Background:  Vicriviroc (VCV), a new CCR5 antagonist, demonstrated significant efficacy in addition to PI/r-containing regimens in Phase 2 trials in subjects with few treatment options. We describe Phase 3 VCV trials of similar design in highly treatment-experienced subjects conducted between 2007 and 2009.

Methods:  Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic (by Trofile) HIV-infected subjects with documented resistance to at least 2 ARV classes were conducted in Latin and North America, Europe, and South Africa. Subjects were required to have a PI/r in an Optimized Background Therapy (OBT) containing at least 2 fully active drugs. Non-nucleosides, other than etravirine, were excluded; newly approved raltegravir (RAL) and darunavir (DRV) were allowed. There were 857 subjects randomized 2:1 to VCV 30 mg QD vs PBO. The primary endpoint was % subjects with <50 copies/mL HIV RNA at 48 weeks in each study and a planned pooled analysis. Secondary endpoints addressed standard measures of safety and efficacy.

Results:  The pooled mITT population included 721 treated CCR5 HIV (by Trofile ES®) subjects. Baseline characteristics included mean age 43 years, 29% females, 40% non-white, mean HIV RNA 4.6 log₁₀ copies/mL, and mean CD4 count 257 cells/µL. OBT included ≥3 fully active ARV in 61% of subjects. In this study, 76% subjects completed 48 weeks; 24% discontinued, 12% due to virologic failure, 3% AE, 9% other. The % of subjects with <50 copies/mL at 48 weeks was not significantly different in VCV vs PBO: 64 and 61%, respectively (P =0.6).  There were no significant differences between VCV and PBO in AIDS-defining events, malignancies or other adverse events of interest in the CCR5 class. Multiple planned and post-hoc analyses showed that use of RAL ± DRV in OBT strongly influenced outcome; the pooled subset (n = 261) with ≤2 active drugs in OBT showed efficacy of VCV: 70% vs 55% (P =0.02). 

Conclusions:  With several new potent ARV now available, the goal of treatment at all stages of HIV infection is full viral suppression (<50 copies/mL) using at least 2, and preferably 3, active drugs. Additional active drug(s) rarely provide incremental benefit. This compendium of ARV is a remarkable achievement that benefits HIV patients for whom the drugs are available; however, for patients with limited treatment options, these data suggest that VCV may provide useful benefit.  Future trials designed for advanced patients must account for changes in the therapeutic landscape.