title: Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection.
abstract: Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ruian
authors.initials: R
authors.lastname: Ke
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America; CNRS/UPMC Univ Paris 06, UMR 8237, Laboratoire Jean Perrin LJP, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Loverdo
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Hangfei
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, United States of America; The Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, United States of America; Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, United States of America; Zhejiang University, Hangzhou, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America; Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: James O
authors.initials: JO
authors.lastname: Lloyd-Smith
mesh_terms: D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019295:Computational Biology; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D056084:Genetic Fitness; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D055118:Medication Adherence; D008954:Models, Biological
chemical_list: D000998:Antiviral Agents