Background: Oral pre-exposure prophylaxis (PrEP) may be an effective prevention strategy against HIV-1 transmission. All completed PrEP clinical trials have tested ARV acting post-viral entry in the target cell. We present results of the first PrEP study evaluating the potential of an entry inhibitor, maraviroc, in a phase IV, multi-site, open-label, randomized controlled pharmacokinetic and ex vivo pharmacodynamic clinical trial.
Methods: 56 healthy adult female (n=26) and male participants (n=30) were randomized to a control arm (Arm A n=6 who had tissue samples taken at two time points one month apart) or to one of 4 intervention arms (n=12 per arm) where a single oral maraviroc 300 mg dose was taken at two time points prior to sampling, one month apart (Arm B: first sampling 2 h post first dose and second sampling 24 h post second dose; Arm C: 4 h and 36 h; Arm D: 6 h and 48 h; Arm E: 12 h and 72 h). Sampling to determine maraviroc concentration included blood, oral fluid and rectal fluid for all. In addition, men provided a urethral swab and a rectal biopsy and women provided a cervico-vaginal aspirate and a vaginal biopsy. Anti-viral activity was assessed by ex vivo challenge with R5-tropic HIV-1BaL of explants cut from mucosal tissue biopsies and measurement of p24 antigen levels in supernatants during 15 days of culture.
Results: Viral replication capacity of HIV-1BaL was significantly reduced (p=0.0005 two-tailed t-test) in vaginal biopsies harvested 2h post dosing with p24 levels in culture supernatant at day 15 of culture of 26.74 ± 17.27 pg/ml compared to 200.24 ± 45.89 pg/ml in untreated tissue. No significant reduction of p24 levels were detected at any other time point in vaginal tissue and at no dosing time point in rectal tissue. No Adverse events were reported.
Conclusions: A transient inhibition of ex vivo HIV infection was demonstrated in vaginal tissue 2h after a single oral 300mg maraviroc dose. The lack of inhibition in rectal tissue, despite the ability of Maraviroc to penetrate into the rectum, reveals significant mucosal differences affecting the activity of maraviroc in vaginal and rectal transmission sites. Multi-dosing of maraviroc in humans should be investigated for HIV prevention.