Background: On demand pre-exposure prophylaxis (PrEP) in msm has not been evaluated in Africa and the dosing requirement for insertive sex is unknown. The CHAPS trial (NCT03986970) aims to optimize on-demand PrEP dosing for insertive sex for young men in sub-Saharan Africa. Methods: Phase II open-label, randomised controlled trial (RCT) in Uganda and South Africa of 144 HIV negative men aged 13-24yrs, eligible for voluntary medical male circumcision (VMMC) and randomized to one of 9 arms receiving F/TDF, F/TAF or no PrEP at 1 (2 tablets) or 2 (2+1 tablets) consecutive days with final dose 5 or 21h prior to VMMC. Inner and outer foreskins explants were exposed to HIV-1BaL at a high (HVT) or a more biological relevant, low viral titre (LVT). Explants were further dosed ex vivo using the same oral PrEP drug 20h post-challenge. Infection was assessed at different time points during 15 days of culture by measurement of p24 in culture supernatants. TFV-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) tissue levels were measured using LC-MS methods (LLQ = 0.04 pmol/sample). Parallel systemic PK/PD evaluation was performed in isolated PBMCs at VMMC. We present data from South Africa. Results: Tissue TFV-DP concentrations (detected in 88% of tissue samples) were â¼2-fold higher with F/TAF vs. F/TDF dosing (p=0.02). FTC-TP levels were â¼10-fold higher than TFV-DP, and no significant differences were seen between regimens. TFV-DP levels were â¼40% higher with 2+1 vs. 2 tablets F/TDF dosing. No TFV-DP dose accumulation was evident for F/TAF. Following ex vivo HIV-1BaL challenge, greater decrease of p24 relative to control arm was observed with 2+1 than with 2 PrEP tablets dosing (F/TDF dosing: p=0.24 for HVT; 0.62 LVT; F/TAF dosing: p=0.12 for HVT; 0.39 LVT). Further decrease was observed in PBMCs (F/TDF dosing: p=0.20 for HVT; 0.57 LVT; F/TAF dosing: p=0.07 for HVT; 0.57 LVT). Ex vivo protection levels against LVT with F/TDF and F/TAF were not significantly different. Conclusion: Oral on demand PrEP dosing with 2 tablets of F/TDF or F/TAF from 5-21h before HIV-exposure provides ex vivo protection of foreskin tissue which increases with 2+1 dosing. PrEP efficacy needs to be evaluated in blood and mucosal compartments. Ex vivo challenge studies in human foreskin explants may facilitate dosing requirements and evaluation of new drugs for PrEP.
