abacavir and Acquired-Immunodeficiency-Syndrome

Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols.. Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n = 786) regimens in ACTG protocols 384, A5142, A5095, and A5202.. Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P < 5 × 10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition.. No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Genome-Wide Association Study; HIV Infections; HIV-1; Humans; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Treatment Outcome

UNAIDS estimates that 34 million people are currently living with the human immunodeficiency virus (HIV) worldwide. Currently recommended regimens for initiating HIV treatment consist of either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir-boosted protease inhibitor (PI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs). However, there may be some patients for whom NNRTIs and PIs may not be appropriate. This is an update of the review published in the Cochrane Library Issue 3, 2009.. To evaluate the effects of any fixed-dose combination of three NRTIs (co-formulated abacavir-lamivudine-zidovudine) for initial treatment of HIV infection.. Between December 2010 and July 2011, we used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language or publication status.. We selected randomised controlled trials (RCTs) with a minimum follow-up time of six months which compared co-formulated abacavir-lamivudine-zidovudine with either PI-based or NNRTI-based therapy among antiretroviral-naive HIV-infected patients aged at least 13 years.. Three authors independently selected eligible studies, assessed risk of bias, and extracted data; resolving discrepancies by consensus. We calculated the risk ratio (RR) or mean difference (MD), as appropriate, with its 95% confidence interval (CI) and conducted meta-analysis using the random-effects method because of significant statistical heterogeneity (P<0.1).. We identified 15 potentially eligible RCTs, four of which met our inclusion criteria. The four included RCTs were conducted in the United States of America (USA); USA, Puerto Rico, Guatemala, Dominican Republic, and Panama; USA and Mexico; and Botswana, respectively. The RCTs compared co-formulated abacavir-lamivudine-zidovudine to treatment based on efavirenz (NNRTI), nelfinavir (PI), atazanavir (PI), and co-formulated lopinavir-ritonavir (PI), respectively. Overall, there was no significant difference in virological suppression between co-formulated abacavir-lamivudine-zidovudine and NNRTI- or PI-based therapy (4 trials; 2247 participants: RR 0.73, 95% CI 0.39 to 1.36). However, the results showed significant heterogeneity (I(2)=79%); with co-formulated abacavir-lamivudine-zidovudine inferior to NNRTI (1 trial, 1147 participants: RR 0.35, 95%CI 0.26 to 0.49) but with a trend towards co-formulated abacavir-lamivudine-zidovudine being superior to PI (3 trials, 1110 participants: RR 1.07, 95%CI 1.00 to 1.16; I(2)=0%). We found no significant differences between co-formulated abacavir-lamivudine-zidovudine and either PI or NNRTI on CD4+ cell counts (3 trials, 1687 participants: MD -0.01, 95%CI -0.11 to 0.09; I(2)=0%), severe adverse events (4 trials: RR 1.22, 95%CI 0.78 to 1.92; I(2)=62%) and hypersensitivity reactions (4 trials: RR 4.04, 95% CI 0.41 to 40.02; I(2)=72%). Only two studies involving PIs reported data on the lipid profile. One study found that the mean increase in total cholesterol from baseline to 96 weeks was significantly lower with co-formulated abacavir-lamivudine-zidovudine than with nelfinavir, but there were no differences with triglyceride levels. The second study found the fasting lipid profile to be comparable in both co-formulated abacavir-lamivudine-zidovudine and atazanavir arms at 48 weeks.The significant heterogeneity of effects for most outcomes evaluated was largely due to differences in the control therapy used in the included trials (i.e. NNRTIs or PIs). Using the GRADE approach, we rated the overall quality of the evidence on the relative effects of co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection as moderate. The main reason for downgrading the quality of the evidence was imprecision of the findings. The estimate of the treatment effect for each outcome has wide confidence intervals, which extend from the fixed-dose NRTI combination regimen being appreciably better to the regimen being a. This review provides evidence that co-formulated abacavir-lamivudine-zidovudine remains a viable option for initiating antiretroviral therapy, especially in HIV-infected patients with pre-existing hyperlipidaemia. The varied geographical locations of the included trials augment the external validity of these findings. We are moderately confident in our estimate of the treatment effects of the triple NRTI regimen as initial therapy for HIV infection. In the context of the GRADE approach, such moderate quality of evidence implies that the true effects of the regimen are likely to be close to the estimate of effects found in this review; but there is a possibility that they could be substantially different.  Further research should be geared towards defining the subgroup of HIV patients for whom this regimen will be most beneficial.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Lamivudine; Nelfinavir; Oligopeptides; Pyridines; Randomized Controlled Trials as Topic; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Darunavir; Decompressive Craniectomy; Dideoxynucleosides; Female; Humans; Intracranial Hypertension; Lopinavir; Medication Adherence; Meningoencephalitis; Organophosphonates; Sulfonamides; Tenofovir; Treatment Outcome

Treatment of HIV infection has typically been carried out using two nucleoside analogs and a protease inhibitor. Such regimens can be complex and have high pill burdens. Use of alternative regimens, such as triple nucleoside-based regimens, can improve adherence and decrease toxicities associated with protease inhibitor therapy. A formulation of abacavir sulfate/lamivudine/zidovudine allows a dosing schedule of one pill twice daily. The components have performed favorably compared with protease inhibitor-based regimens, such as indinavir. Compared with efavirenz-based regimens, abacavir sulfate/lamivudine/zidovudine has not performed as well. The combination is being studied as a cornerstone for induction maintenance strategies, in which switching a patient to abacavir sulfate/lamivudine/zidovudine has been associated with similar virologic outcomes as continuing with either protease inhibitor- or efavirenz-based regimens. Administration of abacavir sulfate/lamivudine/zidovudine also avoids side effects of antiretroviral therapy, such as hyperlipidemia, but its use is associated with a hypersensitivity reaction in a small number of patients. The combination of abacavir sulfate/lamivudine/zidovudine is an important part of the HIV armamentarium. Its potency and ease of administration make it worth consideration in the treatment of HIV, either by itself or in combination with other agents.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Treatment Outcome; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Cross-Sectional Studies; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Female; HIV Infections; Humans; Hyperlipidemias; Incidence; Lamivudine; Lipodystrophy; Male; Randomized Controlled Trials as Topic; Risk Assessment

The novel carbocyclic nucleoside, abacavir, is metabolized in cells to carbovir triphosphate which is a potent inhibitor of HIV reverse transcriptase (K(i) 0.021 microM with calf thymus DNA template primer). Abacavir exhibits potent in vitro antiviral activity against wild-type HIV-1 (IC(50) 4.0 microM, MT-4 cells) but this activity is lower than the activity of AZT (IC(50) 0.040 microM, MT-4 cells). However, there is no significant difference between the levels of activity of abacavir (IC(50) 0.26 microM) and AZT (IC(50) 0.23 microM) against clinical isolates of HIV-1. The in vitro toxicity data (CC(50)) of abacavir were: 160 microM (CEM cells); 140 microM (CD4+ CEM cells) and 110 microM (normal bone progenitor cells, BFU-E). Abacavir has been approved in the United States for the treatment of pediatric and adult HIV infection and current recommendations consist of combination therapy in children with HIV infection. Resistance to abacavir develops relatively slowly, with most of the mutations conferring minimal resistance. The M184V mutation appears to be the cornerstone of higher level resistance in regimens containing abacavir, imparting a 2-4 fold reduction in the susceptibility of HIV to abacavir.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Child; Dideoxynucleosides; Drug Design; Drug Resistance, Viral; HIV-1; Humans

Monotherapy to treat the human immunodeficiency virus (HIV) is now a thing of the past. Combination drug therapies and several new anti-HIV drugs in clinical trials offer new promise for slowing the progress and deleterious effects of this disease.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Chemistry, Pharmaceutical; Cyclopropanes; Dideoxynucleosides; Drug Approval; Furans; HIV Protease Inhibitors; Humans; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202.. Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms.. Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10).. Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Creatinine; Cyclopropanes; Dideoxynucleosides; Female; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Ritonavir; Tenofovir

The side-effects of anti-retroviral drugs are different between Japanese and Caucasian patients. Severe central nerve system (CNS) side-effects to efavirenz and low rate of hypersensitivity against abacavir characterize the Japanese.. The objective of this study was to select a once daily regimen for further non-inferior study comparing the virological efficacy and safety of the first line once daily antiretroviral treatment regimens in the current HIV/AIDS guideline.. The study design was a randomized, open label, multicenter, selection study. One arm was treated with efavirenz and the other with ritonavir-boosted atazanavir. A fixed-dose lamivudine plus abacavir were used in both arms. The primary endpoint was virologic success (viral load less than 50 copies/mL) rate at 48 weeks. Patients were followed-up to 96 weeks with safety as the secondary endpoint. Clinicaltrials.Gov (NCT00280969) and the University hospital Medical Information Network (UMIN000000243).. A total of 71 participants were enrolled. Virologic success rates in both arms were similar at week 48 [efavirenz arm 28/36 (77.8%); atazanavir arm 27/35 (77.1%)], but were decreased at week 96 to 55.6% in the efavirenz arm and 68.8% in the atazanavir arm (p=0.33). At the 96-week follow-up, 52.8% of the EFV arm and 34.3% of the ATV/r arm reached total cholesterol more than 220 mg/dL and required treatment. None of the patients developed cardiovascular complications in this study by week 96.. There was no significant difference in the efficacy of efavirenz and ritonavir-boosted atazanavir combined with lamivudine plus abacavir at 48 weeks. The evaluation of safety was extended to 96 weeks, which also showed no significant difference in both arms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alanine Transaminase; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cholesterol; Cyclopropanes; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Japan; Lamivudine; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

The use of mycophenolate mofetil in combination with highly active antiretroviral therapy (HAART) has been proposed in order to inhibit HIV replication. Due to the low doses involved, pharmacokinetic-pharmacodynamic monitoring is recommended.. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic monitoring of low doses of mycophenolate mofetil (0.25 g twice daily) in HIV-infected patients treated with HAART and after programmed discontinuation of HAART, in order to assess whether low doses of this immunosuppressive agent provide a biological effect.. Mycophenolic acid (MPA) plasma levels (assessed by high-performance liquid chromatography) and the capacity of patients' sera to inhibit CEM cell line proliferation (assessed by (3)H-thymidine uptake) were measured post-dose at 0, 20, 40 minutes and 1, 2, 4, 6, 8, 10 and 12 hours in nine HIV-infected patients treated with a combination of abacavir, nelfinavir and efavirenz (HAART) and mycophenolate mofetil 0.25 g twice daily at days 7, 28, 120 and 150 (30 days without HAART) after the treatment initiation. A control group of eight patients was treated with HAART alone.. In the 35 post-dose curves analysed, no differences were found in MPA levels between days 7, 28, 120 and 150: area under the plasma concentration-time curve - mean value 15.3 mg . h/L, range 10.4-24.4 mg . h/L; minimum plasma concentration - mean value 0.60 mg/L, range 0.20-4.67 mg/L; maximum plasma concentration mean value 2.60 mg/L, range 0.94-7.98 mg/L. Pretreatment patients' sera did not inhibit CEM proliferation. Post-treatment patients' sera inhibited CEM proliferation to <40% in 25 of 35 curves at 0 hours (six of nine patients), in 34 of 35 curves at 1 hour, in 32 of 35 curves at 2 hours, in 22 of 35 curves at 4 hours, and in 8 of 35 curves at 12 hours. The MPA level versus CEM proliferation inhibition had a concentration that produces 50% of the maximum drug effect (EC(50)) of 0.33 mg/L. Viral load at day 150 was >200 copies/mL in all control patients and in three of nine patients receiving mycophenolate mofetil. These three patients were the only ones repeatedly unable to inhibit pre-dose CEM proliferation to <40%.. Mycophenolate mofetil pharmacokinetic profiles in HIV patients under HAART are not significantly different from those found in transplant patients. Sera from the majority of patients receiving low doses of mycophenolate mofetil inhibited lymphocyte proliferation during most of the inter-dose interval, despite low MPA plasma levels. For some patients, higher doses may be necessary: the capacity of sera to inhibit CEM proliferation may help to identify these patients.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cell Line; Cell Proliferation; Cyclopropanes; Dideoxynucleosides; Female; HIV-1; Humans; IMP Dehydrogenase; Male; Mycophenolic Acid; Nelfinavir; Oxazines; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Adenine; Anti-HIV Agents; Dideoxynucleosides; Drug Industry; Drug Therapy, Combination; Humans; Organophosphonates; Organophosphorus Compounds; Tenofovir; Treatment Failure

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; HIV-1; Humans; Indinavir; Male; Nelfinavir; Organophosphonates; Oxazines; Phenotype; Reverse Transcriptase Inhibitors; Treatment Failure

To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with 'Virtual Phenotype' interpretation).. At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare.. Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Child; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; HIV-1; Humans; Lamivudine; Nelfinavir; Phenotype; RNA, Viral; Zidovudine

This randomized study evaluated the efficacy and tolerability of continued treatment with protease inhibitor plus nucleoside-analogue combination regimens (n=79) or a change to the simplified regimen of abacavir-lamivudine-zidovudine (n=84) in patients with suppressed human immunodeficiency virus type 1 (HIV-1) RNA for > or = 6 months who did not have the reverse transcriptase 215 mutation. After a median follow-up of 84 weeks, virologic failure was 6% in the continuation and 15% in the simplified group (P=.081). Previous zidovudine monotherapy or dual therapy and archived reverse transcriptase resistance mutations in HIV-1 DNA at baseline were significant predictors of failure. Study treatment was discontinued because of adverse events in 20% of the continuation and 7% of the simplified group (P=.021). Simplification to abacavir-lamivudine-zidovudine significantly decreased nonfasting cholesterol and triglyceride levels; however, this switch strategy carries a risk of virologic failure when treatment history or resistance testing suggest the presence of archived resistance mutations to the simplified regimen.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV-1; Humans; Lamivudine; Lipids; Male; Prospective Studies; RNA, Viral; Treatment Failure; Viral Load; Zidovudine

To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy.. In a randomized, double-blind study, 173 antiretroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) > 400 copies/ml could add other antiretrovirals. From weeks 11 to 48, samples with vRNA > 400 copies/ml were collected for genotyping and phenotyping.. At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was > 400 copies/ml in seven of 72 (10% patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone (n = 3 cases), WT (n = 3) and M184V plus thymidine analogue mutations (TAMs) (n = 1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone (n = 37), WT ( n= 1) and M184V plus TAMs (n = 3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA < 400 copies/ml (intent-to-treat with missing = failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1-2 log,10 below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively.. Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Genotype; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Phenotype; Zidovudine

Abacavir (ABC) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We compared the efficacy, safety, and tolerability of combination therapy with ABC, lamivudine (3TC), and zidovudine (ZDV) versus 3TC and ZDV in antiretroviral experienced HIV-1-infected children over 48 weeks.. Two hundred five HIV-1-infected children who had received previous antiretroviral therapy and had CD4(+) cell counts >/=100 cells/mm(3) were stratified by age and by previous treatment. Participants were randomly assigned to receive ABC (8 mg/kg twice daily [BID]) plus 3TC (4 mg/kg BID) and ZDV (180 mg/m(2) BID; ABC/3TC/ZDV group) or ABC placebo plus 3TC (4 mg/kg BID) and ZDV (180 mg/m(2); 3TC/ZDV group). Participants who met a protocol-defined switch criteria (plasma HIV-1 RNA >0.5 log(10) copies/mL above baseline at week 8 or >10 000 copies/mL after week 16) had the option to switch to open-label ABC plus any antiretroviral combination or continue randomized therapy or withdraw from the study.. The Kaplan-Meier estimates (95% confidence interval) of the proportion of participants who maintained HIV-1 RNA levels 10 000 copies/mL, a significantly higher proportion of participants in the ABC/3TC/ZDV group had HIV-1 RNA

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Confidence Intervals; Dideoxynucleosides; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Growth; HIV-1; Humans; Infant; Lamivudine; Male; RNA, Viral; Zidovudine

A Phase II clinical trial was designed to evaluate the efficacy and tolerability of twice-daily abacavir, amprenavir, and zidovudine (ZDV)/lamivudine (3TC) in HIV-1-infected study subjects naive to protease inhibitors and 3TC. Plasma and cerebrospinal fluid (CSF) HIV-1 RNA levels and T-cell subsets were measured. In all, 27 newly diagnosed and 12 chronically HIV-1-infected study subjects are included in the analysis. Week 48 plasma HIV-1 RNA levels were <500 copies/ml in 100% of study subjects, and <50 copies/ml in 80% of chronically infected and 100% of newly infected study subjects. The mean change in CD4 was (+)150 cells/microl (newly infected, p <.001), and (+)155 cells/microl (chronically infected, p <.001). At Week 48, evidence of cellular activation persisted in both cohorts. A twice-daily regimen of amprenavir, abacavir, and ZDV/3TC affords potent viral suppression and significant increases in total CD4(+) cells in HIV-1--infected study subjects. Patient intolerance may limit the efficacy of this combination.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS Dementia Complex; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Chronic Disease; Dideoxynucleosides; Digestive System; Drug Synergism; Ethnicity; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Lymphocyte Subsets; Male; Pregnancy; Research Design; RNA, Viral; Sulfonamides; Treatment Refusal; Zidovudine

To assess the effect of replacing protease inhibitors (PIs) with abacavir on insulin sensitivity and plasma lipids. -. Pilot study including 31 patients with sustained virological control on their first PI-containing HAART regimen. 16 patients were switched from PIs to abacavir (ABC group), 15 patients continued on PIs (PI group). In all patients, nucleoside-analogue reverse transcriptase inhibitors were continued.. Insulin sensitivity (using an intravenous insulin tolerance test) and fasting total cholesterol and triglycerides were determined at baseline, month 3, 6, 9 and 12.. In the ABC group, there was a significant increase in median insulin sensitivity from baseline within 6 months (+ 49 micromol/l/min), and a significant decrease in both triglycerides (-41mg/dl) and cholesterol (-40mg/dl) at month 3. These changes were sustained through month 12. In addition, a reversal of baseline insulin resistance, hypercholesterolemia and hypertriglyceridemia was observed in the majority of patients. In the PI group, no significant changes in insulin sensitivity, triglycerides and cholesterol were observed. There was a significant correlation between the changes in insulin sensitivity, triglycerides and cholesterol.. Switching from PIs to abacavir is associated with an improvement of insulin sensitivity and a decrease of cholesterol and triglycerides in the majority of patients with HAART-associated metabolic alterations and therefore might be an alternative for patients to PI-containing HAART regimens.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cholesterol; Dideoxynucleosides; HIV Protease Inhibitors; Humans; Insulin Resistance; Middle Aged; Reverse Transcriptase Inhibitors; Triglycerides; Viral Load

The heterozygous 32 base pair deletion of the chemokine receptor 5 (Delta32CCR5) has been associated with a more benign course of HIV-1-infection. To study the influence of Delta32CCR5 on the response to antiviral therapy we analyzed the presence of Delta32CCR5 by PCR in PBMC from 107 randomly selected HIV-1-infected patients treated with HAART for at least three months. 24 of 107 patients were heterozygous for Delta32CCR5 (22.4%). Before initiation of HAART Delta32CCR5 heterozygous patients (d/w) did not differ from homozygous CCR5 wild-type patients (w/w) regarding viral load and CD4 counts. After a median treatment time on HAART of 17.5 months (d/w, range 6-31 months, p = n.s.) or 19 months (w/w, range 3-33 months) all 24 patients (100%) with the Delta32CCR5 mutation, but only 58/83 patients (69.9%) with wild-type CCR5 showed a suppression of HIV-1-viremia below 500 copies/ml (p = 0.0020). Furthermore, 20/24 (83.3%) of the Delta32CCR5 heterozygous patients achieved CD4 counts above 200/microliter, but only 57/83 (68.7%) of the patients homozygous for CCR5 wild-type (p = 0.011). Our data indicate that the presence of heterozygous Delta32CCR5 is associated with a better response to HAART suggesting that therapeutic strategies targeting CCR5 could be of value for a sustained suppression of HIV-1 by HAART.

Topics: Acquired Immunodeficiency Syndrome; Alleles; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Resistance, Microbial; Female; HIV-1; Humans; Lamivudine; Male; Receptors, CCR5; Zidovudine

To compare antiretroviral efficacy, safety and tolerance of three dosing regimens of the novel nucleoside reverse transcriptase inhibitor, abacavir (1592U89) over 24 weeks and its efficacy in open-label combination with zidovudine and lamivudine.. Sixty HIV-1-infected antiretroviral therapy naive subjects (entry criteria; CD4+ cell count > or = 100 cells/mm(3), plasma HIV-1 RNA > or = 30 000 copies/ml), randomized into 20 subjects per cohort received 100, 300 or 600 mg abacavir twice daily. Subjects successfully completing 24 weeks' randomized therapy could switch to open label therapy (abacavir, zidovudine, lamivudine at 300, 300 and 150 mg twice daily, respectively) for a further 24 weeks of studly, as could subjects meeting one or more switch criteria.. Subjects were assessed for antiretroviral activity by measuring changes in plasma HIV-1 RNA load and CD4+ cell counts. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses.. At week 4, subjects receiving 300 or 600 mg abacavir twice daily had greater reductions in plasma HIV-1 RNA (median changes -1.55 and -1.61 log10) copies/ml, respectively); differences (P = 0.007 and P < or = 0.001, respectively) than subjects receiving 100 mg abacavir twice daily (median change, -0.63 log10 copies/ml). Differences between the 300 and 600 mg twice daily groups were not clinically or statistically significant. At 24 weeks, analysis showed a median change in plasma HIV-1 RNA of -0.70 and -1.30 log10 copies/ml in the 300 and 600 mg twice daily groups, respectively. During the open label phase in which zidovudine/lamivudine was added to 300 mg abacavir twice daily, a further median reduction in plasma HIV-1 RNA of 1.74 log10 copies/ml was seen. At 48 weeks pooled data from all abacavir-treated subjects showed a sustained reduction in plasma HIV-1 RNA of 2.8 log10) copies/ml; 65% and 43% of subjects had < or = 400 and < or = 50 HIV-1 RNA copies/ml, respectively, and a further median increase of 111 CD4+ cells/mm3 were seen. Abacavir was generally well tolerated with few clinically significant adverse events. Two subjects (3.3%) developed hypersensitivity reactions to abacavir. There were no differences between the groups with regard to serious adverse events.. In terms of antiretroviral therapy naive subjects, treatment with 300 or 600 mg abacavir twice daily was statistically superior to a 100 mg twice daily dose at 4 weeks. Combinations therapy containing abacavir-zidovudine-lamivudine was a highly effective antiretroviral regimen, resulting in substantial reductions in plasma HIV-1 RNA which may be comparable to combinations containing protease inhibitors. Abacavir was generally tolerated.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; HIV-1; Humans; Lamivudine; RNA, Viral; Time Factors; Viral Load; Zidovudine

To evaluate, over 12 weeks, the antiretroviral activity and safety of abacavir, used alone and in combination with zidovudine (ZDV), as treatment for HIV-1-infected subjects who had limited or no antiretroviral treatment.. Seventy-nine HIV-1-infected subjects, with CD4 cell counts 200-500 x 10(6)/l and <12 weeks of previous treatment with ZDV were enrolled in a multicenter study. Subjects were randomly assigned to one of four cohorts receiving abacavir monotherapy for the first 4 weeks (200, 400, or 600 mg every 8 h daily, or 300 mg every 12 h daily) and, thereafter, combination therapy of abacavir with 600 mg ZDV or ZDV placebo, administered in a double-blind manner for an additional 8 weeks.. Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4+ cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities during the 12-week period and for 4 weeks post-treatment.. Treatment with abacavir, alone or in combination with ZDV, produced marked decreases in plasma HIV-1 RNA loads and increases in CD4+ cell counts in all groups. At week 4, median plasma HIV-1 RNA loads decreased by 1.11-1.77 log10 copies/ml and median CD4+ cell counts increased by 63-111 x 10(6)/l in all groups. At week 12, median HIV-1 RNA loads decreased by 1.02-2.24 log10 copies/ml (abacavir monotherapy) and by 1.81-2.01 log10 copies/ml (abacavir-ZDV); median CD4+ cell counts increased by 79-195 x 10(6)/l (abacavir monotherapy) and by 93-142 x 10(6)/l (abacavir-ZDV). At week 12, the percentage of subjects who had plasma HIV-1 RNA levels below 400 and 40 copies/ml were 28 and 11%, respectively (abacavir monotherapy) and 69 and 22%, respectively (abacavir-ZDV). Eight subjects (10%) discontinued the study prematurely because of adverse events; nausea (n = 4) and hypersensitivity (n = 3) were the most common reasons for withdrawal. There were no deaths among the study subjects.. In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV-1; Humans; Male; RNA, Viral; Time Factors; Viral Load; Zidovudine

Immune reconstitution inflammatory syndrome (IRIS) represents paradoxical immune-mediated inflammation in response to an infecting pathogen, occurring after initiation of antiretroviral therapy (ART), concomitantly with immune system recovery. It has also been described in Kaposi's sarcoma (KS). We report a case of a 9-year-old Guinean girl, who developed Kaposi's sarcoma, following introduction of ART. KS associated with immune reconstitution inflammatory syndrome is rare, especially in children, but with the increased use of ART is becoming more prevalent.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Dideoxynucleosides; Drug Therapy, Combination; Female; Humans; Immune Reconstitution Inflammatory Syndrome; Lamivudine; Lopinavir; Ritonavir; Sarcoma, Kaposi

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

Women are very much susceptible for acquired immunodeficiency syndrome (AIDS) and other sexually transmitted diseases (STDs), mainly due to unprotected heterosexual vaginal intercourse and for some other social and economical disadvantages. Our aim was to formulate and optimize vaginal film of abacavir, a potent nucleoside reverse transcriptase inhibitor, for the treatment of AIDS and HIV. Abacavir films were prepared by solvent evaporation method using sodium alginate (Na-alginate) as the main polymer, Hydroxypropyl Methylcellulose E 15 (HPMC E 15) as the copolymer and glycerol as a humectant. Abacavir sulphate (ABC) was used here as a drug. Films were optimized for various physicochemical parameters such as tensile strength, % elongation at break, swelling capacity, drug content (mg/cm(2)), thickness, folding endurance, bioadhesion, pH, moisture content and SEM. Drug polymer interaction was studied by FTIR Spectra. The drug release study was accomplished in dissolution apparatus. In vivo study was also carried out. This newly formed film was one kind of sustain release type and can be considered as a novel drug carrier system for the treatment of AIDS and other STDs. It was suitable for local as well as systemic effect. The films showed good physicochemical property with good aesthetic appeal.

Topics: Acquired Immunodeficiency Syndrome; Alginates; Animals; Anti-HIV Agents; Chromatography, High Pressure Liquid; Dideoxynucleosides; Drug Delivery Systems; Female; Glucuronic Acid; Glycerol; Hexuronic Acids; HIV Infections; Humans; Hydrogen-Ion Concentration; Hypromellose Derivatives; Kinetics; Materials Testing; Microscopy, Electron, Scanning; Rabbits; Spectroscopy, Fourier Transform Infrared; Stress, Mechanical; Tensile Strength; Vagina

The authors had for objective to describe HIV-infected patients treated with ABC (Ziagen(®), ABC), and the immune, virological, and clinical treatment outcome between 2003 and 2008.. We performed a retrospective analysis of the Dat'AIDS database on patients who were treated with ABC for the first time between 2003 and 2008.. Eight hundred and thirty-six patients were included. Before initiation of ABC, 26.3% has stopped the previous treatment because of immuno-virological failure, 30.5% because of adverse events, and 29.8% for other reasons. Thirteen percent were antiretroviral naive. One third of patients were ranked as CDC class C, and more than 2/3 had a viral load<5 log copies/mL or a CD4 count≥200mm(3). ABC was mainly included in a combination containing 2 NRTI and 1 PI (63%), or 1 non-NRTI (16%). Thirty-two percent of patients were still treated with ABC after 2years of treatment and the median of ABC treatment was 11months (IQ 84days-2years). The main causes for stopping ABC were therapeutic simplification (47.4% of patients), intolerance (19.0%), and immuno-virological failure (9.8%). Suspected hypersensitivity reactions were the main cause of discontinuation due to intolerance (27.6%); the rate was 3.8% when ABC had been introduced before the routine use of the screening test HLA-B*5701. The incidence of myocardial infarction was 3.8 per 1000 patient-years; 70.6% of patients received a fixed combination including ABC after discontinuation of ABC as a single agent (Ziagen(®)).. This retrospective analysis confirmed the effectiveness and the good tolerance of ABC in the therapeutic strategy, between 2003 and 2008.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drug Utilization; Electronic Health Records; Female; France; Genetic Predisposition to Disease; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Viremia

Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on HLA-B57:01 epitope-binding in vitro and the quality and quantity of self-peptides presented by HLA-B57:01 from abacavir-treated cells.. An HLA-B57:01-specific epitope-binding assay was developed to test for effects of abacavir, didanosine or flucloxacillin on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B57:01, a B-cell line secreting soluble human leucocyte antigen (sHLA) was cultured in the presence or absence of abacavir, peptides were eluted from purified human leucocyte antigen (HLA), and the peptide epitopes comparatively mapped by mass spectroscopy to identify drug-unique peptides.. Abacavir, but not didansosine or flucloxacillin, enhanced binding of the FITC-labeled self-peptide LF9 to HLA-B57:01 in a dose-dependent manner. Endogenous peptides isolated from abacavir-treated HLA-B57:01 B cells showed amino acid sequence differences compared with peptides from untreated cells. Novel drug-induced peptides lacked typical carboxyl (C) terminal amino acids characteristic of the HLA-B57:01 peptide motif and instead contained predominantly isoleucine or leucine residues. Drug-induced peptides bind to soluble HLA-B57:01 with high affinity that was not altered by abacavir addition.. Our results support a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLA-B57:01. Drug-induced loading of novel self-peptides into HLA, possibly by abacavir either altering the binding cleft or modifying the peptide-loading complex, generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multiorgan systemic toxicity.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Autoimmunity; Cells, Cultured; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Hypersensitivity; Histocompatibility Testing; HLA-B Antigens; Humans; Models, Immunological; Peptide Fragments; Self Tolerance; Spectrum Analysis

Many different antiretroviral regimens can be used as initial therapy for infection with HIV. While all recommended regimens have been shown to be highly effective in suppressing HIV replication to undetectable levels, some differences may exist with regard to the level of immune reconstitution (eg, CD4+ cell population) that occurs. We report a case of a patient with profound and prolonged lymphopenia, despite undetectable HIV RNA levels, that reversed following a switch from a fixed-dose combination of tenofovir/emtricitabine to abacavir/lamivudine in the patient's regimen.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Anti-HIV Agents; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; Humans; Lamivudine; Middle Aged; Organophosphonates; Tenofovir

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Female; Humans; Male; Middle Aged; T-Lymphocytes

Regimens containing abacavir (ABC), tenofovir (TDF), and lamivudine (3TC) have recently been demonstrated to have high failure rates. This poses a clinical dilemma of how to manage patients currently being treated with other regimens containing tenofovir/abacavir. We evaluated the outcomes of tenofovir/abacavir regimens in our clinical practice through a retrospective review of 2655 charts. Two hundred patients (7%) were on a tenofovir/abacavir-containing regimen. Fifty-nine patients met the criteria for analysis and were grouped into three groups: (1) antiretroviral naïve, (2) virally suppressed patients switched to TDF/ABC, and (3) patients with failure of their first antiretroviral regimen. Rates of viral suppression in the naïve, switch, and first-failure groups were 95%, 86%, and 46%, respectively. In the first-failure group, viral suppression was 66% without and 18% with a preexisting M184V. A composite analysis of the groups revealed a success rate of 86% when the regimen contained zidovudine (ZDV) and 62% when it did not. No K65R mutations were noted. These findings support continued caution in the use of TDF/ABC in combination. However, these data suggest that this combination may be successfully used in selected situations such as in combination with ZDV. In patients already virally suppressed on a TDF/ABC-containing regimen, considerations include continuing the regimen or adding zidovudine, in the attempt to protect against the development of a K65R mutation and/or virologic failure, versus changing a stable regimen.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Aged; Anti-HIV Agents; Baltimore; Dideoxynucleosides; Drug Therapy, Combination; Female; Humans; Male; Medical Records; Middle Aged; Multicenter Studies as Topic; Organophosphonates; Retrospective Studies; Tenofovir; Treatment Failure; Urban Population; Viral Load

Our objective was to compare the rate of viral rebound and therapy failure in patients receiving abacavir or efavirenz as the third drug (in addition to 2 non-abacavir nucleosides) in combination antiretroviral therapy (cART) and to compare the rate of metabolic alteration associated with these regimens.. We conducted a multicohort prospective observational study of human immunodeficiency virus-infected patients who had attained viral loads < or = 80 copies/mL while receiving cART, without having previously received antiretrovirals. The rates of virological rebound, therapy failure, and lipid-level alteration during follow-up were calculated as the number of events divided by person-years of follow-up (PYFU). A multivariable analysis was performed using a Poisson regression model.. We studied a total of 744 patients; the median age was 37 years, 27% of the patients were female, and 41% were heterosexual. There was a total of 854 PYFU spent receiving efavirenz and 285 spent receiving abacavir. The nucleoside reverse-transcriptase inhibitor pairs most frequently used were zidovudine/lamivudine (66% of PYFU), stavudine/lamivudine (17.6%), and stavudine/didanosine (5.4%). The adjusted relative rates of virological failure and therapy failure for abacavir, compared with those for efavirenz, were 2.17 (95% confidence interval [CI], 1.12-4.18; P = .02) and 1.41 (95% CI, 1.01-2.01; P = .05), respectively.. Patients with virological suppression while receiving regimens containing abacavir appear more likely to experience virological and therapy failure than those receiving efavirenz as their third drug. Although this is a selected group of adherent patients, bias cannot be ruled out, because this is a nonrandomized comparison.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Alkynes; Benzoxazines; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; History, 21st Century; Humans; Lipids; Male; Middle Aged; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; Time Factors; Viral Load

Cryptococcus neoformans is an opportunistic pathogen that can manifest in immunocompromised patients with acquired immune deficiency syndrome. Prevention of cryptococcosis and other opportunistic diseases is an objective in the management of human immunodeficiency virus (HIV)-infected patients. The goal of highly active antiretroviral therapy (HAART) is to reduce the viral loads and enhance CD4 counts in HIV-infected patients. These 2 mechanisms keep HIV-infected patients healthier and enhance their immune systems, thus reducing and often preventing opportunistic infections such as ocular cryptococcal infections. Discontinuation of HAART can lead to ocular opportunistic infections such as cryptococcal choroiditis.. Presented here is a case of a patient who was treated successfully with HAART of stavudine (D4T), abacavir (Ziagen), ritonavir (Norvir), and saquinavir (Invirase). His last CD4 count before HAART was discontinued was 131 cells/mm(3), and viral load was less than 50 copies/mL. He discontinued his HAART regimen for 2 years and presented to the emergency room with complaints of a severe headache with neck pain, lightheadedness, nausea, disorientation, and unsteady gait. Lumbar puncture results showed cryptococcal infection, and the patient was admitted for the treatment of cryptococcal meningitis with amphotericin B and 5-flucytosine. Cryptococcal choroiditis was diagnosed after treatment of the meningitis. After resolution, his resultant visual acuities were 10/350 in the right eye and 10/600 in the left eye. He is on a maintenance dose of antifungal therapy and has been reinitiated on HAART of abacavir/zidovudine/lamivudine (Trizivir) and lopinavir/ritonavir (Kaletra).. This case exemplifies the importance of HAART in the prevention of opportunistic infections, cryptococcal meningitis/choroiditis in particular. Eye care professionals can play a role in encouraging patients to comply with their HAART regimens.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Choroiditis; Cryptococcus neoformans; Dideoxynucleosides; Eye Infections, Fungal; Follow-Up Studies; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Ritonavir; Saquinavir; Stavudine

To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy.. The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults.. Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed.. Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1-2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with > or = 3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus (P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), > or = 4 mutations were required to diminish virological response significantly (P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense HIV assay and the Antivirogram assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/microl by weeks 12-28.. Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; HIV-1; Humans; Mutation; Phenotype; Regression Analysis; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Failure; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Brain; CD4 Lymphocyte Count; Cidofovir; Cytosine; Dideoxynucleosides; Encephalitis; False Negative Reactions; Fatal Outcome; Humans; Immunocompromised Host; Indinavir; JC Virus; Lamivudine; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Organophosphonates; Substance Abuse, Intravenous; Time Factors; Virus Activation; Zidovudine

Of 75 human immunodeficiency virus (HIV) type 1-infected patients successfully responding to 2 nucleoside reverse-transcriptase inhibitors (NRTIs) plus 1 protease inhibitor (PI), 55 started a simplified abacavir (ABC)-based triple NRTI regimen. Influences of DNA load and DNA reverse-transcriptase (RT) mutations on virological responses were assessed at month 6 after initiation of therapy. Baseline heterogeneity was observed: peripheral blood mononuclear cell (PBMC) genotyping showed 31% RT mutations with 1-5 NRTI-related mutations, 78% protease mutations had 1-5 PI-related mutations; and HIV-1-DNA levels were 1.8-3.5 log(10) copies/10(6) PBMC. Outcomes for 49 patients on a regimen of 2 NRTIs plus ABC were as follows: 22 successes, 10 blips ("blip" defined as intermittent plasma HIV-1 RNA levels between 50 and 100 copies/mL and a return to an undetectable level), and 17 failures, whereas, for patients continuing on a regimen of 2 NRTIs plus 1 PI, there were 19 successes and 1 blip. Previous treatment regimens, baseline provirus level, and PBMC genotype predicted virological outcome.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; DNA, Viral; Drug Therapy, Combination; Female; Genotype; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Mutation; RNA, Viral; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; Humans; Lamivudine; Male; Middle Aged; Retrospective Studies; Viral Load; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Australia; Dideoxynucleosides; Ethnicity; Humans; Hypersensitivity; Immune System; Reverse Transcriptase Inhibitors

Mycophenolic acid (MPA) enhances the in vitro activity of abacavir (ABC) and other nucleoside analog reverse transcriptase inhibitors (NRTIs) against sensitive and NRTI-resistant HIV-1. This may occur via depletion of intracellular deoxyguanosine triphosphate (dGTP). Mycophenolate mofetil (MMF) 500 mg twice daily was added as a single agent to the antiretroviral regimens of five patients failing maximal available therapy. Therapy included ABC, and in most cases didanosine (DDI) and tenofovir (TDF). At entry, mean plasma HIV-1 RNA (VL) was 5.02 log copies/mL (median 4.78, range 4.71-5.63) and mean CD4 count was 106/microL (median 117, range 11-174). MMF was well tolerated. CD4 cell counts did not change significantly from baseline for up to 60 weeks of follow-up. Three of five subjects had VL declines of >0.5 log copies/mL immediately after adding MMF; a fourth subject had a sustained decline of >0.5 log copies/mL after week 8. Declines of >0.5 log copies/mL were lost in two patients at 6 and 8 weeks, and persisted in two patients at 36 and 60 weeks of follow-up, respectively. An increase in the ratio of carbovir triphosphate (CBV-TP), the active antiviral metabolite of ABC, to dGTP was documented in 3 of 4 subjects in temporal association with decreased VL. Trough plasma MPA levels ranged from 0.26-1.67 microg/mL; peak levels 90 minutes after dosing from 1.20-7.77 microg/mL. AUC of MPA appeared little changed when measured over 28 weeks of therapy. Declines in VL were observed in association with measurable changes in the CBV-TP/dGTP ratio in some patients, whereas MPA AUC was below the 30-60 microg*hr/mL range targeted in organ transplantation. The possibility that MMF may enhance the effect of selected NRTIs and be tolerated in late stage HIV disease deserves careful randomized study.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Apoptosis; CD4 Lymphocyte Count; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV-1; Humans; Mycophenolic Acid; RNA, Viral

Topics: Acquired Immunodeficiency Syndrome; Dideoxynucleosides; Drug Combinations; Drug Labeling; Humans; Lamivudine; United States; United States Food and Drug Administration; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Humans; Lamivudine; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Adult; Anaphylaxis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Humans; Male; Reverse Transcriptase Inhibitors

Abacavir and amprenavir, a nucleoside reverse transcription inhibitor and a protease inhibitor, respectively, are new drugs used for the treatment of HIV. Methadone blood concentrations were measured in five addict patients receiving methadone maintenance therapy before and after introduction of abacavir plus amprenavir. The administration of these two drugs for a median period of 14 days resulted in a significant reduction (P = 0.043) of methadone concentration, with a median decrease to 35% of the original concentration (range 28-87%). Two patients reported on several occasions nausea in the morning before the intake of the daily methadone dose, which is compatible with withdrawal reaction to opioids. Because amprenavir is a cytochrome P4503A4 substrate and is involved in the metabolism of methadone, reduction of methadone concentrations could be explained by an induction of cytochrome P4503A4.

Topics: Acquired Immunodeficiency Syndrome; Analgesics, Opioid; Carbamates; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; HIV-1; Humans; Methadone; Reverse Transcriptase Inhibitors; Substance-Related Disorders; Sulfonamides

Abacavir (1592U89) is a nucleoside inhibitor of human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT). Resistance to abacavir was studied with abacavir alone and with abacavir in combination with other nucleoside analogues in cell culture, in virus isolates from zidovudine/lamivudine clinical trials, and in the first dose-escalating 12-week clinical trial (CNA2001) to evaluate abacavir clinical potency. Abacavir alone in vitro selected for mutations at HIV RT codons K65R, L74V, Y115F, and M184V. However, abacavir combined with zidovudine selected against virus with the M184V mutation. Abacavir therapy in vivo resulted in large decreases in HIV load (>1 log), even in 1 subject who had the M184V mutation at baseline. A total of 51% of subjects showed new mutations at any of codons K65R, L74V, and M184V after abacavir monotherapy, compared with 11% who received zidovudine/abacavir. Small changes (2- to 4-fold) in abacavir susceptibility were detected. On stopping therapy, reselection of the pretherapy sequence occurred within 4 weeks.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Codon; Dideoxynucleosides; Drug Resistance; Drug Therapy, Combination; HIV Reverse Transcriptase; Humans; Mutation; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

Concerns regarding metabolic perturbations occurring during protease inhibitor (PI)-based regimens have led to investigation of switching from a PI-based to a non-nucleoside reverse transcriptase inhibitor- or abacavir-based regimen. There appear to be considerable benefits to switching from a PI-based regimen to one of these PI-sparing regimens. In particular, patients appear generally pleased with the improved administration characteristics of the new regimens, and improvements in quality of life have been reported. However, resolution of the metabolic abnormalities that may arise during PI therapy is incomplete. Peripheral or subcutaneous fat mass improvements are not evident in the studies reported to date. Weight gain, probably in part due to removal of PI-related dietary restrictions, has been observed and may lead to improvements in appearance. Maintenance of virologic control varies among studies but is generally in the range of 85% to 100% of the patients receiving the PI-sparing regimen. The extent of prior drug exposure (or drug resistance) in patients entering the studies may be a key risk factor for loss of virologic control.

Topics: Acquired Immunodeficiency Syndrome; Adipose Tissue; Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Protease Inhibitors; Humans; Lipodystrophy; Nevirapine; Oxazines

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Anti-HIV Agents; Carbamates; Coronary Disease; Dideoxynucleosides; Drug Therapy, Combination; Furans; Hepatitis B; HIV Protease Inhibitors; Humans; Hyperlipoproteinemias; Male; Middle Aged; Pancreatitis; Risk Factors; Ritonavir; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiviral Agents; Child; Clinical Trials as Topic; Dideoxynucleosides; Enzyme Inhibitors; Guanidines; Hepatitis B; Humans; Influenza, Human; Lamivudine; Neuraminidase; Pyrans; Reverse Transcriptase Inhibitors; Sialic Acids; Zanamivir

Abacavir is a novel nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection. A simple and rapid high-performance liquid chromatographic method for the quantification of abacavir in human plasma suitable for pharmacokinetic research purposes is described. Sample pretreatment consists of protein precipitation with perchloric acid. The supernatant is injected directly into the chromatographic system after centrifugation. The drug is separated from endogenous compounds by isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection at 285 nm. The method has been validated over the range of 20-2000 ng/ml using a volume of 300 microl of plasma. The assay is linear over this concentration range as indicated by the F-test for lack-of-fit. Within- and between-day precisions are less than 7.5% for all quality control samples. The lower limit of quantitation is 20 ng/ml and the recovery of abacavir is 88.1% (+/-1.3%). Frequently coadministered drugs did not interfere with the described methodology. Abacavir is stable in human plasma under various relevant storage conditions, for example when stored for 51 days at -20 degrees C. This validated assay is suited for use in pharmacokinetic studies with abacavir in human plasma and can readily be implemented in the setting of a hospital laboratory for the monitoring of abacavir concentrations.

Topics: Acquired Immunodeficiency Syndrome; Chemical Precipitation; Chromatography, High Pressure Liquid; Dideoxynucleosides; Drug Stability; Humans; Hydrogen-Ion Concentration; Perchlorates; Quality Control; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Sulfonamides; Viral Load

The 12th World AIDS Conference in Geneva brought together AIDS researchers, medical care providers, advocates, and people living with HIV to discuss implications related to providing global access to care. New drugs have decreased deaths and opportunistic infections in developed countries, but developing countries are becoming overwhelmed by the number of new patients. The World Health Organization estimates that the majority of the 30.6 million people infected with HIV/AIDS worldwide will die within a decade unless a cure is found or treatments are made accessible to them. Researchers are no longer optimistic about the feasibility of viral eradication, and instead are looking for strategies to overcome the virus that continues to live in latent reservoirs in the body. Descriptions are given of several new drugs currently being studied, including abacavir, amprenavir, efavirenz, ABT 378, and Hydroxyurea. Progress is also highlighted about dosing regimens, antiretroviral resistance, and reconstitution of the immune system.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Furans; Health Services Accessibility; HIV Protease Inhibitors; Humans; Hydroxyurea; Lopinavir; Oxazines; Patient Care Planning; Pyrimidinones; Remission Induction; Reverse Transcriptase Inhibitors; Sulfonamides; Switzerland; Virus Replication

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

Topics: Acquired Immunodeficiency Syndrome; Adenosine Deaminase; Administration, Oral; Animals; Anti-HIV Agents; Antiviral Agents; Area Under Curve; Biotransformation; Cells, Cultured; Dideoxynucleosides; Drug Resistance, Microbial; Female; Half-Life; HIV-1; Humans; Injections, Intravenous; Macaca fascicularis; Male; Rats; Structure-Activity Relationship

Glaxo Wellcome has announced a compassionate use program for its experimental nucleoside analog, 1592 (abacavir). The program will enroll 2,400 patients who have CD4 counts fewer than 100 and viral loads above 30,000. Participants must have had prior treatment with two nucleoside analogs or an intolerance to previous treatment regimens. A pediatric program is also enrolling 250 children. Enrollment information is included.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Child; Dideoxynucleosides; Humans