Exploring HIV Entry Blockade as a Pre-exposure Prophylaxis Strategy in Women

RATIONALE Globally, over half of HIV-infected adults are women, and in the United States, 25% of all HIV/AIDS cases occur in women. Women often lack control over many available prevention measures, underscoring a critical need to enhance HIV prevention options for women. Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy in which antiretroviral (ARV) drugs are used prior to potential HIV exposure to reduce the likelihood of infection. This strategy, which usually contains the drug tenofovir disoproxil fumarate (TDF), has recently shown promise, but efficacy data suggest room for improvement, particularly for women, in whom these data are conflicting. This study aims to prospectively examine ARV pharmacology and mucosal immunology in order to evaluate a novel PrEP strategy in women - blockade of HIV entry from its target cells at the mucosal surface using the CCR5 receptor antagonist maraviroc (MVC). These actions of CCR5 receptor antagonism, if validated, could lead to reduced HIV acquisition risk at more favorable dosing strategies than available for current PrEP. Knowledge of pharmacological modulation of mucosal immunity and HIV acquisition risk is fundamental to understanding, improving, and designing new PrEP strategies. DESIGN This is a prospective, observational cohort study with an intensive pharmacokinetic component conducted in HIV-negative healthy women. Genital tract and whole blood samples will be collected before, during, and after treatment with 7 days of oral MVC, dosed at 300mg twice daily (standard) or 300mg daily (reduced) compared with no treatment (control). Genital tract and plasma MVC concentration will be measured using intensive pharmacokinetic sampling to generate concentration-time profiles. Peripheral blood mononuclear cells (PBMC) and endocervical cells harvested from whole blood and cervicovaginal lavage respectively will be analyzed for CCR5 receptor occupancy, the number of CCR5-expressing HIV target cells, and level of T cell activation. DURATION 21 days after the first visit of the last participants. Enrollment is expected to take 12 months. SAMPLE SIZE 30 subjects (10 subjects per study group) POPULATION HIV-negative healthy women, age 18 years or older, with normal menses.