Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection - A randomized controlled trial

Context Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen. Objective To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection. Design The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1-infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG. Interventions Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/ lamivudine/abacavir plus efavirenz (4-drug regimen). Main Outcome Measures Time to virologic failure ( defined as time to first of 2 successive HIV-1 RNA levels >= 200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes. Results Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log(10) ( 72 444) copies/mL and CD4 cell count of 240 cells/mm(3) were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different ( hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P=. 73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients ( adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P=. 003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively ( P=. 59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients ( P=. 39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different. Conclusions In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit.