Twice-daily Trizivir versus Combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: a formulation-switch trial

To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg-lamivudine 150 mg-zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300-mg tablet, administered twice/day, in antiretroviral-experienced, human immunodeficiency virus (HIV)-1-infected patients. Randomized, open-label, parallel-group, multicenter, formulation-switch study. Twenty seven outpatient treatment sites. Adults with HIV-1 RNA levels of 400 copies/ml or less and CD4+ cell counts above 200 cells/mm3 who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir-ABC. Patients were randomized 1:1 to Trizivir (97 patients) or Combivir-ABC (98) for 24 weeks. The primary study end point was the proportion of patients who maintained less than a 0.5-log10 increase from baseline in HIV-1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir-ABC was -0.12 or greater. Trizivir was clinically equivalent to Combivir-ABC. The intent-to-treat observed analysis at week 24 with Trizivir and Combivir-ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL -0.026), of patients with HIV-1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV-1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent-to-treat missing = failure analysis showed comparable results. Changes in CD4+ cell count from baseline, overall mean self-reported adherence (Trizivir 97%, Combivir-ABC 92%), and adverse events did not differ significantly between treatments. No ABC-related hypersensitivity reactions occurred. Trizivir was clinically equivalent to Combivir-ABC and may be substituted for the latter to simplify treatment and reduce pill burden

Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/ emtricitabine with lopinavir/ritonavir for initial HIV treatment

, for the HEAT study team M Background: Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ ritonavir in antiretroviral-naive patients. Methods: Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing ¼ failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks. Results: At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing ¼ failure, 95% confidence interval on the difference À6.63 to 7.40, P ¼ 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval À5.41 to 9.32, P ¼ 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA ! 100 000 copies/ml or CD4 þ cell counts below 50 cells/ml. Median CD4 þ recovery (ABC/3TC vs. TDF/FTC, cells/ml) was þ250 vs. þ247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups. Conclusion: Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: Selection of thymidine analog regimen therapy (Start II)

Objective: Comparison of stavudine (d4T), didanosine (ddl) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. Design: Randomized, open-label. Setting: Fourteen HIV Clinical Research Centers. Patients: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts ≥ 200 x 10 6/l and plasma HIV-1 RNA levels ≥ 10 000 copies/ml. Interventions: Stavudine 40 mg and ddl 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. Main outcome measures: The proportion of patients with plasma HIV-1 RNA levels \u3c 500 copies/ml and ≤ 50 copies/ml and changes in CD4 cell counts were compared. Results: In an analysis of the primary endpoint, 61% of patients on d4T + ddl + IDV and 45% of patients on ZDV+ 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 \u3c 500 copies/ml [95% confidence interval (Cl) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels \u3c 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddl + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% Cl, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were ≤ 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P \u3e 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10 6/l cells for the d4T arm and 106 x 10 6/l cells for the ZDV arm (P = 0.001). The occurrence of serious adverse events was not significantly different between arms. Conclusion: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddl and a protease inhibitor as an initial antiretroviral treatment. (C) 2000 Lippincott Williams and Wilkins

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection