An integrated, mechanistic model of viral eradication and its clinical applications in treatment regimens with direct-acting antivirals for chronic hepatitis C
Bambang S. Adiwijaya(1), Tara Kieffer(1), Joshua Henshaw(1), Karen Eisenhauer(1), Holly Kimko(2), Varun Garg(1)
(1) Vertex Pharmaceuticals, Incorporated; (2) Johnson&Johnson Pharmaceutical Research and Development
Background: The treatment objective in patients chronically infected with hepatitis C virus (CHC) is a sustained viral response (SVR), which is indicative of viral eradication. In phase 3 studies, a novel combination regimen of a direct-acting antiviral telaprevir (T, an HCV NS3-4A protease inhibitor) and peginterferon-alfa/ribavirin (PR) significantly increased SVR rates in patients with genotype 1 CHC compared with PR alone.
Objectives: To develop a mechanistic model of viral eradication that integrates in vitro potency and resistance data, pharmacokinetics, and viral dynamic response during and after treatment to a combination regimen of telaprevir and PR (TPR) and to apply the model to optimize treatment regimens.
Methods: The model incorporates the presence of HCV variants with differing telaprevir-resistance and fitness, and the diversity in patient responses to PR treatment. The model integrates TPR pharmacokinetics into HCV viral dynamics. The model was developed using in vitro and clinical response data from 28 patients treated with 2 weeks of telaprevir monotherapy  and from 478 treatment-naïve CHC treated with either PR or TPR. Model-predicted SVR rates from these studies and from late phase clinical studies were compared with observed data.
Results: The model-predicted SVR rates, generated prospectively, were comparable to the observed rates from 2380 CHC in late-phase clinical trials of regimens with different treatment durations. The model produced consistently predictive results for treatment-naïve. For prior PR-treatment experienced populations, model predictions were generally consistent with the observed SVR rates despite being trained only for treatment-naïve, with more predictive results in prior relapsers than in prior non-responders. The model aided understanding of the novel CHC treatment regimen by integrating resistance and fitness levels, antiviral inhibition by each drug, and patient diversity in IFN-responsiveness, and connected these factors to the ultimate treatment outcome of SVR. The model predicted different eradication times for each HCV variant, which suggested different optimal treatment durations of telaprevir and of PR, which was confirmed in clinical trials.
Conclusion: The proposed model provides a framework to integrate multifaceted mechanistic information and give insight into novel CHC treatment regimens that include direct-acting antiviral agents to optimize treatment strategies.
Adiwijaya et al. PLOS Comput Biol. 2010;6(4):e1000745