Coverage of CROI 2008 (Conference on Retroviruses and Opportunistic Infections)

February 4–6, 2008, Boston, MA

Best use of Selzentry still in question

by Paul Dalton, February 5, 2008

Further results from the pivotal studies of the recently approved CCR5 antagonist Selzentry (maraviroc) were presented in an oral presentation and poster at CROI. Project Inform has written extensively on the development of Selzentry, especially in the past two years as it moved closer to FDA approval. These new results confirm earlier research but also leave important questions open about this new drug.

As reported here, the first set of results from the MERIT study were presented at the 2007 IAS meeting. MERIT compared Selzentry to Sustiva (efavirenz) both taken with the NRTI fixed-dose combination Truvada (Viread/tenofovir + Emtriva/emtricitabine) in people taking HIV drugs for the first time. Overall, Selzentry didn’t quite match up to Sustiva. Surprisingly, the difference between the drugs was only seen in people in the southern hemisphere.

In MERIT, more people stopped Selzentry due to treatment failure than Sustiva (11.9% vs. 4.2%). Further analysis of this treatment failure sought to explain what caused it. Several explanations were presented. In some cases (3.3%), participants’ HIV shifted from R5-only to dual/mixed between the time they were screened for the study and when they started Selzentry. Among people who failed on Selzentry with R5-only HIV when they started the drug, about a third had X4-using HIV emerge. This also led them to develop resistance to the NRTIs they were taking. Among those who failed while still having R5-only HIV, Selzentry resistance was detected in only a small number while most had developed resistance to their NRTIs.

These results raise more questions about using Selzentry in people taking HIV drugs for the first time. One issue is the reliability of the Trofile test—the only widely used test that tells whether a person’s HIV is only R5 or can use X4. A small but significant group of people had different results in the short time between screening and taking their first dose. This issue is important because it takes 3 or more weeks to get the results of the Trofile test back.

However, the biggest problem is the higher rates of treatment failure compared to Sustiva, which is widely used as first line treatment. While it’s true that more people stopped taking Sustiva due to intolerance in this study, the treatment failures from people who took Selzentry often led them to develop resistance to other drugs in their regimens. This, in turn, limits their future treatment options.

A poster presentation covered both efficacy and safety after 48 weeks of Selzentry compared to placebo. Both were combined with optimized background therapy in people with experience taking HIV drugs in the MOTIVATE study. This poster basically confirmed earlier results. About half the people on Selzentry had HIV levels below 50 copies after 48 weeks, compared to 22% of people on placebo. There was a significant difference in responses between people with pre-treatment HIV levels above vs. below 100,000 copies. For people with high pre-treatment HIV levels, only around 35% had undetectable HIV levels compared to almost 60% of people with lower pre-treatment levels.

There were no significant differences in rates of side effects between these two groups. This is important to emphasize, because there has been a high degree of concern over toxicity with this class of drugs. So far, these concerns haven’t been confirmed with Selzentry.

The best use of Selzentry is still unclear. It has not performed as well as some other recently developed drugs when used in treatment experienced people, but it has shown some significant benefit for a subset of these folks. Many think that CCR5 drugs are better used earlier, when more people are likely to have R5-only HIV. However, the head-to-head studies against Sustiva have raised almost as many questions as it has answered. Muddying the waters further are the concerns over the accuracy, turn around time, and cost of the Trofile test needed to use Selzentry.