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Long-Term T-cell Changes With Maraviroc in Four Randomized Trials
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Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
CD4 counts rose more with maraviroc than comparison regimens through 96 weeks in antiretroviral-naive and experienced people enrolled in four randomized trials [1]. Although CD4 gains were always greater in maraviroc arms than comparison arms, the small difference in previously untreated people may not be clinically meaningful. CD8 counts rose over 96 weeks in antiretroviral-experienced people in the MOTIVATE trials, but not in maraviroc-treated naive patients in the MERIT of 1078 trials.
The analysis involved people with R5 virus enrolled in MOTIVATE 1 and 2 (treatment-experienced people who took maraviroc once or twice daily [n = 414 and 426] with an optimized background regimen versus placebo [n = 209]), MERIT (treatment-naive people who took maraviroc twice daily with zidovudine/lamivudine [n = 360] versus efavirenz plus zidovudine/lamivudine [n = 361]), and the 1078 study (treatment-naive people who took maraviroc once daily with atazanavir/ritonavir [n = 60] versus atazanavir/ritonavir plus tenofovir/emtricitabine [n = 61]).
In all studies median CD4 gains were greater with maraviroc than the comparison regimen after 96 weeks:
-- MOTIVATE maraviroc once daily: +96 CD4s, P < 0.05 vs placebo
-- MOTIVATE maraviroc twice daily: +116 CD4s, P < 0.05 vs placebo
-- MOTIVATE placebo: +24 CD4s
-- MERIT maraviroc twice daily: +183 CD4s, P < 0.05 vs placebo
-- MERIT efavirenz: +155 CD4s
-- 1078 maraviroc once daily: +178 CD4s
-- 1078 TDF/FTC: +173
Looking only at people with a week-96 viral load below 50 copies, the investigators charted nonsignificantly greater median CD4 gains in MERIT and 1078 and in the twice-daily MOTIVATE arm, but not in the once-daily MOTIVATE arm, versus control regimens.
Through 96 weeks in MERIT and the 1078 study, median CD8 counts remained essentially unchanged in maraviroc arms while falling by 122 cells and 76 cells in comparison arms in those trials. In the MOTIVATE trials at 96 weeks, median CD8 counts climbed by 142 and 125 cells in the once- and twice-daily arms, while rising by a median of only 10 cells in the placebo arm. These patterns were similar when the investigators evaluated CD8 changes only in people who reached a viral load below 50 copies. Declining CD8 counts are generally thought to reflect decreasing immune activation as treatment controls HIV replication. The meaning of CD8 changes--or lack of change--in people taking maraviroc over the long term requires further analysis and explanation.
The researchers also evaluated CD4 changes in people who began treatment with a CD4 count below 200. Through 96 weeks in the MOTIVATE trials, the following proportions reached a count above 199, 349 or 499:
Above 199
-- Maraviroc twice daily: 53%
-- Maraviroc once daily: 47%
-- Placebo: 24%
Above 349
-- Maraviroc twice daily: 14%
-- Maraviroc once daily: 13%
-- Placebo: 8%
Above 499
-- Maraviroc twice daily: 4%
-- Maraviroc once daily: 3%
-- Placebo: 3%
In the MERIT trial, the same kind of analysis yielded these results:
Above 199
-- Maraviroc twice daily: 85%
-- Efavirenz: 75%
Above 349
-- Maraviroc twice daily: 37%
-- Efavirenz: 34%
Above 499
-- Maraviroc twice daily: 13%
-- Efavirenz: 9%
Linear regression analysis of factors contributing to better CD4 gains at week 96 of MOTIVATE and MERIT identified treatment with maraviroc as one of those variables. The others were younger age, higher baseline CD4 count, being treatment naive at baseline, and having a viral load below 50 copies at week 96.
Two meta-analyses compared CD4 responses in treatment-experienced people taking maraviroc or vicriviroc and people taking other regimens without CCR5 antagonists [2,3]. One found an advantage with CCR5 antagonists [2] but the other did not [3].
References
1. Lazzarin A, Sierra-Maderno JG, Battegay M, et al. Maraviroc increases CD4+ and CD8+ cells: long-term data from the maraviroc clinical development program. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract O422.
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. 3-6 February 2008. Boston. Abstract 800. http://www.retroconference.org/2008/Abstracts/31374.htm
3. 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. 12-15 September 2010. Boston. Abstract H-1813. http://www.natap.org/2010/ICAAC/ICAAC_38.htm
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