title: Multiscale Systems-Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV-1.
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.
authors.affiliation: Department of Mathematics & Computer Science, Freie Universität Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Duwal
authors.affiliation: Department of Mathematics & Computer Science, Freie Universität Berlin, Berlin, Germany.|Konrad-Zuse-Institut für Informationstechnik, Berlin, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Sunkara
authors.affiliation: Department of Mathematics & Computer Science, Freie Universität Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von Kleist
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D064887:Observational Studies as Topic / Q000706:statistics & numerical data; D065129:Pre-Exposure Prophylaxis / Q000379:methods / Q000706:statistics & numerical data*; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D012307:Risk Factors; D013597:Systems Analysis; D016896:Treatment Outcome; D019562:Viral Load / Q000706:statistics & numerical data
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors