Background:  Vicriviroc (VCV) is a next-generation small molecule CCR5 antagonist, administered orally once-daily, now in worldwide phase III development for treatment of HIV. This phase II study determined the optimal dose for Phase 3 in combination with an optimized background antiretroviral regimen (OBT) containing a ritonavir (RTV) -boosted protease inhibitor (PI) based on efficacy, safety and durability of antiretroviral effect.

Methods:  This was a multinational, randomized, double-blind, placebo-control trial of VCV 20 or 30 mg once-daily vs placebo for 48 weeks. Eligible subjects were CCR5-tropic HIV-infected adults who had received ≥2 prior classes of ART with ≥1000 copies/mL plasma HIV RNA despite current 3-drug ART regimen. Subjects with hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection were allowed; prior seizure disorder or malignancy was excluded. OBT could include any available ART, except efavirenz (EFV), including those on EAP.

Results: We randomized 116 subjects 1:1:1 to VCV 20 mg, 30 mg, or placebo once-daily, administered with a new OBT. Mean age was 45 years; 77% were male; 68% white, 17% black, 72% Latino. Mean plasma HIV RNA was 4.5 log₁₀ and CD4 count was 210 cells/µL; 51% had an AIDS-defining event prior to study; 6 (5%) were HCV co-infected. OBT included ≥2 active drugs in 43% subjects; 27 (23%) received darunavir (DRV). Of the total, 2 never received the study drug, 21 (18%) discontinued prematurely because of virologic failure (14 on placebo), and 2 discontinued because of adverse events, neither of which was attributed to the study drug. At 24 weeks (n = 91), mean decline in HIV RNA was –2.04, –2.04, and –0.96 log₁₀ in the 3 groups, respectively (p <0.001, active vs placebo). Percentage with HIV RNA <400 copies were 75%, 72%, and 34% (p <0.01) and <50 copies were 58%, 64%, and 26% (p <0.01) in the 3 groups, respectively. Mean CD4 counts rose 100, 94, and 56 cells/µL in the 3 groups, respectively (p = 0.15). No toxicities or signals of safety issues were observed.

Conclusions:  VCV at 20 mg and 30 mg once-daily demonstrated superior antiviral efficacy over optimized ART alone. Virologic benefit was achieved even when OBT contained ≥2 to 3 active drugs; there was no geographical difference in efficacy. The most stringent criteria of efficacy favored VCV 30 mg once-daily. No clinically significant differences in the safety profile between VCV and placebo groups emerged in this study including hepatotoxicity, opportunistic infections, malignancies, or other conditions. Efficacy and safety supported 30 mg once-daily for phase III studies; 48-week results will be available.