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Multistudy Analysis Shows Enhanced CD4 Gain With CCR5 Antagonists
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
CCR5 antagonists boost CD4 counts more than other new antiretrovirals, independent of their effect on viral load, according to results of a multistudy analysis by Timothy Wilkin and Roy Gulick of New York's Cornell Medical College and Heather Ribaudo of Harvard [1]. The researchers could not figure out why CCR5 antagonists have this enhanced CD4 effect, and they called for further study of the phenomenon.
Wilkin and colleagues cited earlier research showing that CCR5 inhibitors may quell immune activation by preventing binding of beta chemokines [2], that the drug thwarts binding of free HIV gp120 to CCR5 and resulting cell killing in lab studies [3], and that people with dual/mixed-tropic HIV reaped CD4 benefits from maraviroc even though the CCR5 drug could not control replication of that virus [4].
Their curiosity piqued, the researchers analyzed CD4 trends in phase 2 and 3 trials of the CCR5 inhibitors maraviroc and vicriviroc, the fusion inhibitor enfuvirtide, the integrase inhibitor raltegravir, the nonnucleoside etravirine, and the protease inhibitors darunavir and tipranavir. They compiled relevant baseline data along with week 24 changes in CD4 counts and sub-50-copy virologic response. Then they devised a multivariate linear regression model to sort out predictors of week 24 CD4 gains.
The analysis included 37 treatment arms from 16 trials, including nine arms from four trials of maraviroc or vicriviroc and multiple arms from well-known trials of other novel antiretrovirals, including the BENCHMRK studies of raltegravir, the DUET studies of etravirine and darunavir, the POWER trials of darunavir, the RESIST trials of tipranavir, and the TORO trials of enfuvirtide.
In the final model three factors independently predicted the following estimated 24-week CD4-cell gains:
· Use of a CCR5 inhibitor: +32 CD4s (95% CI 19 to 54), P < 0.0001
· Virologic suppression per 10% higher proportion below 50 copies: +12 CD4s (95% confidence interval [CI] 9 to 14), P < 0.0001
· Baseline viral load per 10-fold higher: +43 CD4s (95% CI 14 to 71), P = 0.003
Baseline CD4 count and gender did not correlate with CD4 gains in this analysis.
Wilkin and coworkers caution that their study could not account for baseline factors such as use of enfuvirtide or genotypic or phenotypic sensitivity scores for drugs in the salvage regimens. Still, they believe further study should explore the potential role of CCR5 antagonists in people who have a poor CD4 response to other regimens.
References
1. Wilkin T, Ribaudo H, Gulick R. The relationship of CCR5 inhibitors to CD4 cell count changes: a meta-analysis of recent clinical trials. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 36.
2. Watson C, Jenkinson S, Kazmierski W, Kenakin T. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol Pharmacol. 2005;67:1268-1282.
3. Klasse PJ, Moore JP. Is there enough gp120 in the body fluids of HIV-1-infected individuals to have biologically significant effects? Virology. 2004;323:1-8.
4. Mayer H, van der Ryst E, Saag M, et al. Safety and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimized background therapy for the treatment of antiretroviral-experiences subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0215.
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