A Multi-Variant, Viral Dynamic Model of Genotype 1 HCV to Assess the in vivo Evolution of Protease-Inhibitor Resistant Variants

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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. Hepatitis C virus (HCV) infects an estimated 170 million people worldwide. Current treatment for HCV is 48 weeks of peginterferon and ribavirin of which patient response has large variability. Recently, specifically targeted antiviral therapies for HCV (STAT-C) are under clinical development and have shown potentials to improve response. Within a patient, HCV exists as quasispecies consisting of multiple variants. Models of HCV dynamics in response to peginterferon and ribavirin treatment have been proposed elsewhere, with HCV quasispecies assumed to respond homogenously to treatment. However, some of the HCV variants possess different degrees of sensitivity to a STAT-C compound, and therefore, selections and competitions among variants have been observed in patients treated with STAT-C. We have developed a viral dynamic model that quantifies the evolution of multiple variants in patients dosed in monotherapy with telaprevir, a compound specifically designed to inhibit HCV NS3.4A protease. Our novel modeling approach integrated data from both in vitro and in patients, both during and after dosing with telaprevir. Our model quantified the antiviral response to telaprevir and the in vivo fitness of variants. The model provides a useful framework for the designs of STAT-C during clinical development and for understanding the consequences of failure to STAT-C.