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Pharmacokinetics, the immunological impact and the effect on HIV ex-vivo infectivity of maraviroc, raltegravir and lopinavir in MSM using Post-exposure Prophylaxis.

Most of the studies using the colorectal tissue explants challenge model have been conducted after one single-dose and before reaching a steady-state. We consider that longer exposure as in 28-day post-exposure prophylaxis (PEP) course and in an at-risk setting, such as after a sexual risk exposure to HIV could give us valuable information about these drugs. In a substudy we assessed pharmacokinetics, changes on immune system and ex-vivo rectal mucosal susceptibility to HIV-1 infection after taking maraviroc (MVC), raltegravir (RAL) and ritonavir-boosted lopinavir (LPV/r) PEP-based regimens in 30 men who have sex with men. Participants received 28 days of twice-daily MVC (n=11), RAL (n=10) or LPV/r (n=9) all with tenofovir/emtricitabine backbone. Blood, rectal fluid (RF) and rectal tissue (RT) samples were collected at day 7, 28 and 90 after starting PEP. The samples obtained at day 90 were considered baseline. All studied antiretrovirals were quantifiable at 7 and 28 days in all tissues. Activation markers were increased in CD4 mucosal mononuclear cells (MMC) after 28 days of MVC: CD38+ 68.5 vs 85.1, p=0.008 and CD38+DR+ 16.1 vs 26.7, p=0.008. Exposure to MVC at both end-points (7 and 28 days) was associated with significant suppression of HIV-1BAL (p=0.005 and p=0.028) but we did not observe this effect with RAL or LPV/r. Merging together changes in MMC in all arms, we found a positive correlation in the CD8 T-cell lineage between the infectivity at day 7 and activation (CD38+ r=0.43, p=0.025, DR+ r=0.547, p=0.003 and 38+DR+ r=0.526, p=0.05), senescence (CD57+CD28- r=0.479, p=0.012), naïve cells (RA+CCR7+ r=0.484, p=0.01) and CCR5 expression (r=0.593, p=0.001). We conclude that maraviroc in combination with tenofovir/emtricitabine was associated with viral suppression in rectal explants and that overall ex-vivo HIV infectivity correlated with activation and senescence in CD8 mucosal mononuclear cells.