The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

• Published in: Blood Vol. 121; no. 23; pp. 4635 - 4646
• Main Authors: Hunt, Peter W., Shulman, Nancy S., Hayes, Timothy L., Dahl, Viktor, Somsouk, Ma, Funderburg, Nicholas T., McLaughlin, Bridget, Landay, Alan L., Adeyemi, Oluwatoyin, Gilman, Lee E., Clagett, Brian, Rodriguez, Benigno, Martin, Jeffrey N., Schacker, Timothy W., Shacklett, Barbara L., Palmer, Sarah, Lederman, Michael M., Deeks, Steven G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2013; American Society of Hematology
• Subjects: Adult; CCR5 Receptor Antagonists; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Clinical Trials and Observations; Cyclohexanes - therapeutic use; Female; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - immunology; Gastrointestinal Tract - virology; Graft vs Host Disease - drug therapy; Graft vs Host Disease - immunology; Graft vs Host Disease - virology; HIV Fusion Inhibitors - therapeutic use; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - immunology; Humans; Immunophenotyping; Lymphocyte Activation - drug effects; Lymphoid Tissue - drug effects; Lymphoid Tissue - immunology; Lymphoid Tissue - virology; Male; Maraviroc; Middle Aged; Rectum - immunology; Rectum - pathology; Rectum - surgery; RNA, Viral - blood; RNA, Viral - genetics; Triazoles - therapeutic use; Viral Load - drug effects
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-06-436345

The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm3 and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART) to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at week 24 (+2.2% vs −0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). The % CD38+HLA-DR+ CD4+ and CD8+ T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1β) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligand-mediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072. •Maraviroc intensification unexpectedly increases T-cell activation in peripheral blood and rectal mucosa during treated HIV infection.•Maraviroc appears to redistribute CD8+ T cells from the gut to peripheral blood during treated HIV infection.