Optimal Therapy of Hepatitis C Dynamics and Sampling Based Analysis

TL;DR

This paper models hepatitis C treatment dynamics and uses sampling to analyze patient variability, showing combination therapy improves response rates and highlighting the importance of infected hepatocyte death rate in therapy outcomes.

Contribution

It introduces an optimal control framework for hepatitis C therapy and applies sampling-based analysis to assess patient variability and treatment efficacy.

Findings

Combination therapy yields higher response rates than monotherapy.

Optimal therapy involves an initial high-efficacy period followed by decline.

Infected hepatocyte death rate strongly correlates with viral clearance time.

Abstract

We examine two models for hepatitis C viral (HCV) dynamics, one for monotherapy with interferon (IFN) and the other for combination therapy with IFN and ribavirin. Optimal therapy for both the models is determined using the steepest gradient method, by defining an objective functional which minimizes the infected hepatocyte levels, virion population and the side-effects of the drug(s). The optimal therapy for both the models shows an initial period of high efficacy, followed by a gradual decline. The period of high efficacy coincides with a significant decrease in the infected hepatocyte levels as well as viral load, whereas the efficacy drops after liver regeneration through restored hepatocyte levels. The period of high efficacy is not altered significantly when the cost coefficients are varied, as long as the side effects are relatively small. This suggests a higher dependence of the optimal therapy on the model parameters in case of drugs with minimal side effects. We use the Latin hypercube sampling technique to randomly generate a large number of patient scenarios (i.e, model parameter sets) and study the dynamics of each set under the optimal therapy already determined. Results show an increase in the percentage of responders (as indicated by drop in viral load below detection levels) in case of combination therapy as compared to monotherapy. Statistical tests performed to study the correlations between sample parameters and the time required for the viral load to fall below detection level, show a strong monotonic correlation with the death rate of infected hepatocytes, identifying it to be an important factor in deciding individual drug regimens.