Repository: Freie Universität Berlin, Math Department

Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir & Prophylactic Efficacy against HIV-1 Infection.

Duwal, S. and Schütte, Ch. and von Kleist, M. (2012) Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir & Prophylactic Efficacy against HIV-1 Infection. PLoS One, 7 (7). e40382.

Full text not available from this repository.


Antiviral pre-exposure prophylaxis (PrEP) can protect healthy individuals from HIV-1 infection. While current PrEP-strategies are based on daily drug administration, shortcourse prophylaxis before-, after- or around the time of viral exposure has not been investigated to date. 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 the number of transmitted viruses, timing of TDF administration and adherence. We developed a pharmacokinetic model for TDF and its active anabolite tenofovirdiphosphate (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 probability of HIV-1 infection for (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). The predicted prophylactic efficacy of TDF was decreasing with increasing numbers of transmitted viruses for all evaluated regimens and is limited by a slow accumulation of active compound and variable TFV-DP half-life. Once daily TDF-based PrEP yielded <80% protection, which was relatively unaffected by poor adherence. Sd-PrEP with 300mg or 600mg TDF could prevent <50% infections, when given at least 24h before virus exposure. The efficacy dropped to <10%, when given 1h before exposure and did not provide a benefit if a large number of viruses were transmitted. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. TDF-based PrEP efficacy may be synergistically combined with strategies that lower the number of transmitted viruses, such as `treatment for prevention'/`test-and-treat' strategies.

Item Type:Article
Subjects:Mathematical and Computer Sciences > Mathematics > Mathematical Modelling
Mathematical and Computer Sciences > Mathematics > Applied Mathematics
Biological Sciences > Microbiology > Virology
Medicine and Dentistry > Clinical Medicine
Divisions:Other Institutes > Matheon > A - Life Sciences
Department of Mathematics and Computer Science > Institute of Mathematics > BioComputing Group
ID Code:1130
Deposited By: Dr Max von Kleist
Deposited On:22 Mar 2012 12:45
Last Modified:25 Jan 2013 10:05

Repository Staff Only: item control page