The higher eRVR rate in group C resulted in a higher proportion of patients being assigned to abbreviated treatment (24 weeks) than in groups A or B. The abbreviated regimen was insufficient to HM781-36B cell line sustain an off-treatment response (SVR) in many patients, especially those with difficult-to-cure characteristics, such as cirrhosis or a non-CC genotype. Virologic breakthrough was observed in

some patients during dual Peg-IFNα-2a/RBV therapy after completion of mericitabine therapy. Collectively, these observations can explain the progressively lower overall SVR rates and progressively higher relapse rates in groups A, B, and C, when compared to group D, and the generally poor performance of these regimens in patients with difficult-to-cure characteristics. The lack of correlation between on-treatment VR and SVR is puzzling, given the consistently high barrier to resistance shown by mericitabine. Mericitabine is a prodrug that is converted to a pyrimidine (cytidine) nucleoside analog, which, in turn, is taken up by hepatocytes and sequentially phosphorylated to form the active chain

terminator. When given as monotherapy, mericitabine is associated with a relatively slow first-phase decline in HCV RNA that extends throughout at least 14 days,[12] likely because the first phosphorylation step is thought to be rate Akt inhibitor limiting in the production of the active triphosphate species.[13] This slow onset of activation as the triphosphate may explain the lack of sustained efficacy observed with only 12 weeks of mericitabine therapy in this trial. Indeed, another investigational medchemexpress pyrimidine nucleotide analog inhibitor (sofosbuvir), that is formulated as a uridine monophosphate,[14] bypasses the first phosphorylation reaction and has been shown to have more-rapid early-phase kinetics and produce high SVR rates (90%) when administered for 12 weeks together

with Peg-IFNα-2a/RBV.[15] If the rate of activation of mericitabine is critical to achieving an SVR, then one might expect longer treatment durations to offset the slower onset of action of the drug and to be more efficacious. Indeed, a significant increase in SVR-24, compared to a control group, was observed when mericitabine was administered with Peg-IFNα-2a/RBV for 24 weeks in JUMP-C.[16] This result is particularly striking, because more than 60% of mericitabine-treated patients in JUMP-C stopped all treatment after only 24 weeks, compared to the control group, in which all patients received 48 weeks of treatment with Peg-IFNα-2a (40 kD) plus RBV alone.[16] One potential limitation of this study is the lack of stratification by HCV G1 subtype (1a, 1b) and the lack of evaluation of VRs by HCV G1 subtype.