Due to ongoing interest in exploring safe and effective on-demand PrEP dosing strategies for cisgender women, investigators used a previously published pharmacokinetic/pharmacodynamic (PK/PD) model to identify regimens that could achieve protective drug exposure in the female genital tract over 5-10 days post-sex.  Protective thresholds were defined as any concentration profile achieving ≥90% of maximal protection (EC90).  Tested regimens extended the 2-1-1 reference schedule across 3-4 days: 3-day regimens included 2-2-1 and 2-2-2, while 4-day regimens included 2-1-1-1, 2-2-1-1, 2-2-2-1, and 2-2-2-2.  The proportion of predicted profiles achieving ≥EC90 at 5, 7, and 10 days post-sex was calculated (these time points were selected based on the general belief that HIV propagates and disseminates to regional lymph nodes over a 3- to 6-day window following a transmission event, and that local dissemination occurs within ~6 days).  At 5 days, all regimens demonstrated >80% achievement of EC90.  Extending to 4 days of dosing increased the proportion achieving EC90 to >80% at 7 days.  Investigators concluded that their model suggests prevention of HIV using on-demand TDF/FTC dosing is likely for female genital tract exposures, with >80% reaching EC90 for 5 days after sex.  A fourth day of dosing is required to extend protection from 5 to 7 days post-sex.

These data, which were shared at CROI 2025, suggest that 4-day, on-demand dosing strategies involving a “loading” double-dose of F/TDF may offer high levels of protection for female genital tract exposures.  Although the selected model did not account for all conditions and potential variables of interest, these are highly compelling findings which warrant further clinical evaluation to confirm study observations, discern whether safety and tolerability differences might favor a particular dosing strategy, and advance our understanding of how to optimize PrEP options for cisgender women.