Open AccessMultiscale Systems‐Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV‐1
Author(s) -
Duwal S,
Sunkara V,
von Kleist M
Publication year - 2016
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12095
Subject(s) - emtricitabine , pre exposure prophylaxis , tenofovir , medicine , clinical trial , human immunodeficiency virus (hiv) , reverse transcriptase inhibitor , pharmacology , clinical efficacy , virology , antiretroviral therapy , viral load , men who have sex with men , syphilis
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.