The investigational CCR5 antagonist vicriviroc did not meet a pre-defined threshold for superiority to an optimised background regimen in two large studies of treatment-experienced people, according to a presentation at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) taking place this week in San Francisco.
But vicriviroc was well tolerated and did well against a weaker background regimen, raising questions about how best to test new drugs in an era of highly effective therapies.
HIV can use two different surface co-receptors – CCR5 and CXCR4 – to gain entry into CD4 cells. CCR5 antagonists such as vicriviroc and maraviroc (Celsentri, Selzentry) are designed to work against virus strains that use only the CCR5 gateway.
VICTOR-E3 and E4 studies were identical double-blind, placebo-controlled Phase 3 trials conducted in different geographical regions in North America, Latin America, Europe, and South Africa.
More than 800 participants were randomly assigned to receive either 30mg once-daily vicriviroc or placebo in combination with an optimised background regimen; a total of 721 patients in both studies together, with exclusively CCR5-tropic virus, were included in the modified intent-to-treat population, 486 of them in the vicriviroc arms and 235 in the placebo arms.
Participants were treatment-experienced and had documented resistance to at least two of the three initial antiretroviral drug classes. CCR5 tropism was initially determined using the original Trofile test, but was confirmed by the more sensitive Trofile ES.
Most participants (about 70%) were men, a majority were white (about 65% in VICTOR-E3 and about 55% in VICTOR-E4), and the average age was 43 years. Among the entire study population, the mean baseline viral load was about 40,000 copies/ml and the average CD4 cell count was approximately 260 cells/mm3.
All patients had at least two active drugs in their background regimen, one of which was a ritonavir-boosted protease inhibitor. Just over 60% had three active drugs. Use of the newer drugs etravirine (Intelence), darunavir (Prezista), and raltegravir (Isentress) was permitted, but their availability varied across study sites.
At week 48, similar proportions of patients in the two treatment groups achieved a viral load below 50 copies/ml: 64% in the vicriviroc arms and 62% in the placebo arms. Rates were also equivalent for viral load below 400 copies/ml: 72% and 71%, respectively.
CD4 cell increases were also statistically similar, with a gain of 138 cells/mm3 in the vicriviroc arms and 129 cells/mm3 in the placebo arms. In this study, vicriviroc did not produce greater immune recovery, as seen in studies of the approved CCR5 antagonist maraviroc.
However, vicriviroc did have an advantage when participants were divided according to number of active drugs in their background regimen. Looking at people with three or more active drugs, the proportions achieving viral load below 50 copies/ml were 61% in the vicriviroc arms and 65% in the placebo arms, similar to the overall rates.
But among participants who started with two or fewer active background drugs, 70% in the vicriviroc arms achieved undetectable viral load, compared with 55% in the placebo arms, which was a statistically significant difference (p = 0.02).
About one-quarter of participants did not complete the full 48 weeks of treatment, mostly due to treatment failure. About 14% in the vicriviroc arms and 8% in the placebo arms stopped early due to adverse events.
The frequency of side-effects was low overall, and similar in the vicriviroc and placebo groups. Of note, the researchers did not see more cases of seizures, lymphoma, or other cancers in the vicriviroc arms, which were raised as concerns in earlier studies. Few patients (about 4%) treated with vicriviroc developed resistance to the drug.
The VICTOR studies bring up the issue of how new drugs are tested in the era of highly effective antiretroviral regimens. As presenter Joseph Gathe explained, with the drugs available today, even many patients who are heavily treatment-experienced and have multiple resistance mutations can put together a regimen that suppresses HIV.
In other words, vicriviroc failed to work better than a potent background regimen that was already working well. Antiretroviral drugs approved in the past, in contrast, were competing against less potent regimens. This raises the question of whether new standards for evaluation should be adopted now that treatment is highly effective.
"For subjects with two or fewer available active drugs, vicriviroc provided additional opportunity to achieve full viral suppression," the researchers concluded. "With the success of recently available therapies for treatment-experienced subjects, new agents will require novel study designs to demonstrate efficacy."
Based on these results, developer Merck has indicated that it will not submit a New Drug Application to the US Food and Drug Administration (FDA) for vicriviroc for treatment-experienced individuals.
Gathe J et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly greater superiority over potent background regimens alone. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 54LB, San Francisco, 2010.