Abstract
BackgroundOngoing HIV-1 replication in lymphoid cells is one explanation of the persistence of HIV-1 reservoirs despite highly active antiretroviral therapy (cART). We tested the potential of cART intensification by Maraviroc plus Raltegravir to decrease proviral HIV-1 DNA levels in lymphoid cells during a randomized trial.Patients and methodsWe randomly assigned for 48 weeks 22 patients to continue their current first line regimen of Truvada® plus Kaletra® or intensify it with Maraviroc and Raltegravir. The primary objective was to obtain a 50% decrease in proviral HIV-1 DNA levels in lymphoid cells with intensification. Blood samples were drawn at W-2, W0, W2, W4, W12, W24 and W48. Plasma viremia, cellular proviral DNA and cellular RNA, 2-LTR circles and lymphocytes subsets were assayed using validated methods. Patients in the intensified group underwent a gut biopsy at baseline and W48 to measure proviral DNA levels. Statistical analysis used parametric and non-parametric tests.ResultsTen patients in each arm completed the trial. The 2 populations were comparable at baseline. No change in the reservoir size was observed in the intensified arm compared to the control arm measured in peripheral blood mononuclear cells (PBMCs). No change in the reservoir size was observed in gut proviral DNA in the intensified arm. In this group, no increase in 2-LTR circles was observed as early as 2 weeks after intensification and no change was found in residual plasma RNA levels measured by the single copy assay. However, a decrease in CD8+ T cells activation was observed at 24 and 48 weeks, as well as in PBMCs HIV-1 RNA levels.ConclusionWe conclude that the intensification of a Protease Inhibitor regimen with Maraviroc and Raltegravir does not impact the blood proviral DNA reservoir of HIV but can decrease the cell-associated HIV RNA, the CD8 activation and has a possible impact on rectal proviral HIV DNA in some patients.Trial registrationClinicalTrials.gov identifier number NCT00935480
Highlights
With the advent of combined antiretroviral therapy, HIV-1 replication can become undetectable in the plasma for years
No change in the reservoir size was observed in the intensified arm compared to the control arm measured in peripheral blood mononuclear cells (PBMCs)
No increase in 2-LTR circles was observed as early as 2 weeks after intensification and no change was found in residual plasma RNA levels measured by the single copy assay
Summary
With the advent of combined antiretroviral therapy (cART), HIV-1 replication can become undetectable in the plasma for years. CART intensification could reduce the residual HIV-1 replication and, the HIV-1 reservoir. The aim of this trial was to test the efficacy of cART intensification in first line treated patients to decrease the proviral HIV-1 reservoir in circulating peripheral blood mononuclear cells (PBMCs). We used Maraviroc, a CCR5 inhibitor and Raltegravir, an integrase inhibitor for intensification, with the objective to get at least a 50% decrease in proviral DNA levels in PBMCs. Ongoing HIV-1 replication in lymphoid cells is one explanation of the persistence of HIV-1 reservoirs despite highly active antiretroviral therapy (cART). We tested the potential of cART intensification by Maraviroc plus Raltegravir to decrease proviral HIV-1 DNA levels in lymphoid cells during a randomized trial
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