Adherence is critical for effective HIV pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), yet remains a clinical challenge. TDF/FTC PrEP users are interested in less-than-daily and event-driven dosing [PMCID: PMC7228850]. Using a published model of TDF/FTC pharmacokinetics/pharmacodynamics (PK/PD) in rectal (RT), cervical (CT), and vaginal (VT) tissue [PMCID: PMC4907409], we predicted the efficacy of several dosing schedules being used off-label by PrEP users.
For each regimen, 1000 virtual PK profiles were simulated (NONMEM 7.4) for TDF and FTC; as per PMC4907409, drug metabolite:endogenous nucleotide (EN) ratios were created from simulated concentrations of tenofovir diphosphate (TFVdp) and FTC triphosphate (FTCtp) and randomly sampled EN (dATP and dCTP, for TFVdp and FTCtp, respectively) concentrations for each tissue. These ratios predicted the synergistic effect of TDF/FTC, with model parameters derived from in vitro CD4+ cell experiments. Maximal efficacy (ME) was defined as ?95% of profiles >EC90; the % of profiles achieving this are presented. Regimens included Friday/Saturday (FS) dosing, Tuesday/Thursday/Saturday/Sunday (TTSS) dosing, and 3 pericoital regimens with the 2nd dose occurring 24, 36, or 48 hrs after the 1st dose.
In the 1st week, FS and TTSS do not achieve ME in RT until 27hr and 40hr post-1st dose, respectively; repeated dosing predicts ME within the 1st week and ongoing RT ME. For pericoital regimens, ME in RT occurred after the 2nd dose, at 30 hr, 38 hr, and 49hr for the 24hr, 36hr and 48 hr regimens, respectively. Within 4hr of 1st dose, ~50% of RT profiles achieved ME; ~88% achieved it 24hr post-dose. No regimen achieves ME in CT; ~70% of CT profiles achieved EC90 at 24hr post-dose. ME was achieved in VT within 4hr of 1st dose, but 50% of profiles were With this approach, we predict pericoital dosing of an initial single-dose of TDF/FTC will be 82% protective in MSM and 70% protective in women. An initial double-dose, such as in IPERGAY, is needed for the best chance of immediate ME in men and women [PMC7228850], though women are protected for less time post-coitus. Consistent with earlier work showing CT/VT requires ?4 doses/week but RT requires ?2 doses/week to achieve ME, regular FS dosing is a viable PrEP strategy for anal intercourse but is unlikely to be protective for vaginal intercourse.