Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model Journal Article

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Authors: Rong, L; Guedj, J; Dahari, H; Coffield, D. J., Jr; Levi, M; Smith, P.; Perelson, A. S.
Article 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.
Journal Title: PLoS computational biology
Volume: 9
Issue: 3
ISSN: 1553-7358; 1553-734X
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: e1002959
Language: eng
DOI/URL:

10.1371/journal.pcbi.1002959

10.1371/journal.pcbi.1002959
Notes: GR: AI028433/AI/NIAID NIH HHS/United States; GR: OD011095/OD/NIH HHS/United States; GR: P20-GM103452/GM/NIGMS NIH HHS/United States; GR: R01 AI028433/AI/NIAID NIH HHS/United States; GR: R34-HL109334/HL/NHLBI NIH HHS/United States; GR: R56/R01-AI078881/AI/NIAID NIH HHS/United States; JID: 101238922; OID: NLM: PMC3597560; 2012/07/23 [received]; 2013/01/16 [accepted]; 2013/03/14 [epublish]; ppublish