Background: HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on the protective efficacy in receptive sex, with limited research on dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic/pharmacodynamic (PK/PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. Methods: Inner and outer fore-skin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1BaL at a high (HVT) or a low viral titer (LVT). Infection was assessed by measurement of p24 in foreskin culture supernatants. TFV, TAF and TFV-diphosphate (TFV-DP) concentrations were measured in tissue, culture supernatants, dosing and washing solutions. Results: Dose-response curves were obtained for both drugs with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV-DP in foreskin explants were approximately 6-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV-DP and p24 concentrations following HVT. Conclusions: Pre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding
