Background:  In a prior study of ARV-naïve subjects, once-daily dosing of lopinavir/ritonavir (LPV/r) soft-gelatin capsules (SGC) was not inferior to twice-daily dosing when co-administered with NRTI; diarrhea rates were higher in the once-daily group. Study M05-730 evaluates once-daily vs twice-daily LPV/r+NRTI in ARV-naïve subjects receiving the LPV/r tablet formulation.

Methods:  We randomized 664 ARV-naive HIV-1-infected subjects 1:1:1:1 to LPV/r once-daily SGC, twice-daily SGC, once-daily tablet, twice-daily tablet for 8 weeks. All subjects received tenofovir (TDF) + emtricitabine (FTC) once-daily. At week 8, subjects taking LPV/r SGC were switched to the tablet formulation while maintaining their once-daily or twice-daily dosing schedule. All subjects will be followed for as long as 96 weeks. Results of the primary week 48 analysis are presented. The pre-defined non-inferiority margin was –12% for the comparison of once-daily vs twice-daily in the intent-to-treat, noncompleter = failure (ITT NC=F) analysis of the proportion with HIV-1 RNA <50 copies/mL.

Results: Baseline characteristics were similar among groups, with overall mean HIV-1 RNA and CD4 cell count of 5.0 log₁₀ copies/mL and 216 cells/mm³. Through 48 weeks, 14% (once-daily) and 16% (twice-daily) discontinued prematurely. At week 48, 77% (once-daily) and 75% (twice-daily) had HIV-1 RNA <50 copies/mL (ITT NC=F, p = 0.65). The 95%CI for the difference in response rates (once-daily minus twice-daily:  –4.8 to 8.1%) confirmed the non-inferiority of the once-daily regimen. HIV-1 RNA was <50 copies/mL at week 48 (ITT NC=F) in 78% and 75% with baseline HIV-1 RNA <100,000 or ³100,000 copies/mL, and in 76%, 73%, and 78% with baseline CD4 count <50, 50 to <200, and ³200 cells/mm³, with no differences between once-daily and twice-daily in any group (p≥ 0.443). Mean increases in CD4⁺ T cell count at week 48 were 187 (once-daily) and 198 (twice-daily) cells/mm³ (p = 0.343). Adverse event rates, including gastrointestinal AEs, were similar between the once-daily and twice-daily arms. LPV/r-related, moderate/severe diarrhea was reported in 17% (once-daily) and 15% (twice-daily; p = 0.594). Adverse event-related discontinuations occurred in 4.5% of once-daily-treated and 2.4% of twice-daily-treated subjects (p = 0.202). Among 13 subjects with rebound genotypes, no new protease inhibitor (PI) mutations were observed, and 2 of 8 (once-daily) and 1 of 5 (twice-daily) demonstrated the M184I/V mutation.

Conclusions:  Through 48 weeks, LPV/r once-daily was not inferior to twice-daily when co-administered with TDF+FTC in ARV-naïve subjects. Efficacy was similar regardless of baseline HIV-1 RNA or CD4 cell count. Once-daily dosing of LPV/r tablets was similarly well tolerated when compared to twice-daily dosing of LPV/r tablets. Consistent with prior LPV/r trials in ARV-naïve subjects, no new PI mutations were detected upon virologic rebound.