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

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

Maraviroc for previously treated patients with R5 HIV-1 infection

Background CC chemokine receptor 5 antagonists are a new class of antiretroviral agents.Methods We conducted two double- blind, placebo- controlled, phase 3 studies - Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment- Experienced Patients ( MOTIVATE) 1 and MOTIVATE 2 - with patients who had R5 human immunodeficiency virus type 1 ( HIV- 1) only. They had been treated with or had resistance to three antiretroviral- drug classes and had HIV- 1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy ( OBT) based on treatment history and drug- resistance testing. Safety and efficacy were assessed after 48 weeks.Results A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV- 1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV- 1 RNA from baseline was greater with maraviroc than with placebo: - 1.66 and - 1.82 log(10) copies per milliliter with the once- daily and twice- daily regimens, respectively, versus - 0.80 with placebo in MOTIVATE 1, and - 1.72 and - 1.87 log(10) copies per milliliter, respectively, versus - 0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV- 1 RNA levels of less than 50 copies per milliliter ( 42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P< 0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo ( increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P< 0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups.Conclusions Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV- 1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV- 1 who were receiving OBT. (ClinicalTrials. gov numbers, NCT00098306 and NCT00098722.)