A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection.

Bambang S Adiwijaya,Robert S Kauffman,Joshua Henshaw,Karen Eisenhauer,Varun Garg,John J Alam,Tara L Kieffer,Holly Kimko

doi:10.1371/journal.pcbi.1002339

Abstract

We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.

Highlights

Chronic hepatitis C (CHC) affects approximately 180 million people worldwide and is a frequent cause of increased risk for hepatic fibrosis, cirrhosis, hepatic failure, and hepatocellular carcinoma [1,2,3,4]
The treatment aim for patients chronically infected with hepatitis C is viral eradication or sustained viral response (SVR)
Approved HCV protease inhibitors, in combination with peginterferon-alfa and ribavirin, have demonstrated higher sustained virologic response (SVR) rates compared to peginterferon-alfa and ribavirin alone

Summary

Introduction

Chronic hepatitis C (CHC) affects approximately 180 million people worldwide and is a frequent cause of increased risk for hepatic fibrosis, cirrhosis, hepatic failure, and hepatocellular carcinoma [1,2,3,4]. A combination therapy of telaprevir and PR treatment (TPR) achieved potent antiviral activity and higher SVR rates compared to treatment with PR alone [7,8,9,10,11,12,13]. Variants with lower-level resistance (3 to 25fold increase in telaprevir IC50 in vitro: V36A, V36M, R155K, R155T, T54A, A156S) have higher fitness than variants with higher-level resistance (25-fold increase in telaprevir IC50 in vitro: A156T, A156V, V36M/R155K) [18] These variants retain sensitivity to PR treatment in vitro [20] and in patients [16,21,22]. WT virus was eliminated more rapidly in the presence of telaprevir than with interferon-based regimens alone in clinical trials [23,24]

Methods

Results

Discussion

Conclusion