Barrier Independent, Fitness Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus
ABSTRACT Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct acting antiviral agents such as telaprevir or daclatasvir, but fitness dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low and high fitness HCV populations and biological clones derived from them were used to infect Huh 7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high fitness HCV populations, without the acquisition of sofosbuvir specific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high fitness individual biological clones. In independently derived high fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvir specific resistance mutations, linked to in vivo fitness of pretreatment viral populations.
Antimicrobial Agents and Chemotherapy