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). 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. Author Summary: Chronic infection with hepatitis C virus (HCV) remains an important health-care problem worldwide despite significant progress in the development of HCV therapy since the discovery of the virus in 1989. Current treatment options are focused on direct-acting antiviral agents (DAAs) that target specific steps of the HCV life cycle. Danoprevir, one of the DAAs that inhibit the HCV NS3-4A protease, has induced substantial viral load reductions in patients receiving therapy. 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 HCV life cycle that are targeted by DAAs. We examine the biological parameters contributing to different phases of the viral decline after treatment initiation. We also explore the mechanisms of action of danoprevir and estimate its treatment effectiveness. The multiscale model provides a theoretical framework for studying virus dynamics in hepatitis C patients treated with other DAAs currently in clinical development, and may help one to optimally combine drugs with complementary modes of action to maximize the HCV cure rate.