WEPDC0105 - Poster Discussion
High maraviroc concentrations in rectal secretions after oral dosing do not prevent rectal SHIV transmission in macaques
Presented by J. Gerardo Garcia-Lerma (United States).
I. Massud, W. Aung, A. Martin, S. Bachman, J. Mitchell, F. Deyounks, E. Kersh, C.-P. Pau, W. Heneine, J.G. Garcia-Lerma
Center for Disease Control and Prevention, Atlanta, United States
Background: MVC is a potent CCR5 co-receptor antagonist that is being considered for pre-exposure prophylaxis for HIV prevention. We evaluated in macaques the pharmacokinetic (PK) profile of MVC and assessed efficacy of MVC in preventing rectal SHIV transmission.
Methods: The PK profile of oral MVC (44 mg/kg) was evaluated at first dose in plasma and rectal secretions in 12 macaques. Half-life of CCR5-bound MVC was measured using a MIP1-β internalization assay. Relationship between MVC concentration, CCR5 occupancy, and protection from infection was evaluated in vitro. Efficacy of MVC in preventing rectal virus transmission was investigated using a macaque model consisting of weekly SHIV162p3 exposures. Six macaques received a dose of MVC 24h before each virus exposure and a second dose 2h thereafter. Four untreated macaques were controls. Infection was monitored by serology and PCR.
Results: MVC PK profile in macaques was similar to humans. MVC concentrations peaked at 2h in plasma (median=451 ng/ml) and at 5-48h in rectal secretions (median=2,329 ng/ml). MVC AUC0-24h in rectal secretions was 7.5 times as high as in plasma (median=12,720 and 1,685 ngxhr/ml, respectively). At day 4, MVC concentration in rectal secretions (median=44 ng/ml) was 21.8 times as high as the IC50 value, and was sufficient to fully occupy CCR5 in PBMCs. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable PK profile, 5/6 animals receiving MVC were infected during 5 rectal SHIV exposures as did 3/4 controls.
Conclusions: We identified a dose of MVC that results in local and systemic drug exposures comparable to humans receiving 300 mg. Despite high and durable MVC concentrations in rectal secretions, MVC did not prevent SHIV infection in macaques. This model suggests that higher MVC concentrations are needed for rectal protection and highlights the need to better understand the mechanism of low efficacy and identify protective MVC regimens.
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