Discussion
TAF
HIV INFECTIONS
CHAPS is a trial of on-demand PrEP in young men in Uganda and South Africa, evaluating F/TAF for PrEP and PEP timing and dosing to prevent HIV acquisition after The aim of the study was to provide guidance for dosing requirements and time to protection following starting PrEP. Our primary outcome demonstrated that an on-demand double dose regimen of F/TDF or F/TAF, given on a single occasion, is protective between 5 and 21 h prior to insertive intercourse, and that post-coital dosing conferred additional protection in PBMCs but not tissue. Our data did not show clear superiority of TAF to TDF in protecting foreskins against HIV infections, however the higher TFV-DP intracellular concentrations we report in those who received TAF suggest that protection may be of longer duration, or that the dosing requirements for on-demand F/TAF are somewhat lower than for F/TDF. The results of this study align with findings from the social science arm of CHAPS, which clearly showed that young men in Uganda, Zimbabwe and South Africa favoured on-demand PrEP and if possible, a pre-coital only PrEP regime.Both F/TDF and F/TAF were well tolerated and highly effective against PBMC metabolite exposures achieved in the F/TDF arms were comparable to those reported in the IPERGAY single dose pharmacokinetic study.Intracellular TFV-DP accumulated in foreskin, which is potentially attributed to its long intracellular half-life in mucosal tissues (34–53 h in cervicovaginal tissuesThis study has successfully measured phosphorylated antiretroviral nucleosides in CD4± cells isolated from foreskin tissue. Data from this small sub-study revealed that, unlike the PBMCs compartment, dosing with TAF did not confer preferential distribution of TFV-DP into foreskin HIV target cells. The lack of correlation between PBMCs and foreskin CD4+ fractions, further supports the notion that CD4+ cells are a distinct cellular sub-population. However, the small sample size, low detection rate, and high inter-subject variation mean that these preliminary data should be interpreted with caution.A key strength of the trial design is the ability to assess several important PrEP variables including PrEP drug, PrEP dose and timing, and link tissue and cellular pharmacokinetics to pharmacodynamics. Unlike studies with HIV incidence as an outcome, no participants were exposed to additional risk of HIV due to group allocation.Our study had some limitations. Firstly, this was an open-label study with blinding of arm allocation to laboratory staff but not participants or clinical personnel. Second, one foreskin specimen and two PBMC specimens from the control arm were not infected following In an era when efficacy studies for HIV protection are large and prohibitively expensive, evidence from phase II studies of this nature will maximise the chance of identifying the most efficacious dosing strategy and filling data gaps around onset and offset of protection. This factorial design using the p24 protein as a surrogate endpoint can be used to efficiently select drug combinations and dosing regimens for testing in phase III, while obviating the unnecessary costs of futile regimens. The results from this study and future 