Background:  Abacavir (ABC) -based 3-nucleoside reverse transcriptase inhibitor (NRTI) regimens have potential advantages over standard nevirapine (NVP) -based first-line ART in Africa, as they avoid interactions with tuberculosis (TB) therapy, spare 2 classes for second-line therapy, and have low pill burden. We have previously shown a trend toward lower toxicity and discontinuation with ABC vs NVP, but their clinical, immunological, and virological efficacy have not been compared in Africa.

Methods:  A randomized trial comparing the safety of NVP vs ABC was conducted in 2 Ugandan centers within the DART trial. We allocated 600 ART-naive adults with CD4 <200 cells/mm³ to combivir plus ABC (n = 300) or NVP (placebo-controlled for the first 24 weeks to the 1° toxicity endpoint). Plasma HIV-1 RNA was retrospectively assayed at 0, 24, and 48 weeks using Roche Amplicor. CD4 was measured weekly in real time for 12 weeks, and clinical events documented and independently reviewed. All analyses are intent to treat.

Results:  Of the total, 430 patients were women (72%); at baseline, 111 (19%) had WHO stage 4 disease, median age was 36 years (range 18 to 66), CD4, 99 cells/mm³ (1 to 199) and HIV-1 RNA 284,600 copies/mL (mean 5.4 log₁₀, SD 0.7). In all, 563 (94%) patients completed 48 weeks; 25 (4%) died and 12 (2%) were lost. In total, 21 (7%) ABC vs 34 (11%) NVP patients were off randomized drug at 48 weeks/last alive (most had substituted TDF); 62% ABC vs 76% NVP had HIV RNA <50 copies/mL at week 24, and 62% ABC vs 77% NVP at week 48 (both n = 551, p <0.001); 74% vs 87% were <400 copies/mL at week 48 (p <0.001). Mean CD4 increases from baseline in ABC vs NVP were +111 vs +134 cells/mm³ at week 24 (p = 0.003) and +147 vs +173 at week 48 (p = 0.006). In contrast, 17 (6%) ABC vs 29 (10%) NVP patients developed new WHO 4 events or died by 48 weeks (HR = 0.57 [95%CI 0.31 to 1.03] p = 0.06, similar to WHO 3 events p = 0.06). First events were esophageal Candida (4A, 3N), extra-pulmonary TB (2A, 5N), cryptococcus (3N), other WHO 4 (4A, 5N), or death (7A, 11N). Most (13A, 23N) occurred in the first 12 weeks; 9 (3%) ABC vs 16 (5%) NVP patients died (HR = 0.55 [0.24 to 1.25] p = 0.15), all but 1 (N) in the first 24 weeks and most (7A, 12N) in the first 12 weeks.

Conclusions:  NVP has superior virological and immunological efficacy compared with ABC over 48 weeks, although viral load suppression and CD4 gains were substantial in both groups. Further follow-up will important to monitor the observed trend toward clinical superiority of the ABC arm during this period. The potential contribution of IRIS to these conflicting results also requires further study.