title: Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model.
abstract: The current paradigm for studying hepatitis C virus (HCV) dynamics in patients utilizes a standard viral dynamic model that keeps track of uninfected (target) cells, infected cells, and virus. The model does not account for the dynamics of intracellular viral replication, which is the major target of direct-acting antiviral agents (DAAs). Here we describe and study a recently developed multiscale age-structured model that explicitly considers the potential effects of DAAs on intracellular viral RNA production, degradation, and secretion as virus into the circulation. We show that when therapy significantly blocks both intracellular viral RNA production and virus secretion, the serum viral load decline has three phases, with slopes reflecting the rate of serum viral clearance, the rate of loss of intracellular viral RNA, and the rate of loss of intracellular replication templates and infected cells, respectively. We also derive analytical approximations of the multiscale model and use one of them to analyze data from patients treated for 14 days with the HCV protease inhibitor danoprevir. Analysis suggests that danoprevir significantly blocks intracellular viral production (with mean effectiveness 99.2%), enhances intracellular viral RNA degradation about 5-fold, and moderately inhibits viral secretion (with mean effectiveness 56%). The multiscale model can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C.
authors.affiliation: Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, Michigan, USA.
authors.forename: Libin
authors.initials: L
authors.lastname: Rong
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Coffield
authors.forename: Micha
authors.initials: M
authors.lastname: Levi
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019295:Computational Biology; D003521:Cyclopropanes; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000494:pharmacology / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008954:Models, Biological; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000032:analysis / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D013449:Sulfonamides; C553752:danoprevir; D011392:Proline