August 17, 2006

IAC: Vicriviroc Shows Promise

August 17, 2006 (AIDSmeds)—The AIDS Clinical Trials Group has reported results from a clinical trial of vicriviroc, an experimental entry inhibitor being developed by Schering-Plough. Results from the study were reported today at the International AIDS Conference (IAC) in Toronto.

The primary goal of the study (A5211) was to see how well vicriviroc worked over 14 days in HIV-positive people who had tried other HIV treatments in the past and who were failing their current HIV regimen. Other goals were to study the safety of vicriviroc and to study the effects of vicriviroc on viral load and CD4 cell counts (T cell counts) – when used in combination with other HIV medications – over 24 weeks.

After HIV binds to the CD4 protein on T-cells, the virus must then latch onto another receptor on the cell's surface – either CCR5 or CXCR4. Vicriviroc, like another entry inhibitor maraviroc, blocks CCR5 and, in turn, prevents HIV from entering CD4 cells that carry this receptor.

Study participants were randomized to add one of three doses of vicriviroc (5mg, 10mg, or 15mg once a day) or a placebo to their current HIV drug regimen. After two weeks, participants continued vicriviroc, or placebo, and changed their other HIV drugs to an optimized background treatment (OBT) consisting of approved HIV medications that their virus may be sensitive to.

An independent study monitoring board reviewed the clinical trial for safety from time to time. At their review on October 6, 2005, the committee recommended stopping the 5mg vicriviroc dose because it wasn't working as well as the other doses. At their review on February 15, 2006, they noted five cancers in participants taking vicriviroc and recommended that all participants be told whether they were taking vicriviroc or not.

The results, reflecting data collected up until February 15, were reported at IAC by Roy Gulick, MD, MPH, of Weill Cornell Medical College in New York. Dr. Gulick said that 118 patients were enrolled in the study. The average viral load at study entry was 36,380 and the average CD4 count was 146. Unlike the patients in the maraviroc study also reviewed at the conference today (see this AIDSmeds report), all patients in A5211 had HIV that targeted CCR5 on CD4 cells.

After two weeks, participants taking either 10mg or 15mg vicriviroc decreased their viral loads by approximately 1.15 and 0.92 log, respectively. Participants taking placebo experienced a slight increase in their viral loads.

Over 24 weeks, participants taking placebo or 5mg vicriviroc plus OBT were more likely to see their viral loads rebound compared to patients taking either 10mg or 15mg vicriviroc plus OBT. In the 10mg vicriviroc group, viral loads decreased, on average, by 1.86 log after 24 weeks; in the 15mg vicriviroc group, the average viral load drop was 1.68 log. These results were significant compared to the viral load change seen in the placebo group after 24 weeks – only a 0.29 log drop.

The percentage of subjects with viral loads below 400 at week 24 was 11% in the placebo group, 53% in the 10mg vicriviroc group, and 47% in the 15mg vicriviroc group. The percentage of subjects with viral loads below 50 at week 24 was 7% in the placebo group, 40% in the 10mg vicriviroc group, and 27% in the 15mg vicriviroc group.

Dr. Gulick also reported changes in CD4 counts after six months of treatment. In the placebo group, CD4 counts decreased by 6 cells, compared to a 142-cell increase in both vicriviroc groups.

A central concern with entry inhibitor treatment targeting CCR5 is that it will result in the emergence of HIV using CXCR4, a form of the virus that is believed to be associated with more rapid disease progression. In A5211, CXCR4 virus emerged in 13 patients, including one patient in the placebo group, three patients in the 10mg vicriviroc group, and two patients in the 15mg vicriviroc group (the rest were in the 5mg vicriviroc group). At this point in time, however, it is not clear if this CCR5-to-CXCR4 "switch" is really associated with more rapid disease progression or if the switch is permanent once the CCR5-blocking medication is discontinued.

As for side effects, there were no differences between the placebo and vicriviroc groups. However, the five cancers reported – all in patients taking vicriviroc – are concerning and still being investigated.