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CCR5 Antagonists Have No Special CD4-Boosting Power in Meta-Analysis
(from Jules: I don't buy this)
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50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
Meta-analysis of 10 placebo-controlled trials assessing new antiretrovirals in antiretroviral-experienced people found no special CD4-boosting prowess with CCR5 antagonists [1], a possibility that emerged in clinical trials of these agents. This finding is at odds with an earlier meta-analysis [2] but confirms results of a small observational study [3] and a pilot trial in which adding maraviroc to a suppressive regimen did not substantially inflate CD4 counts in people with a suboptimal CD4 response [4].
For the meta-analysis, French investigators searched for placebo-controlled trials published or presented since 2003 that assessed CD4 and viral load responses of new antiretrovirals at week 48 in antiretroviral-experienced people. They found 10 studies, four testing maraviroc or vicriviroc and six evaluating enfuvirtide, raltegravir, etravirine, darunavir, or tipranavir. The primary analysis, which controlled for virologic response, involved the average CD4 difference between the new antiretroviral and placebo at week 48.
The CCR5 antagonist trials included two maraviroc studies (A4001029 and MOTIVATE 1 and 2 combined) and two vicriviroc studies (VICTOR-E1 and VICTOR-E3 and E4 combined). The trials of other new antiretrovirals were TORO 1 and 2 combined (enfuvirtide), DUET 1 and 2 combined (etravirine), TMC125-C223 (etravirine), BENCHMRK 1 and 2 combined (raltegravir), RESIST 1 and 2 combined (tipranavir), and POWER 1 and 2 combined (darunavir).
New antiretrovirals routinely raised CD4 counts more than placebo at week 48, by an average 39 cells (95% confidence interval 27 to 51) in a pooled analysis. Use of a CCR5 antagonist, compared with other new antiretrovirals, did not explain the CD4 advantage (P = 0.22). The trials included the A4001029 study of maraviroc, which enrolled people with CXCR4-using virus [5]. But eliminating that trial from the analysis did not substantially affect results.
Four factors did correlate with greater CD4 gains in these studies: a higher proportion with a lower genotypic sensitivity score (GSS) in the optimized background regimen (GSS 0, P = 0.001; GSS < 1, P = 0.017; GSS < 2, P = 0.045), male gender (P = 0.014), an undetectable viral load in the placebo group at week 48 (P = 0.042), and baseline CD4 count (P = 0.06).
The French team suggested that their results are not consistent with the earlier meta-analysis [2] for methodological reasons. For example, the earlier study considered each clinical trial arm as a single data point while they considered the difference in CD4 gains between two trial arms. The investigators noted two limitations of their study: its observational design and the ability to adjust calculations only for data collected during the trial. They cautioned that their findings may not apply to CD4 nonresponders or to antiretroviral-naive people who start a CCR5 antagonist.
The investigators concluded that "CCR5 inhibitors do not allow a better CD4 cell recovery when compared to others new antiretroviral agents in treatment-experienced patients."
References
1. Pichenot M, Deuffic-Burban S, Cuzin L, et al. CCR5 inhibitors and CD4 cell count change in treatment experienced patients. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-1813.
2. Wilkin T, Ribaudo H, Gulick R. The relationship of CCR5 inhibitors to CD4 cell count changes: a meta-analysis of recent clinical trials in treatment-experienced subjects. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 800. http://www.retroconference.org/2008/Abstracts/31374.htm
3. Stepanyuk O, Chiang TS, Dever LL, et al. Impact of adding maraviroc to antiretroviral regimens in patients with full viral suppression but impaired CD4 recovery. AIDS. 2009;23:1911-1913.
4. 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. Abstract 285. http://www.retroconference.org/2010/PDFs/285.pdf
5. Saag M, Goodrich J, Fatkenheuer G, et al. A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis. 2009;199:1638-1647.
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