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Title: Analysis of Hepatitis C Virus Decline during Treatment with the Protease Inhibitor Danoprevir Using a Multiscale Model

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). In this paper, 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%). Finally, the multiscale modelmore » can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7]
  1. Oakland Univ., Rochester, MI (United States). Dept. of Mathematics and Statistics. Center for Biomedical Research
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; Univ. Paris Diderot, Paris (France); National Inst. of Health and Medical Research (INSERM), Paris (France)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; Univ. of Illinois, Chicago, IL (United States). Dept. of Medicine; Loyola Univ., Chicago, IL (United States). Dept. of Medicine
  4. Univ. of Michigan, Flint, MI (United States). Mathematics Dept.
  5. Roche, Nutley, NJ (United States). Pharma Research and Early Development. Clinical Pharmacology; Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States)
  6. Roche, Nutley, NJ (United States). Pharma Research and Early Development. Clinical Pharmacology
  7. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
Publication Date:
OSTI Identifier:
1321717
Report Number(s):
LA-UR--12-21815
Journal ID: ISSN 1553-7358
Grant/Contract Number:
AC52-06NA25396; DMS-1122290; PHY-1125915; R56/R01-AI078881; P20-GM103452; AI028433; R34-HL109334; OD011095
Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 9; Journal Issue: 3; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Science Foundation (NSF) (United States); National Inst. of Health (NIH) (United States); Univ. of Illinois Water Payton Liver Center GUILD (United States); Roche (United States)
Contributing Orgs:
Oakland Univ., Rochester, MI (United States); Univ. of Michigan, Flint, MI (United States); Roche, Nutley, NJ (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES biological science; viral load; approximation methods; antimicrobial resistance; antiviral therapy; Hepatitis C virus; virions; viral replication; protease inhibitor therapy