Background:  Phase I and in vitro studies have shown vicriviroc, a novel small molecule inhibitor of the CCR5 receptor, to be a potent inhibitor of viral entry and replication.

Methods:  Protocol P03802 was a phase 2 randomized, placebo-controlled trial in treatment-naïve subjects with R5-tropic HIV. The 92 subjects enrolled in the study were administered placebo, or vicriviroc 25, 50, or 75 mg once daily, for 14 days; combivir (CBV) was then added to each vicriviroc regimen and placebo was replaced by open-label efavirenz in addition to CBV. Planned duration was 48 weeks. Primary endpoint was mean change in log₁₀ HIV RNA from baseline at 2 weeks. An ANOVA model was used to assess effects due to treatment. Categorical endpoints were analyzed using c² test.

Results:  The study was terminated prematurely after review by an independent Data Safety Monitoring Board because of late virologic breakthrough in the vicriviroc arms. Mean duration of patient follow-up was 31.8 weeks (1 to 53.8). Vicriviroc was well tolerated; no safety concerns were raised—specifically, no liver toxicity was observed. Primary analysis at 2 weeks showed a mean change in RNA of –0.93 log₁₀ RNA in the 25-mg arm, –1.19 in the 50-mg arm, –1.34 in the 75-mg arm, and –0.07 in the placebo arm (p <0.001 for each vicriviroc arm vs placebo). Mean change in CD4 count from baseline at week 2 was +24 cells in the 25-mg group, +85 in the 50-mg group, +90 in the 75-mg group, and +3 in placebo (p <0.001 for 50- and 75-mg vicriviroc arms vs placebo). At the time of study closure, preliminary analysis revealed the proportion of subjects with virologic breakthrough (RNA ≥50 copies/mL) was 2 of 24 (8%) placebo group, 13 of 23 (57%) 25 mg, 10 of 22 (45%) 50 mg, and 5 of 23 (22%) 75 mg (p <0.001, pooled vs control). All subjects with evaluable genotypes at virologic breakthrough had treatment-emergent M184V mutations. Preliminary data suggest vicriviroc pharmacokinetic parameters were as predicted. Tropism shifts were seen in both treatment and control arms. Neither tropism shifts, vicriviroc IC₅₀ nor percentage maximal viral suppression fully explain virologic breakthrough. Additional studies are ongoing.

Conclusions:  Despite excellent tolerability and potent antiviral activity in vitro, in phase I studies, and at 14 days in this study, vicriviroc in combination with CBV did not provide durable suppression of plasma HIV RNA. Detailed analyses from this and ongoing studies are continuing to determine the role of selective entry inhibitors in potent antiviral therapy regimens.