 |
|
|
| |
Vicriviroc Does Not Outdo Placebo Regimen in Phase 3 Trials
|
| |
| |
17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
The CCR5 antagonist vicriviroc plus an active background regimen did not control HIV better than an active background regimen alone in two phase 3 placebo-controlled trials of treatment-experienced people [1]. Use of stout new salvage drugs--darunavir, etravirine, and raltegravir--in the trials appears to explain the equivalent potency of the placebo regimens. An earlier phase 2 placebo-controlled trial run by the AIDS Clinical Trials Group (ACTG) found significantly greater viral suppression with vicriviroc plus other antiretrovirals than with placebo after 2 and 24 weeks [2]. People in that trial did not take darunavir, etravirine, or raltegravir.
The identical phase 3 trials involved an intention-to-treat population of 721 people in North and South America, Europe, and South Africa who were randomized 2-to-1 to 30 mg of vicriviroc once daily (with a ritonavir-boosted protease inhibitor) or to placebo plus at least two fully active drugs [1]. Everyone had resistance to drugs in two of the first three antiretroviral classes or at least 6 months of antiretroviral experience. More than 60% of study participants took at least three fully active drugs with or without vicriviroc. Raltegravir or darunavir made up part of 30% to 40% of background regimens.
Starting viral load averaged about 40,000 copies and starting CD4 count 257. The investigators used the enhanced Trofile assay to make sure study participants had virus that uses the CCR5 coreceptor.
Equivalent proportions of people (24% on vicriviroc and 22% on placebo) discontinued treatment, though the discontinuation rate for investigator-defined treatment failure was higher in the placebo arm than the vicriviroc arm (60% versus 46%). But the protocol-defined virologic failure rates were equivalent in the two arms--15% with vicriviroc and 16% with placebo. Adverse events compelled discontinuations in 14% taking vicriviroc versus 8% taking placebo.
After 48 weeks pooled results of the two trials showed no significant difference between the vicriviroc and placebo arms in the primary endpoint, proportion of people with a viral load below 50 copies in an intention-to-treat analysis: 64% with vicriviroc and 62% with placebo (P = 0.6). When the investigators focused only on people taking two or fewer fully active drugs with vicriviroc or placebo, the sub-50-copy response rate at 48 weeks was significantly greater with vicriviroc (70% versus 55%, P = 0.02).
Session cochair David Cooper (University of New South Wales) expressed some surprise at the low overall response rate, given the potent rescue regimens clinicians can concoct today. Joseph Gathe, who presented the results, suggested the relatively high dropout rate accounts for the lower-than-usual intention-to-treat response.
Of the 71 protocol-defined virologic failures on vicriviroc, 9 failures (13%) involved dual-mixed or X4-using virus and 3 (4%) involved resistance to vicriviroc. Resistance to drugs in the background regimen emerged in about 20% of failures in both treatment arms.
People taking vicriviroc gained an average 138 CD4 cells through 24 weeks, compared with 129 in the placebo group. That finding confirms a separate study of maraviroc [3] contradicting the earlier belief that CCR5 antagonists enjoy an advantage over some antiretrovirals in hiking CD4 counts.
The vicriviroc and placebo groups did not differ significantly in new AIDS diagnoses, malignancies, or other major adverse events. The phase 2 trial kindled concern about malignancy--especially non-Hodgkin lymphoma--as a vicriviroc side effect when new cancers developed in 6 people randomized to vicriviroc and 2 randomized to placebo [2]. But subsequent analyses indicate that cancer is probably not a consequence of vicriviroc therapy, and the phase 3 results apparently confirm that conclusion.
In the phase 2 ACTG study, researchers added vicriviroc or placebo to a failing ritonavir-boosted regimen for 14 days, then optimized the background regimen [2]. Enfuvirtide was the leading salvage drug of the day. Viral loads dropped an average 1.15 log at 14 days with 10 mg of vicriviroc and 0.92 log with 15 mg, while rising slightly with placebo. After 24 weeks, average viral load drops measured 1.86 log with 10 mg of vicriviroc, 1.68 log with 15 mg, and 0.29 log with placebo.
References
1. 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. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 54LB.
2. Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis. 2007;196:304-312.
3. Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 5256. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 285.
|
| |
|
|
|
|
|
