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Raltegravir Intensification in Antiretroviral-treated Patients Exhibiting a Suboptimal CD4+ T Cell Response
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Reported by Jules Levin
CROI 2010
Hiroyu Hatano*1, T Hayes2, V Dahl3, E Sinclair1, T-H Lee4, P Hunt1, S Palmer3, M Busch4, B Shacklett2, and S Deeks1
1Univ of California, San Francisco, US; 2Univ of California, Davis, US; 3Karolinska Inst, Solna, Sweden; and 4Blood Systems Res Inst, San Francisco, CA, US
Background: The factors influencing the maintenance of the latent reservoir in patients with suboptimal immune recovery despite treatment-mediated viral suppression are unclear. We conducted a randomized, double-blinded, placebo-controlled study of raltegravir intensification to assess whether residual viral replication contributes to the replenishment of the latent reservoir, and assessed whether HIV-specific T cell responses in gut-associated lymphoid tissue (GALT) may limit the size of the latent reservoir.
Methods: In this study, 30 subjects with undetectable viral loads on HAART for at least 1 year were randomized to add raltegravir 400mg twice daily or placebo for 24 weeks. The primary endpoint was proportion of subjects with undetectable plasma HIV RNA levels using a single copy assay at week 12. Cell-associated RNA and proviral DNA levels were measured at baseline and weeks 4 and 24. GALT samples were obtained from 21/30 subjects at baseline and weeks 6 and 22. T cell activation (CD38+/HLA-DR+) and HIV gag-specific responses were measured in blood and GALT at baseline and weeks 4 and 24.
Results: Duration of HIV infection was 18 years and duration of HAART was 23 months. Baseline CD4+ T cell count was 232 cells/mm3 and nadir CD4+ T cell count was 53 cells/mm3. Median baseline plasma HIV RNA level was 5.2 copies/mL (9/28 subjects were below the limit of the assay). The proportion of subjects with undetectable plasma RNA levels at week 12 was not different across the 2 groups (P =0.42). As compared to placebo, raltegravir intensification did not have a significant effect on proviral DNA (P =0.56), cell associated RNA (P =0.47), blood CD8+ (P =0.33) or CD4+ (P =0.67) T cell activation, or GALT CD8+ (P =0.53) or CD4+ T cell activation (P =0.14). In addition, intensification did not significantly affect gag-specific responses in blood or GALT. However, higher levels of gag-specific IL2+INF-γ CD4+ T cells and CD8+ T cells in GALT were associated with lower levels of cell associated RNA (rho = -0.52, P =0.02 for CD4+ T cell responses; rho = -0.53, P =0.04 for CD8+ T cell responses); similar trends were observed between gag-specific CD8+ T cell responses and proviral DNA levels.
Conclusions: Low-level cryptic viral replication is not likely to be a major determinant of suboptimal CD4 gains during HAART. In the context of complete or near complete viral suppression, mucosal HIV-specific T cell responses may be a major determinant of the size of the latent reservoir.
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