Sulav Duwal(1), Christof Schütte(1) and Max von Kleist(1)
(1) Freie Universität Berlin, Department of Mathematics and Computer Science
Objectives: Almost thirty years after the discovery of HIV-1, the AIDS epidemic is still not controlled. While the search for a vaccine continues, the use of antiretroviral drugs to prevent HIV-1 infection has been suggested. One key strategy is antiviral pre-exposure prophylaxis (PrEP), which, when taken by healthy individuals at risk, aims to protect them from acquiring infection. The pro-drug tenofovir-disoproxil-fumarate (TDF) is a key component in all currently tested regimens. The aim of this study is to predict the efficacy of different prophylactic strategies with TDF and to assess the sensitivity towards the number of transmitted viruses, timing of TDF administration and adherence.
Methods: 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. The pharmacokinetics of TFV-DP was coupled to a model of HIV dynamics. Subsequently, viral decay following TDF mono-therapy was predicted, consistent with available data [1]. A stochastic approach was then 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 taken before viral challenge (sd-PrEP).
Results: The predicted relative prophylactic efficacy of TDF was negatively correlated with the number of transmitted viruses for all evaluated regimens. Once daily TDF-based PrEP with 300mg could prevent approx. 80% infections, in agreement with clinical data (TDF-only sub-study of Partners PrEP) and was relatively unaffected by poor adherence. Sd-PrEP efficacy with 300mg or 600mg was limited by a slow accumulation of active compound and could prevent approx. 50% infections, when given at least 24h before virus exposure. The efficacy dropped to about 10%, when given 1h before. Efficacy was marginally increased with increasing dosage or prolonged (one week) administration. Post-exposure prophylaxis was likewise limited by a slow accumulation of active compound.
Conclusions: The prophylactic efficacy of TDF depends on the number of transmitted viruses, which may be exploited by combining prophylactic strategies with strategies that lower the number of transmitted viruses, such as ‘treatment for prevention'/ ‘test-and-treat' strategies [2].
References:
[1] Barditch-Crovo et al. (2001) Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 45: 2733-2739.
[2] Hallett et al. (2011) Optimal uses of antiretrovirals for prevention in HIV-1 serodiscordant heterosexual couples in south africa: a modelling study. PLoS Med 8: e1001123.
Reference: PAGE 21 (2012) Abstr 2465 [www.page-meeting.org/?abstract=2465]
Poster: Infection