title: Multi-scale model for hepatitis C viral load kinetics under treatment with direct acting antivirals.
abstract: Hepatitis C virus (HCV) infections are a global health problem, and extensive research over the last decades has been targeted at understanding its molecular biology and developing effective antiviral treatments. Recently, a number of potent direct acting antiviral drugs have been developed targeting specific processes in the viral life cycle. Here, we developed a mathematical multi-scale model of the within-host dynamics of HCV infection by integrating a standard model for viral infection with a detailed model of the viral replication cycle inside infected cells. We use this model to study patient time courses of viral load under treatment with daclatasvir, an inhibitor of the viral non-structural protein NS5A. Model analysis predicts that treatment efficacy can be increased by combining daclatasvir with dedicated viral polymerase inhibitors, corresponding to promising current strategies in drug development. Hence, our model presents a predictive tool for in silico simulations, which can be used to study and optimize direct acting antiviral drug treatment.
authors.affiliation: Technische Universität Dresden, School of Medicine, Institute for Medical Informatics and Biometry, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Clausznitzer
authors.affiliation: Technische Universität Dresden, School of Medicine, Institute for Medical Informatics and Biometry, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: diana.clausznitzer@tu-dresden.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Harnisch
authors.affiliation: Technische Universität Dresden, School of Medicine, Institute for Medical Informatics and Biometry, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
mesh_terms: D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D002219:Carbamates; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000821:virology; D015233:Models, Statistical; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012367:RNA, Viral; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir
keywords: Direct acting antiviral treatment; Hepatitis C virus; Ordinary differential equations model; Pharmacodynamics; Viral kinetics