Background: Current 3-drug regimens fail to adequately suppress HIV RNA viral load in a significant proportion of patients starting ART so new strategies are needed to improve efficacy. FORTE is the first trial to report on an induction strategy with 4-drugs followed by a 3-drug regimen. Previous trial results with induction from 3- or 4-drug to 2-drug regimens were disappointing.

Methods: Induction/maintenance (2 NRTI+NNRTI+PI for 24 to 32 weeks to reach viral load <50 copies/mL then 2 NRTI+NNRTI) was compared to standard therapy (2NRTI+NNRTI) in treatment-naïve patients. Primary endpoints were time to virologic failure, defined as viral load >50 copies/mL at 24 (and 32) weeks or subsequent rebound >400. Secondary endpoints were changes at 48 weeks in viral load, CD4 count, and proportion of patients with viral load <50 (and <400), progression to AIDS/death, and toxicity.

Results: We randomized 122 patients (62 induction/maintenance, 60 standard treatment) and followed them for a median of 81 weeks. At baseline, the median CD4 count was 160 cells/mm³ (IQR 92 to 260), and median viral load 98,830 copies/mL (IQR 37,500 to 241,290). The trial closed June 2003. The commonest 2 NRTI were ddI/d4T 52%, AZT/3Tc 42%; NNRTI, NVP 64%, EFZ 36%; and PI, NFV 71%, LPV 27%. Patients adhered to the allocated strategy for 83% and 89% of patient time by 48 weeks in the induction/maintenance and standard therapy arms respectively. In the induction/maintenance arm, 19 patients (31%) stopped > 1 drug before 24 weeks (15 for toxicity). On ITT analyses, more patients on the standard therapy arm had virological failure at or after 24 weeks (48% vs 31%, p = 0.06 log rank test) and this difference was greater and statistically significant for virological failure at or after 32 weeks (43% vs 18%, p = 0.002). The mean fall in viral load at 48 weeks was 0.86 (SE 0.35) log₁₀ copies/mL greater in the induction/maintenance arm (p = 0.01). At 48 weeks, 81% of patients in the induction/maintenance arm and 65% in the standard therapy arm had viral load <50 (p = 0.07), and 100% in the induction/maintenance arm and 86% in the standard therapy arm had a viral load <400 (p = 0.01). The median increase in the CD4 count at 48 weeks was 20 cells greater (95%CI:  35 to 75, p = 0.7) in the induction/maintenance arm. There were no significant differences in the number of patients with serious adverse events (17 vs 13), grade 3 and 4 adverse events (21 vs 15), adverse events leading to stopping an HIV drug (25 vs 24), or progression to AIDS/death (7 vs 4) in the induction/maintenance and standard therapy arms, respectively.

Conclusions:  On starting ART an induction/maintenance strategy (adding a fourth drug for 24 to 32 weeks to standard 3-drug ART) improved virological outcomes compared with a 3-drug regimen without significantly increasing toxicity.

Keywords: Induction therapy; treatment naive patients; antiretroviral therapy