Repository: Freie Universit├Ąt Berlin, Math Department

Multiscale Systems-Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV-1

Duwal, S. and Sunkara, V. and von Kleist, M. (2016) Multiscale Systems-Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV-1. CPT: Pharmacometrics & Systems Pharmacology, 5 (7). pp. 377-387. ISSN 2163-8306

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Official URL: http://onlinelibrary.wiley.com/doi/10.1002/psp4.12...

Abstract

While HIV-1 continues to spread, the use of antivirals in preexposure prophylaxis (PrEP) has recently been suggested. Here we present a modular systems pharmacology modeling pipeline, predicting PrEP efficacy of nucleotide reverse transcriptase inhibitors (NRTIs) at the scale of reverse transcription, target-cell, and systemic infection and after repeated viral exposures, akin to clinical trials. We use this pipeline to benchmark the prophylactic efficacy of all currently approved NRTIs in wildtype and mutant viruses. By integrating pharmacokinetic models, we find that intracellular tenofovir-diphosphate builds up too slowly to halt infection when taken "on demand" and that lamivudine may substitute emtricitabine in PrEP combinations. Lastly, we delineate factors confounding clinical PrEP efficacy estimates and provide a method to overcome these. The presented framework is useful to screen and optimize PrEP candidates and strategies and to understand their clinical efficacy by integrating the diverse scales which determine PrEP efficacy.

Item Type:Article
Subjects:Biological Sciences > Microbiology > Immunology
Mathematical and Computer Sciences
Biological Sciences > Microbiology > Virology
Divisions:Department of Mathematics and Computer Science > Institute of Mathematics > BioComputing Group
ID Code:1971
Deposited By: BioComp Admin
Deposited On:28 Oct 2016 08:20
Last Modified:28 Oct 2016 08:20

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