Barrier-independent, fitness-associated differences in sofosbuvir-efficacy against hepatitis C virus.

Barrier-independent, fitness-associated differences in sofosbuvir-efficacy against hepatitis C virus. Antimicrob Agents Chemother. 2016 Apr 11; Authors: Gallego I, Sheldon J, Moreno E, Gregori J, Quer J, Esteban JI, Rice CM, Domingo E, Perales C 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 high phenotypic barrier to resistance. Low and high fitness HCVs populations and biological clones derived from them were used to infect hepatoma cells Huh-7.5. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages, and 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 i...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research