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Effect of the Intensification with a CCR5 Antagonist on the Decay of the HIV-1 Latent Reservoir and Residual Viremia
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Reported by Jules Levin
CROI 2010
Carolina Gutierrez1, L Diaz2, B HernAndez-Novoa1, A Vallejo1, C Page1, R Lorente2, N Madrid1, S Palmer3, M A Munoz-FernAndez2, and S Moreno1
1Hosp Univ Ramon y Cajal, Madrid, Spain; 2Hosp General Univ Gregario Maranon, Madrid, Spain; and 3Swedish Inst of Infectious Diseases Control and Karolinska Inst, Stockholm
Background: The stability of the CD4 T cell reservoir could be related to continuous replenishment from plasma residual HIV. Intensification with an entry inhibitor could help eliminate detectable levels of ongoing viral replication.
Methods: Intensification clinical trial (NCT00795444) with maraviroc (MVC) including chronically HIV-infected adults with stable ART consisting of ³3 drugs, and with viral load (VL) <50 copies/mL for ³2 years, CD4 count >350 cells/mm3 and demonstrated CCR5-tropism. Latently-infected resting CD4 cells, residual viremia (RV), and immune activation were determined at baseline (BL) and at week 12 (w12). Latently-infected resting CD4 T cells were quantified using a limiting dilution co-culture assay. RV was measured by quantitative real-time RT-PCR assay (Single Copy Assay, SCA, threshold: 0.3 copies/mL). Enriched episomal 2-LTRs DNA from peripheral blood mononuclear cells was detected by a nested PCR flanking long terminal repeat junction area. Activation was measured on CD4 and CD8 with both anti-HLA-DR and anti-CD38 antibodies (BD Bioscience).
Results: Nine patients have been included. Median time of HIV diagnosis was 103 months (IQR 58 to 240 months), ART was administered for a median of 75 months (IQR 38 to 144 months), and the median BL CD4 count was 711 cells/mm3 (IQR 547 to 793). At BL, the reservoir could be quantified in 6 of 9 patients (mean 2.04 infectious units per million (IUPM)). At w12 of MVC intensification, all patients maintained VL <50 copies/mL (median CD4 count: 686 cells/mm3 (IQR 589 to 1,005 cells/mm3). A decrease in the latent reservoir was observed in 5 patients, while no decrease was found in one (mean 0.08 IUPM, P =0.048 compared to BL). Even though the BL RNA levels were at the assay limit for 8 of 9 patients, after w12 of intensification viral RNA level increased in 6 patients (range 0.5 to 9.2 copies/mL). Episomal 2-LTRs DNA was undetectable in the 9 patients at BL and turned detectable in 4 of them at w12. A significant decrease in the proportion of CD3+CD4+CD38+HLA-DR+ was observed at wk12 of intensification (median 2.9% (2.5 to 3.3) at BL vs 0.6% (0.4 to 2.4) after intensification, P =0.003. A trend of a decrease in CD3+CD8+CD38+HLA-DR+ was observed after intensification, median 5.4% (4.7 to 7.6) vs 2.3% (0.4 to 2.9), P =0.079.
Conclusions: In this preliminary analysis, intensification with MVC seems to accelerate the decay of the HIV latent reservoir. Unexpectedly, an increase in RV measured by SCA and episomal 2-LTRs DNA detection has been observed. A decrease in the activation of CD4 and CD8 cells was observed at wk12 of intensification.
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