(HEPATOLOGY 2012) Combination therapy with peginterferon alfa/ribavirin (P/R) has been the standard approach to the management of chronic hepatitis C virus (HCV) infections for the last decade. Sustained virological response (SVR) rates of 54% to 56% were achieved in the pivotal trials of peginterferon alfa-2a and peginterferon alfa-2b with ribavirin.1, 2 Patients with genotype 1 HCV infections had lower SVR rates (approximately 40%) and required 48 weeks of therapy, whereas higher SVR rates were attained by patients with genotype 2 or 3 infections despite shorter treatment durations.1-5 The troublesome array of toxicities GSK-3 inhibitor associated

with interferon-based therapy led to retrospective analyses of the pivotal trial databases, and these analyses culminated in the identification of robust early stopping rules for futility. It was consistently observed for genotype 1 infections that a failure to attain a ≥2-log reduction in the baseline HCV RNA level by week 12 of therapy was associated with a negative predictive value for SVR of 97% to 100%,1, 6 and this

observation was Temozolomide in vivo incorporated into routine clinical practice early in the era of peginterferon-based therapy.7 This response-guided paradigm has spared many patients destined to fail P/R therapy the futile prolongation of treatment with its attendant side effects and additional costs. Furthermore, the retreatment of interferon-nonresponders has demonstrated that patients with detectable HCV RNA at week 12 of P/R therapy rarely achieve SVR.8 The recently licensed nonstructural 3/4A serine protease inhibitors [boceprevir (Victrelis, Merck, Whitehouse Station, NJ) and telaprevir (Incivek, Vertex Pharmaceuticals, Cambridge, MA)] must be given with P/R because of their low barrier to viral resistance when they are used as monotherapy.9, 10 In contrast to conventional P/R therapy, virological failure with protease

inhibitor–based combination therapy is often attended by the selection of viral variants with resistance to protease inhibitors. This resistance may emerge early during treatment before impending failure becomes apparent by standard monitoring.9-15 The pivotal trials of boceprevir included a Acetophenone 4-week P/R lead-in period for all patients followed by the addition of boceprevir at the beginning of the fifth week. The duration of treatment varied among the different arms of each study. The Serine Protease Inhibitor Therapy 2 (SPRINT-2) study demonstrated that the addition of boceprevir to standard P/R therapy significantly improved SVR rates in previously untreated patients.11 The Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study likewise demonstrated superior response rates with boceprevir plus P/R in patients who had partially responded to or relapsed after a standard course of P/R alone.