The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.


Semin Liver Dis. 2011;31(4):399-409. 

In This Article

Nonnucleoside NS5B Polymerase Inhibitors

Whereas the nucleoside inhibitors bind to the polymerase's active site, the nonnucleoside inhibitors bind to allosteric sites of the enzyme. This induces conformational changes that downregulate the polymerase's activity. Different binding sites disposed in a right hand motif with the thumb (thumb 1 and thumb 2), finger and palm (palm 1 and palm 2) domains are potential targets of nonnucleoside inhibitors. As a result of different target sites, mechanism of inhibition, and potency differences, nonnucleoside inhibitors have a low genetic barrier to resistance compared with nucleoside/nucleotide analogs (Fig. 1).[33]


Setrobuvir (ANA598) is a potent nonnucleoside inhibitor and the most advanced in development. In a phase II combination study with pegIFN and RBV, 72% of patients achieved undetectable HCV RNA at week 8.[34] It is currently in a phase IIb study for the treatment of chronic HCV infection. In this ongoing study, 133 patients naïve to HCV treatment and 141 previously treated patients (n = 133) have been enrolled to receive setrobuvir 200 mg twice daily in combination with pegIFN/RBV. Patients naïve to HCV treatment with undetectable HCV RNA at week 8 and at subsequent visits will complete treatment at week 28 (RGT). Previously treated patients will receive 48 weeks of treatment. Future trials combining ANA598 with DAAs of different classes will likely offer the best SVR results.


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