Modeling hepatitis C virus dynamics: Liver regeneration and critical drug efficacy

Abstract

Mathematical models for hepatitis C viral (HCV) RNA kinetics have provided a means of evaluating the antiviral effectiveness of therapy, of estimating parameters such as the rate of HCV RNA clearance, and they have suggested mechanism of action against HCV for both interferon and ribavirin. Nevertheless, the model that was originally formulated by Neumann et al. [1998. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282 (5386), 103-107] is unable to explain all of the observed HCV RNA profiles under treatment e.g., a triphasic viral decay and a viral rebound to baseline values after the cessation of therapy. Further, the half-life of productively HCV-infected cells, estimated from the second phase HCV RNA decline slope, is very variable and sometimes zero with no clear understanding of why. We show that extending the original model by including hepatocyte proliferation yields a more realistic model without any of these deficiencies. Further, we define and characterize a critical drug efficacy, such that for efficacies above the critical value HCV is ultimately cleared, while for efficacies below it, a new chronically infected viral steady-state level is reached.

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

“…The pseudo steady states of viral production and clearance just before and after the EOT imply that the fold‐increase in viremia soon after the EOT would be 1/(1‐ε), where the treatment efficacy ε is readily estimated from early viral kinetics following the start of therapy. The rise in viremia post‐treatment by the factor 1/(1‐ε) has been recognized earlier using the basic model of viral kinetics in the context of PR treatment assuming a constant target cell population 44. Whether the resulting viremia would lie above or below the intermediate unstable boundary is more difficult to predict because the boundary is less well estimated.…”

Evaluating treatment of hepatitis C for hemolytic anemia management

“…The average clearance rate of free HCV in Dahari et al [7] is 7.8 per day which is estimated in the presence of drugs. It is difficult to find the clearance rate of the virus in vivo in the absence of treatment.…”

“…During estimation, we fix the values of certain parameters (s T ; d T ; d I ; d R ; p; β and h) taken from literature (given in Table 3) [7], [22] and [23]. Recall that our goal is to provide optimal treatment for a HCV patient who otherwise would develop anemia under standard treatment.…”

“…The progression to chronic-stage HCV infection is a result of weak immune response against HCV (reviewed in [6]). Currently, the standard protocol for the treatment of Hep-C involves two antiviral drugs, Interferon-α (IFN) and ribavirin (RBV), given in combination [7,8]. It has been clinically observed that the combination of RBV and IFN demonstrates a synergistic pharmacological effect.…”

“…In the context of Hep-C, mathematical modeling has been extensively used to determine the efficacy of IFN as monotherapy and in combination with RBV [7,14]. Differences in response depending on genotype [15], and the concept of early virological response (EVR) to estimate possibility of achieving SVR [16] have been reinforced with mathematical models.…”