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Antiviral and Immunological Effects of Intensification of Suppressive ART with Maraviroc, a CCR5 Antagonist
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Reported by Jules Levin
CROI 2010
Teresa Evering1, S Mehandru1, M Poles2, P Racz3, K Tenner-Racz3, H Mohri1, N Prada1, D Garmon1, T Parker4, and M Markowitz1
1Aaron Diamond AIDS Res Ctr, The Rockefeller Univ, New York, NY, US; 2New York Univ Sch of Med, NY, US; 3Bernhard Nocht Inst for Tropical Med, Hamburg, Germany; and 4The Rogosin Inst, New York, NY, US
Background: Gastrointestinal tract CCR5+CD4+ T cells are selectively infected and depleted during acute HIV-1 infection. Despite ART, gut-associated lymphoid tissue (GALT) T cell depletion and activation persists. We hypothesized that ART intensification with the CCR5 antagonist maraviroc (MVC) could effect immune reconstitution and decreased immune activation if this was due to ongoing viral replication during ART.
Methods: We enrolled adults infected with CCR5-tropic HIV-1 and treated with ART during acute, early infection. Subjects received ART for an average of 4 years prior to study entry and were randomized 2:1 to Arm A, 4 patients whose MVC was intensified for 24 weeks; or Arm B: whose NRTI was intensified for 12 weeks, 2 of whom were followed by cross-over to MVC for 12 weeks. Phlebotomy and flexible sigmoidoscopy with mucosal biopsies were performed at entry, weeks 12 and 24.
Results: Plasma HIV-1 RNA remained <50 copies/mL for all subjects throughout the study. Gastrointestinal biopsy RNA revealed <50 copies of HIV-1 NL43 gag for all participants at entry through week 24 (mean input of 1.5 x 106 copies of GAPDH/sample). At entry, no significant differences between arms A and B were measured for evaluated parameters. Immunohistochemistry revealed 5.36 ± 0.86 CD4+ T cells/unit area in the lamina propria at entry in Arm A. This did not increase significantly after 24 weeks. In contrast to Arm B, Arm A revealed non-significant decreases (P >0.10) in percentage of proliferating (MIB-1+) CD4+ T cells in the lamina propria between entry and week 12 (11.50% ± 2.50 vs 4.50% ± 1.94) and percentage of proliferating CD8+ T cells in the lamina propria between entry and week 12 (7.50% ± 5.20 vs 3.75% ± 1.11). No further decreases were noted after week 12. In Arm A, flow cytometry revealed significant differences (P <0.02) between the peripheral blood mononuclear cells (PBMC) and gut-associated lymphoid tissue (GALT) at entry in the CD4+CD8+ T cell ratio (1.47 ± 0.14 vs 0.91 ± 0.06) and percentage activated (CD38+) CD8+ T cells (2.61 ± 0.41 vs 17.61 ± 5.02). In Arms A and B, no statistically significant change (P >0.32) was noted in percentage of CD38+ or percentage of proliferating (Ki67+) CD4+ or CD8+ T cells in the GALT between entry, week 12 and week 24. Finally, in both arms, serum endotoxin activity was within the normal range at entry and did not significantly change after 24 weeks.
Conclusions: As previously reported, levels of immune activation and CD4+ T cell depletion in the GALT persist when compared to PBMC. Thus far, we observe no statistically significant effect of intensification of ART with MVC on a variety of immunologic and virologic parameters in the GALT.
RESULTS
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