Dynamic analysis of HCV infection and drug resistance using an age-structured multiscale model

Abstract

Direct-acting antiviral agents (DAAs) are known to interfere with various intracellular stages of the hepatitis C virus (HCV) life cycle and have demonstrated efficacy in treating HCV infection. However, DAA monotherapy can lead to drug resistance due to mutations. This paper explores the impact of DAA therapy on HCV dynamics using a multiscale age-structured partial differential equation (PDE) model that incorporates intracellular viral RNA replication within infected cells and two strains of viruses representing a drug-sensitive strain and a drug-resistant mutant variant, respectively. We derived an equivalent ordinary differential equation (ODE) model from the PDE model to simplify mathematical analysis and numerical simulations. We studied the dynamics of the two virus strains before treatment and investigated the impact of mutations on the evolution kinetics of drug-sensitive and drug-resistant viruses, as well as the competition between the two strains during treatment. We also explored the role of DAAs in blocking HCV RNA replication and releasing new virus particles from cells. During treatment, mutations do not significantly influence the dynamics of various virus strains; however, they can generate low-level HCV that may be completely inhibited due to their poor fitness. The fitness of the mutant strain compared to the drug-sensitive strain determines which strain dominates the virus population. We also investigated the prevalence and drug resistance evolution of HCV variants during DAA treatment.