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Adding Maraviroc Does Not Boost CD4s or Quiet T-Cell Activation
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Adding maraviroc to a suppressive antiretroviral regimen did not improve CD4 counts or dampen T-cell activation through 24 weeks of treatment in a placebo-controlled trial [1]. In fact, levels of activated CD4 and CD8 generally rose among people taking maraviroc, while falling in the placebo group.
Randomized trials of the CCR5 antagonist suggested that it boosts CD4 counts more than some other antiretrovirals. That would be a valuable property in people with a good virologic response to antiretroviral therapy but sluggish CD4 gains. Studies assessing the CD4-boosting potential of maraviroc yielded conflicting results, though earlier work suggested that maraviroc intensification quells CD8-cell activation [2,3]. Therefore, US researchers mounted this placebo-controlled trial of maraviroc intensification.
The trial involved 42 people with a viral load below 48 copies for at least 1 year but a CD4 count still below 350. Everyone had at least one CD4 count below 100 in the past year, and everyone reported better than 90% adherence. The investigators randomized them to add maraviroc or placebo for 24 weeks in a double-blind design. No one had a serious illness in the past 3 months or had taken immunomodulatory or suppressive therapy in the past 4 months. The primary outcome was change in percentage of activated (CD38+ HLA-DR+) CD8 cells in peripheral blood.
Age averaged 50 years in both group, while CD4 count averaged 206 in the maraviroc arm and 202 in the placebo arm. These people had taken antiretrovirals for an average 30 months. Viral load measured by a single-copy assay dropped significantly in both treatment arms, with no difference between arms. CD4 counts rose significantly in both groups, with an estimated yearly gain of 38 CD4s in the placebo group (P = 0.008) and 37 CD4s in the maraviroc group (P = 0.004).
Peripheral CD8 cells increased significantly in the maraviroc group through 24 weeks (+81 cells, +9%, P = 0.03) but not in the placebo group. In a subset of 15 people with serial rectal biopsies, maraviroc tended to reduce CD8-cell activation in rectal tissue (-7%, P = 0.07). However, CD8-cell activation in peripheral blood rose in people taking maraviroc (+18%, P = 0.07) while falling through 24 weeks in the placebo group (-11%, P = 0.039). At 24 weeks the difference in peripheral blood CD8-cell activation between maraviroc and placebo was statistically significant (P = 0.001).
CD4-cell activation in peripheral blood dropped significantly in the placebo group through 24 weeks (-25%, P = 0.001) but not in the maraviroc group. The 24-week difference in CD4-cell activation between arms was statistically significant (P = 0.028). While the percentage of activated T cells in rectal tissue did not change significantly in people taking placebo, percentages of activated CD4 and CD8 cells in rectal tissue nearly doubled in the maraviroc group.
The investigators concluded that maraviroc intensification appears to redistribute CD8 cells from lymphoid tissue to the peripheral circulation, while having little impact on CD4 counts. It seems clear that maraviroc intensification in virologically suppressed people offers no advantage in adding CD4 cells [1,3] or dousing T-cell activation [1].
References
1. Hunt P, Shulman N, Hayes T, et al. Immunomodulatory effects of MVC intensification in HIV-infected individuals with incomplete CD4+ T cell recovery during suppressive ART. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 153LB.
2. Gutierrez C, Diaz L, Hernandez-Novoa B, et al. Effect of the intensification with a CCR5 antagonist on the decay of the HIV-1 latent reservoir and residual viremia. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 284. Poster online at
http://www.retroconference.org/2010/PDFs/284.pdf.
3. Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 525. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 285. Poster online at http://www.retroconference.org/2010/PDFs/285.pdf.
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