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Effect of the Intensification with a CCR5 Antagonist Maraviroc on the Decay of the HIV-1 Latent Reservoir and Residual Viremia - reduced activation
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Reported by Jules Levin
CROI 2010 Feb SF
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
ABSTRACT
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.
RESULTS
HIV-1 latent reservoir decreased after 12 weeks of maraviroc (figura 1 and table 1). In fact, all patients but one showed an undetectable value of latent reservoir after MVC. Residual viremia (figure 1 and table 2) and 2-LTR containing circular DNA become detectable after 12 weeks of MVC intensification (table 2).
A significant decrease in the proportion of activated CD4 cells was observed after
12 weeks of intensification with MVC. On the other hand, the proportion of activated CD8 cells was also observed but reached no statistical significance (figura 3). No difference in absolute CD4 count was observed after 12 weeks of intensification. The proportion of naive CD4 cells was remained stable after intensification (figure 4). The levels of Th1/Th2 citokines were not statistically different after 12 weeks of intensification (table 3).
Figure 3: Immune activation after 12 weeks of intensification with MVC. Values are compared to HIV-1 negative individuals.
Figure 4: CD4 cell count and proportion of naive CD4 cells after 12 weeks of intensification with MVC.
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