title: A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection.
abstract: We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA. bambang_adiwijaya@vrtx.com
authors.forename: Bambang S
authors.initials: BS
authors.lastname: Adiwijaya
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
authors.forename: Joshua
authors.initials: J
authors.lastname: Henshaw
authors.forename: Karen
authors.initials: K
authors.lastname: Eisenhauer
authors.forename: Holly
authors.initials: H
authors.lastname: Kimko
authors.forename: John J
authors.initials: JJ
authors.lastname: Alam
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kauffman
authors.forename: Varun
authors.initials: V
authors.lastname: Garg
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology*; D006801:Humans; D008954:Models, Biological
chemical_list: D000998:Antiviral Agents