Abstract
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.
Highlights
Tenofovir disoproxil fumerate (TDF) is an antiviral pro-drug, belonging to the class of nucleoside reverse transcriptase inhibitors (NRTIs) used for the treatment of the human immunodeficiency virus 1 (HIV-1) [1] and hepatitis B
The goal of the present study is to provide an in silico model that consistently predicts intracellular tenofovir diphosphate (TFV-DP) pharmacokinetics based on different TDF dosing schemes
We have previously shown that the antiviral effect of NRTIs can be regarded by an inhibition of the rate of successful cell infection bT=M and a proportional increase in the number of unsuccessful infection events CLT=M [29]
Summary
Tenofovir disoproxil fumerate (TDF) is an antiviral pro-drug, belonging to the class of nucleoside reverse transcriptase inhibitors (NRTIs) used for the treatment of the human immunodeficiency virus 1 (HIV-1) [1] and hepatitis B. After first pass of TDF through the liver, tenofovir (TFV), an analogue of the endogeneous deoxyadenosine monophosphate (dAMP) [3], is formed. After uptake into HIV target cells, TFV can become sequentially phosphorylated to form tenofovir diphosphate (TFV-DP), the active form, which is an analog of endogeneous deoxyadenosine triphosphate (dATP). TFV-DP subsequently competes with dATP for incorporation into nascent viral DNA during HIV-1 reverse transcription (RT), where it prevents further DNA polymerization during RT, once it becomes incorporated [6]. TFV-DP prevents the production of pro-viral DNA, which is required for stable host cell infection and viral replication
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