The phase 3 trials leading up to the approval of boceprevir and telaprevir showed significant increases in SVR rates in comparison

with those achieved with pegylated interferon (PEG-IFN)/ribavirin dual therapy (67%-68% versus 40%[1] and 69%-75% versus 44%,[2] respectively). Undoubtedly, the addition of these protease inhibitors has improved our ability to cure genotype 1 CHC infections; however, the addition of these agents to click here the treatment regimen has come at a substantial cost: the health care monitoring that is required and adverse events resulting in significant morbidity and even mortality among patients with cirrhosis.[3] In addition to potentiating the anemia seen with PEG-IFN and ribavirin, boceprevir and telaprevir have their own unique side effects. There are also numerous drug-drug interactions that must be addressed with these new agents because of their cytochrome P450 system metabolism. Furthermore, these agents are not approved for non–genotype 1 CHC infections.

Mericitabine (R7128) is a selective NVP-BGJ398 purchase nucleoside analogue inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B RNA–dependent RNA polymerase. A nucleoside analogue inhibitor has several advantages, including low rates of resistance and broad genotypic coverage.[4] Initial studies showed no evidence of resistance in patients treated for 14 days with mericitabine monotherapy,[5] and follow-up studies demonstrated antiviral activity across all HCV genotypes.[6] This issue of Hepatology presents two large, multicenter, phase 2b clinical trials investigating the efficacy of mericitabine plus PEG-IFNα2a and ribavirin versus PEG-IFNα2a and ribavirin alone. Wedemeyer et al.[7] in the PROPEL trial used 4 experimental arms with 500 or 1000 mg of mericitabine twice daily for 8 or 12 weeks and a fifth control arm with PEG-IFN and

ribavirin alone in a treatment-naive genotype 1 or 4 CHC population. A response-guided therapy GBA3 approach was used in all treatment arms; patients for whom HCV RNA was undetectable in serum (virus negativity) at weeks 4 to 22 [extended rapid virological response (eRVR)] discontinued therapy at week 24, whereas all other patients continued PEG-IFN and ribavirin for a total treatment duration of 48 weeks. Patients who received mericitabine showed a high rate of early responses to therapy, with 80% in treatment arms A to D achieving virus undetectability at week 12; however, the SVR rates were not statistically different across the various mericitabine-treated groups or in comparison with PEG-IFN and ribavirin. Although these results did not demonstrate appreciably superior responses in comparison with the standard of care, it is notable that mericitabine demonstrated a high barrier to resistance, and the drug was well tolerated without additional side effects beyond those expected with PEG-IFN and ribavirin alone. Pockros et al.