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.
Highlights
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and a leading reason of liver transplant in the world
We study the viral decline during therapy using a multiscale age-structured model that accounts for the dynamics of intracellular viral replication, and which includes the major steps in the hepatitis C virus (HCV) life cycle that are targeted by direct-acting antiviral agents (DAAs)
A multiscale model We extend the biphasic model by including the dynamics of intracellular viral RNA
Summary
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and a leading reason of liver transplant in the world. Achieving a long-term sustained virologic response (SVR), defined as an undetectable HCV RNA level in serum 24 weeks after the end of treatment, is the most effective way to prevent disease progression [2]. Until 2011, the standard of care for HCV infection has been the combination of weekly injection of pegylated-interferon and daily oral ribavirin (PEG-IFN/RBV). This treatment was limited by both tolerability and efficacy, with only about 50% of patients infected with HCV genotype 1, the most prevalent genotype in Western countries, achieving SVR [3].
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