Background:  INITIO is 1 of 3 large strategy trials begun in 1998/1999 comparing HIV treatment starting with a 3-drug regimen containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) followed by a regimen with a protease inhibitor (PI) for failure or a PI (followed by a regimen with a NNRTI for failure) and a 4-drug regimen containing both NNRTI plus PI.

Methods:  Didanosine/stavudine/efavirenz (ddI/d4T/EFV) followed by zidovudine/lamivudine/abacavir/nelfinavir (ZDV/3TC/ABC/NFV) [S1] was compared to ddI/d4T/nelfinavir (NFV) followed by ZDV/3TC/ABC/EFV) [S2] and ddI/d4T/EFV/NFV (with no specified second regimen) [S3] in treatment-naïve patients. Primary outcome measures were HIV RNA < 50 copies/mL and the change from baseline in CD4 count at 3 years (analysis censored for missing values). Secondary outcome measures included change from baseline in HIV RNA at 3 years, progression to new AIDS events or death and incidence of adverse events. Time on initial regimens included within-class drug substitutions for drug intolerance.

Results:  We randomized 915 patients (79% male) (300 S1, 311 S2, 304 S3) and followed them for a median of 192 weeks when the trial closed in June 2004. At baseline, mean age was 39 years, 21% had AIDS, median CD4 count was 200 cells/mm³ (IQR 80 to 329) and mean HIV RNA 4.93 log₁₀ copies/mL (SD 0.72). The proportion of time on the initial regimen (including substitutions) was 74%, 63%, and 51% in S1, S2, and S3, respectively. On intent-to-treat analyses (using local viral load assays), at 3 years the proportion of patients with HIV RNA < 50 copies/mL was 74%, 62%, and 62% (global p = 0.004). Differences were maintained if missing values were treated as failures. The median change in CD4 count was +271, +275, and + 258 (p = 0.7) and mean change in HIV RNA was –4.4 log₁₀, –3.9 log₁₀, and –3.7 log₁₀ copies/mL (p = 0.0003) in the S1, S2, and S3 groups respectively. There were no significant differences between groups in progression to a new AIDS event/death, in the number of patients with at least one serious adverse event or with at least one adverse event stopping one or more HIV drugs.

Conclusions:  Starting ART with a 3-drug/2-class regimen containing EFV is superior to one with NFV (using d4T and ddI as the initial NRTI backbone) for HIV RNA outcomes (but not CD4 response) at 3 years. There is no evidence to support the use of 4-drug/3-class therapy for the initial treatment of HIV infection.

Keywords: Antiretroviral therapy ; Treatment naïve patients; Treatment strategy