Oral pre-exposure prophylaxis (PrEP) is an effective prevention strategy against HIV-1 transmission. All completed PrEP clinical trials have tested ARV acting post-viral entry in the target cell. Maraviroc (MVC) showed no protection ex vivo following stat dosing [CROI 2105] and daily dosing studies are ongoing. Understanding the drugs levels achieved by stat dosing which failed to show ex vivo protection will help to inform future clinical trials of daily or “on demand” MVC PrEP.
We present results of a PK dosing study of single oral dose MVC 300mg in all HIV exposure compartments and compare men and women, in a phase 2, multi-site, open label, randomised controlled clinical trial.
56 healthy adult female (n=26) and male participants (n=30) were randomized to a control arm (Arm A n=6 with 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 MVC 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 MVC concentrations included blood, saliva and rectal fluid (RF) for all subjects. In addition, men provided a urethral swab and rectal tissue (RT) and women provided cervico-vaginal fluid (VF) and vaginal tissue (VT). MVC drug concentrations were measured by validated LC-MS/MS.
MVC Cmax was reached within 4 hours in all compartments, and exceeded suggested MEC (25 ng/ml). The highest Cmax level was in urethra (median 4 hr compartment-to-plasma ratio =116), RF (99 males and 102 females), RT (9.7 males), VT (3.6) and vaginal fluid (2.6): only saliva (0.22 males and 0.17 females) levels were lower than plasma at Cmax. MVC concentrations remained above the MEC of 25ng/ml until the following times: saliva (2h ), VF 12h, plasma 8h, VT 24h, urethra 60h, RF >72h, RT >72h. All drug levels were above EC90 of 0.5ng/ml for 72 h except saliva; most samples were <0.4 ng/ml at 72 h).
At 72 h drug concentrations in compartments were higher than plasma: saliva (males
MVC concentrations greater than the EC90 occurred in multiple sites of HIV acquisition after single oral 300mg MVC. This suggests that MVC may be a suitable candidate for PrEP. However, the lack of inhibition in rectal and vaginal tissue previously reported suggests that either the ex