Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration
can protect healthy individuals from HIV-1 infection. While PrEP was recently
approved by the FDA, the potential long-term consequences of PrEP
implementation remain entirely unclear. The aim of this study is to predict
the efficacy of different prophylactic strategies with the pro-drug tenofovir-
disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and
mode of TDF administration (daily- vs. single dose), adherence and the number
of transmitted viruses. We developed a pharmacokinetic model for TDF and its
active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data
from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics
were coupled to an HIV model and viral decay following TDF mono-therapy was
predicted, consistent with available data. Subsequently, a stochastic approach
was used to estimate the % infections prevented by (i) daily TDF-based PrEP,
(ii) one week TDF started either shortly before, or -after viral exposure and
(iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical
solutions were derived to assess the relation between intracellular TFV-DP
concentrations and prophylactic efficacy. The predicted efficacy of TDF was
limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP
half-life and decreased with increasing numbers of transmitted viruses. Once
daily TDF-based PrEP yielded 80% protection, if at least 40% of pills were
taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent 50% infections, when
given at least before virus exposure. The efficacy dropped to 10%, when given
1 h before 24 h exposure. Efficacy could not be increased with increasing
dosage or prolonged administration. Post-exposure prophylaxis poorly prevented
infection. The use of drugs that accumulate more rapidly, or local application
of tenofovir gel may overcome the need for drug administration long before
virus exposure