Using in vitro short-term dose-response assays, these polymorphisms do not cause any reduction in sofosbuvir potency, suggesting an indirect mechanism of action in decreasing sofosbuvir efficacy. They are also associated with lower reductions in viral load in the first week of therapy. These polymorphisms are enriched in post-treatment HCV sequences of patients unresponsive to treatment. We find three common polymorphisms in non-targeted HCV NS2 and NS3 proteins are associated with reduced treatment response. We use pre-treatment whole-genome sequences of HCV from 507 patients infected with HCV subtype 3a and treated with sofosbuvir containing regimens to detect viral polymorphisms associated with response to treatment. Sofosbuvir is a common component of current de novo or salvage combination therapies, that targets the HCV NS5B polymerase. With the development of direct-acting antivirals, treatment of chronically infected patients has become highly effective, although a subset of patients responds less well to therapy. Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease, worldwide.
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