A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants.

Bambang S Adiwijaya,Tara Kieffer,Brian Hare,Chao Lin,Paul R Caron,Christoph Sarrazin,John C R Randle,Eva Herrmann,Ann D Kwong,Varun Garg,Stefan Zeuzem

doi:10.1371/journal.pcbi.1000745

Abstract

Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed both during and after telaprevir dosing, as well as to variant prevalence observed after telaprevir dosing. After an initial sharp decline in HCV RNA levels during dosing with telaprevir, HCV RNA levels increased in some subjects. The model predicted this increase to be caused by pre-existing variants with sufficient fitness to expand once available replication space increased due to rapid clearance of wild-type (WT) virus. The average replicative fitness estimates in the absence of telaprevir ranged from 1% to 68% of WT fitness. Compared to the relative fitness method, the in vivo estimates from the viral dynamic model corresponded more closely to in vitro replicon data, as well as to qualitative behaviors observed in both on-dosing and long-term post-dosing clinical data. The modeling fitness estimates were robust in sensitivity analyses in which the restoration dynamics of replication space and assumptions of HCV mutation rates were varied.

Highlights

Hepatitis C virus (HCV) is estimated to infect 170 million people worldwide [1]
Published models of HCV viral dynamics in subjects treated with interferon (IFN), pegylated interferon (Peg-IFN) and RBV have assumed the HCV population within a subject to be relatively homogeneous with respect to sensitivity to these antiviral agents [8,9,10,11]
The basic reproductive ratio of wild-type NS3N4A HCV (WT) HCV R0,WT, relative fitness fi, and clearances c, d were estimated from time series of both plasma HCV RNA and variant prevalences, with details provided in the Methods section

Summary

Introduction

Hepatitis C virus (HCV) is estimated to infect 170 million people worldwide [1]. Current HCV treatment with pegylated interferon (Peg-IFN) and ribavirin (RBV) for the most common genotype 1 strain requires 48 weeks and only 42% to 50% of patients naıve from treatment achieve sustained viral response (SVR) [2,3]. Upon exposure to protease inhibitors, the composition of the HCV quasispecies was altered, as revealed by sequencing of plasma HCV RNA and isolated viral clones obtained from subjects dosed with telaprevir [14,15] and boceprevir [13]. These variants have been reported to exhibit reduced fitness [16,17] and reduced susceptibility to other protease inhibitors in vitro [18]

Methods

Results

Conclusion