Setrobuvir: RNA-directed RNA polymerase inhibitor treatment of hepatitis C virus infection

Setrobuvir is a non-nucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 RNA-directed RNA polymerase (NS5B) that allosterically binds the Palm I site of the enzyme. The usual dose is 200 mg twice daily after an initial loading dose of 800 mg. Its elimination half-life ranges from 22 to 31 hours, with biliary excretion being the major route of elimination. In vitro studies demonstrated that setrobuvir retains activity against multiple common mutations of other drug classes, and conversely, drugs from several other classes are effective against setrobuvir-resistant viruses. Setrobuvir produces a rapid decline in the HCV viral load, but if given as monotherapy, HCV often rapidly selects for resistance. In combination with pegylated interferon (peg-IFN) and ribavirin, setrobuvir increases the proportion of HCV undetectable treatment-naive and -experienced patients at week 12 compared to those treated with peg-IFN, ribavirin and placebo. Subjects with the favorable IL28B CC allele who receive peg-IFN and ribavirin have a slower but comparable response compared to those who receive setrobuvir, but the addition of this drug substantially increases the response of patients with the CT/TT allele. Rash is the only notable effect compared to placebo, and setrobuvir appears to have minimal impact on hematological parameters, as it did not exacerbate anemia or leukopenia in the clinical trials performed to date.