.. We compared the long-term effects of stavudine (10 microM), zidovudine (1 muM), didanosine (10 microM), abacavir (4 microM), lamivudine (10 microM), and tenofovir (1 microM), near their maximum concentration values, on the differentiation, lipid accumulation, survival and mitochondrial function of differentiating 3T3-F442A and differentiated 3T3-L1 adipocytes.. None of the nucleoside reverse transcriptase inhibitors (NRTI) markedly altered the differentiation of 3T3-F442A cells, as shown by the unmodified percentage of cells with lipid droplets on day 7 and the expression of the early differentiation markers CCAAT/enhancer binding protein (C/EBP) beta (on day 2) and sterol regulatory element-binding protein. However, stavudine and zidovudine altered the lipid phenotype, decreasing the lipid content and expression of markers involved in lipid metabolism, namely C/EBPalpha, peroxisome proliferator-activated receptor gamma, adipocyte lipid binding protein 2, fatty acid synthase and acetyl-coenzyme A carboxylase. Stavudine and zidovudine, contrary to the other NRTI, drove 5-10% of 3T3-F442A cells towards apoptosis, and reduced the lipid content and survival of differentiated 3T3-L1 adipocytes. Stavudine and zidovudine increased mitochondrial mass by two to fourfold, and lowered the mitochondrial membrane potential (JC-1 stain) as did zalcitabine (0.2 microM). Co-treatment with zidovudine plus lamivudine, or zidovudine plus lamivudine and abacavir, did not increase the effect of zidovudine on cell viability or apoptosis.. The thymidine analogues stavudine and zidovudine decreased lipid content, mitochondrial activity, and adipocyte survival in vitro.

Topics: 3T3-L1 Cells; Adenine; Adipocytes; Animals; Apoptosis; Cell Differentiation; Didanosine; Dideoxynucleosides; HIV-1; HIV-Associated Lipodystrophy Syndrome; Lamivudine; Lipid Metabolism; Mice; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Zidovudine

To evaluate the safety and efficacy of rechallenging patients who have recovered from nucleoside reverse transcriptase inhibitor (NRTI)-induced symptomatic hyperlactatemia or lactic acidosis with alternative NRTI-containing regimens.. Data in this case series was collected from patients followed at the UCSD Owen Clinic from July 1998 through September 2002. Cases of symptomatic hyperlactatemia were HIV-infected adults receiving NRTI who had symptoms compatible with hyperlactatemia and two lactates > 2 times the upper normal limit. Lactic acidosis was defined as lactate > 5 mmol/l with bicarbonate < 20 mmol/l. The suspected offending NRTI in the prior regimen were replaced with other NRTI thought to have equivalent antiviral potency but less mitochondrial toxicity.. Ten patients diagnosed with symptomatic hyperlactatemia and two with lactic acidosis were later restarted on antiretrovirals that included new NRTI. The NRTI that patients were receiving when symptomatic hyperlactatemia or lactic acidosis was diagnosed included stavudine and lamivudine (n = 6), stavudine and didanosine (n = 4), and stavudine and abacavir (n = 2). The median (range) peak lactate was 5.4 (4.7-19.1) mmol/l. Five patients were rechallenged with abacavir and lamivudine, five with zidovudine, abacavir and lamivudine, and two with zidovudine and lamivudine. Among the 12 patients contributing over 22 years of cumulative reexposure to NRTI-containing therapy, one developed symptomatic hyperlactatemia again yielding a recurrence rate of 45.5 cases/1000 patient-years. Virologic control was maintained in all patients.. This data supports the strategy that in cases of symptomatic hyperlactatemia or lactic acidosis in which the toxicity is associated with stavudine, didanosine or both, it is safe and efficacious to reintroduce NRTI that are less potent inhibitors of mitochondria.

Topics: Acidosis, Lactic; Adult; Alanine Transaminase; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Zidovudine

To evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy.. Cross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Cox's proportional hazards model.. Patients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated > or = 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Cox's proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlactataemia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactataemia. Choice of thymidine analogue did not influence risk. Hyperlactataemia was associated with acid-base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis.. Screening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid-base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Lactic Acid; Longitudinal Studies; Male; Multivariate Analysis; Prospective Studies; Reproducibility of Results; Risk Factors; Sex Factors; Thymidine

To determine the extent to which genotype (GT) or phenotype (PT) methods provide HIV-1 drug resistance information that is overlapping or complementary, both tests were performed on 1378 patient plasma samples. Discordance, defined as determination of reduced susceptibility measured by PT but sensitivity by GT (PT-R/GT-S), or vice versa (PT-S/GT-R), was common: 83, 62, 43, and 28% of samples with evidence of drug resistance had at least 1, 2, 3, or 4 drugs discordant, respectively. Three types of discordance were observed: PT-R/GT-S, and PT-S/GT-R with or without the presence of mixtures at resistance-associated positions (25%, 34%, and 41% of all discordance, respectively). After accounting for mixtures, results for didanosine (30%), zalcitabine (18%), tenofovir (17%), abacavir (14%), lamivudine (12%), and amprenavir (11%) were discordant in >or= 10% of samples. PT-S/GT-R results were most common for didanosine and zalcitabine, whereas PT-R/GT-S results were most common for lamivudine and amprenavir. PT provided quantitative assessment of the degree of reduced susceptibility and identified reduced susceptibility (PT-R/GT-S) or normal susceptibility (PT-S/GT-R) that was not recognized by the GT interpretation algorithm. GT provided valuable information when mixtures were present and minor populations of drug resistant virus were not detected by phenotyping (PT-S/GT-R results). This demonstrates the complementary nature of information provided by PT and GT tests and suggests that their combined use can provide additional clinically-relevant information.

Topics: Adenine; Anti-HIV Agents; Carbamates; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir; Zalcitabine

Clinical studies with tenofovir disoproxil fumarate, an oral prodrug of the nucleotide analog tenofovir, recently approved for the treatment of HIV, have demonstrated antiviral activity and good tolerability in HIV-infected patients. In order to better understand the cytotoxicity profile of tenofovir relative to the other nucleoside reverse transcriptase inhibitors (NRTIs), the in vitro effects of these agents were evaluated in various human cell types. Tenofovir inhibited the proliferation of liver-derived HepG2 cells and normal skeletal muscle cells with CC(50) values of 398 and 870 microM, respectively. In comparison, ZDV, ddC, ddI, d4T, and abacavir all showed lower CC(50) values in these two cell types. Evaluation of hematopoietic toxicity revealed that tenofovir was less cytotoxic towards erythroid progenitor cells (CC(50)>200 microM) than ZDV, d4T, and ddC (CC(50)=0.06-5 microM). Despite some degree of donor-to-donor variability, the inhibitory activity of the tested NRTIs against myeloid cell lineage, in the order of decreasing severity, was consistently ddC>ZDV>d4T>tenofovir>3TC. Finally, tenofovir showed substantially weaker effects on proliferation and viability of renal proximal tubule epithelial cells than cidofovir, a related nucleotide analog with the potential to induce renal tubular dysfunction. In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease.

Topics: Adenine; Anti-HIV Agents; Antigens, CD34; Cell Line; Didanosine; Dideoxynucleosides; Epithelial Cells; Hematopoietic Stem Cells; Humans; Kidney Tubules, Proximal; Liver; Muscle, Skeletal; Organophosphonates; Organophosphorus Compounds; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Tumor Cells, Cultured; Zalcitabine; Zidovudine

Mycophenolate mofetil (MMF), a therapeutically used inhibitor of inosine monophosphate dehydrogenase is hydrolyzed to its active metabolite mycophenolic acid (MPA) in vivo. MPA exhibits anti-HIV activity in vitro. We tested MPA alone and in combination with abacavir (ABC), didanosine (DDI), lamivudine (3TC) and tenofovir (TFV) against wild-type human immunodeficiency virus type-1 (HIV-1) and nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV-1. MPA (62.5-500 nM), when combined with ABC or DDI, synergistically enhanced activity against wild-type HIV and the NRTI-resistant HIV clone DRSM34. MPA also enhanced the activity of TFV against both wild-type HXB2 and TFV-resistant strain HIV(K65R), in a more than additive manner. No significant antiproliferative effect of MPA (< or =0.25 microM) alone or in the presence of ABC, DDI and TFV was observed. This indicates that the antiviral effects of MMF may be clinically achievable without fully blocking T-cell proliferation or inducing immunosuppression. These findings provide further rationale for the clinical testing of MMF in combination with ABC, DDI, and TFV.

Topics: Adenine; Cells, Cultured; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Enzyme Inhibitors; HIV-1; Humans; Leukocytes, Mononuclear; Mycophenolic Acid; Organophosphonates; Organophosphorus Compounds; Reverse Transcriptase Inhibitors; Tenofovir; Virus Replication

Topics: Didanosine; Dideoxynucleosides; Drug Administration Schedule; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, recently diagnosed HIV-1-infected persons, we identified a distinct group of viruses that have mutations at codon 215 of the reverse transcriptase (RT) gene that are different from either the wild-type (WT) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 215D/C/S and were found in 20 patients (3.3%). The 215D, 215C, and 215S mutations differ from 215Y by a 1-nt change compared with 2 nt for the WT T215 and likely represent revertants of 215Y. These viruses all were found to have WT susceptibility to AZT, and all replicated efficiently as WT HIV-1(T215). However, differences in fitness among HIV-1(215D), HIV-1(215C), and HIV-1(215S) were seen when RT backgrounds were changed, demonstrating a role of the RT background in the selection of these revertants. In vitro selection with AZT showed that HIV-1(215D) and HIV-1(215C) acquired 215Y more rapidly than did WT HIV-1(T215), likely reflecting the need for only 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutations at codon 215 replicate efficiently, have WT susceptibility, and are commonly found in treatment-naive persons. The increased ability for selecting resistance mutations defines this class of WT HIV-1 and highlights the higher potential of these viruses to compromise the efficacy of antiretroviral therapy.

Topics: Anti-HIV Agents; Base Sequence; Didanosine; Dideoxynucleosides; DNA, Viral; Drug Resistance, Viral; Evolution, Molecular; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutagenesis; Recombination, Genetic; Reverse Transcriptase Inhibitors; Stavudine; Virus Replication; Zalcitabine; Zidovudine

To compare the efficacy of the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, zidovudine (AZT), lamivudine (3TC), didanosine (ddI), and stavudine (d4T) to inhibit viral replication in brain macrophages. A severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE) was used to monitor spreading viral infection in the CNS.. The development of antiretroviral therapies with CNS efficacy against neuroinvasive virus is important if eradication of HIV-1 can be achieved within critical "hidden reservoirs.". HIV-1-infected human monocyte-derived macrophages (MDMs) (after a single round of viral replication) were inoculated into the caudate and putamen of SCID mice. This resulted in the spreading of viral infection with a concomitant multinucleated giant cell encephalitis (astrogliosis, microglial activation, and neuronal injury). NRTIs were administered to animals at the time of intracerebral MDM inoculations and continued until the time of sacrifice. Antiretroviral effects were assessed by viral load and percentages of infected MDMs.. In brains of SCID mice with HIVE, abacavir and lamivudine reduced HIV-1 p24 antigen-positive cells by 80% and 95%, respectively, whereas both decreased viral load by approximately 1 log. Zidovudine, didanosine, and stavudine showed variable effects.. Abacavir and lamivudine showed significant antiretroviral activity in SCID mice with HIVE when compared with other NRTIs. The extrapolation of these results to humans with HIV-1 dementia awaits future investigations.

Topics: AIDS Dementia Complex; Animals; Cells, Cultured; Didanosine; Dideoxynucleosides; Disease Models, Animal; HIV-1; Humans; Lamivudine; Male; Mice; Mice, SCID; Monocytes; Reverse Transcriptase Inhibitors; Stavudine; Virus Replication; Zidovudine

Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Costs; Drug Therapy, Combination; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine

To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patients.. A total of 255 samples from patients treated with lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and stavudine using a recombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold compared with wild-type (high-level resistance, > 10-fold). A genotypic analysis of plasma-derived reverse transcriptase coding regions was carried out in samples with cross-resistance.. The majority of samples displayed wild-type or greater than wild-type sensitivity to zalcitabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in samples with high ZDV resistance. There was no obvious correlation between cross-resistance and genotype; all but two samples were mutant at codon 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n=27) were four- to eightfold less sensitive to abacavir. There were no other genotypic changes in addition to M184V known to be associated with abacavir resistance.. Cross-resistance was not commonly observed in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavudine or combinations containing abacavir.

Topics: Anti-HIV Agents; Cohort Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Methionine; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Valine; Zalcitabine; Zidovudine