Background:
Simplifying pre-exposure prophylaxis (PrEP) dosing will facilitate implementation. On demand PrEP has not been evaluated in sub-Saharan Africa, young adults nor using TAF-FTC. Dose needed for insertive sex remains unknown. The CHAPS trial addressed these gaps of knowledge and pre-clinically assessed post-exposure prophylaxis (PEP) in foreskin.
Methods:
Phase 2 open-label, randomised controlled trial in Uganda and South Africa. 144 HIV-negative men aged 13-24yrs, randomized to one of nine arms receiving: i) different doses of TDF-FTC or TAF-FTC, or no PrEP ii) different timing of circumcision in relation to PrEP iii) with/without PEP applied 20h post-challenge to foreskin explants. Foreskin explants and PBMCs were exposed to HIV-1BaL at high or more biologically relevant, low viral titre. PEP without PrEP was evaluated with dosing at 1, 24, 48 or 72h post-challenge. Infection was assessed by p24 ELISA of culture supernatants. TFV-diphosphate (TFVdp) and FTC-triphosphate (FTCtp) concentrations were measured using LC-MS in PBMCs, foreskin tissue and CD4+T cells isolated from foreskin. PrEP effect on foreskin proteomics was assessed by western blot evaluation of tight junction proteins and inflammatory cytokines by Luminex.
Results:
Compared to control arm, all PrEP dosing arms significantly decreased p24 levels after ex vivo HIV-1BaL challenge of foreskin tissue (all p< 0.0001) and PBMCs (p 0.002 to < 0.0001) with no differences between drugs (TDF-FTC or TAF-FTC) or timings observed. Ex vivo PEP dosing did not increase protection in tissue but further reduced p24 levels in PBMCs. There was no difference in time to, or duration of protection between PBMCs and explants. Higher levels of TFPdp were obtained with TAF-FTC than TDF-FTC in foreskin and PBMCs (p≤0.0001). Foreskin CD4+ cell TFVdp levels were 42.7|10.9 fmol/106 cells (TAF|TDF: p=ns). PEP protection was lost with dosing after 48h exposure; TAF-FTC was significantly more protective than TDF-FTC at every time point. Tight junction proteins were not significantly affected. TDF-FTC significantly reduced IL-1a levels in foreskin.
Conclusions:
Oral on demand PrEP with TDF-FTC or TAF-FTC provides ex vivo protection of foreskin and PBMCs. TAF-FTC provided higher TFVdp levels in foreskin and PBMCs, and better PEP activity than TDF-FTC in foreskin. PEP protection decayed after 48h post exposure.