Vicriviroc is an investigational CCR5 antagonist that has been undergoing clinical study in both treatment-experienced and treatment-naive individuals. At the 17th Conference on Retroviruses and Opportunistic Infections (CROI) this year, investigators presented results from two parallel randomized, double blind, placebo-controlled Phase 3 studies in treatment-experienced patients.
Study participants were required to have CCR5 tropic virus, as well as resistance to at least 2 of the NRTI, NNRTI, or PI drug classes, or ART experience for at least 6 months. Tropism was determined by the assay available at time of enrollment and confirmed by the enhanced sensitivity assay at the end of the study; data analysis was confined to patients with CCR5 by the more sensitive tropism assay (n = 721).
Study patients were randomized 2:1 to vicriviroc (30 mg once daily) or to placebo, each in combination with an optimized background regimen. At baseline, the mean CD4 count was 250 cells/µL, the HIV RNA was 4.5 log10 copies/mL, and the two groups were well matched for other baseline characteristics. About two thirds of study participants had ≥3 active agents in their background regimen.
In pooled analysis, by intention-to-treat analysis, the rates of HIV RNA suppression to <50 copies/mL at 48 weeks were statistically equivalent in the 2 groups: 64% in the vicriviroc group and 62% in the control group. Among the minority of patients with ≤2 active drugs in the background regimen, however, the vicriviroc group showed significantly higher rates of virologic suppression (HIV RNA <50 copies/mL in 70% in the vicriviroc group vs 55% in the placebo group, p = .02). The mean CD4 increase was 138 cells/µL in vicriviroc recipients and 129 cells/µL in controls.
In each treatment group, 15 % of participants experienced protocol-defined virologic failure. Of vicriviroc recipients with virologic failure, 13% had dual/mixed or X4 virus at time of failure, 4% had vicriviroc resistance. Rates of adverse events, including malignancies, infections, and cardiovascular events, were similar between treatment groups.
Clinical Bottom Line
This study showed that the addition of vicriviroc to an already-strong background regimen did not confer additional benefit. However, inclusion of this agent in regimens containing ≤2 active agents did improve regimen efficacy. In other words, vicriviroc is likely to be effective (and safe) as a component of salvage therapy for appropriate patients.
The study raises important questions about how to design studies to test efficacy of new ARV medications in treatment-experienced patients, now that several active agents are often available for patients with a history of virologic failure. It will be important to develop new study approaches that serve the dual goals of treating patients to the standard of care (with the aim of maximizing the likelihood of virologic suppression) while evaluating the efficacy of a new agent.
As a result of this study, the manufacturer of vicriviroc, Merck & Co, announced that it will no longer seek FDA approval for the use of vicriviroc with treatment-experienced patients, but will continue to study it in treatment-naive individuals.
Gathe J, Diaz R, Fatkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. Abstract 54LB.