A new era of hepatitis C therapy begins.

A new era of therapy for hepatitis C virus (HCV) infection is dawning with the development of two effective HCV protease inhibitors, boceprevir and telaprevir. In this issue of the Journal, the results of two phase 3 trials involving boceprevir, in combination with peginterferon and ribavirin, are presented: the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial (ClinicalTrials.gov number, NCT00705432), by Poordad and colleagues,1 and HCV RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2; NCT00708500), by Bacon and colleagues.2 Both studies focused on patients infected with HCV genotype 1; the SPRINT-2 trial involved those who had not previously received treatment, whereas HCV RESPOND-2 involved those who had previously received treatment. What are the key background concepts to keep in mind when reading these two important studies? First, boceprevir, a competitive inhibitor of the nonstructural 3 (NS3) protease complex of HCV genotype 1, does not have clinically significant activity against other HCV genotypes.3,4 Second, HCV has been shown to rapidly develop resistance when exposed to protease-inhibitor monotherapy, but the addition of interferon reduces the rate of emergence of these resistant variants.5 Third, black patients respond less well to antiviral therapy with peginterferon plus ribavirin than do nonblacks, in part because of the decreased prevalence among blacks of an interleukin-28B gene (IL28B) polymorphism associated with interferon responsiveness.6 Finally, the presence of cirrhosis has a negative impact on response to therapy,7 yet it affects a considerable percentage of patients awaiting treatment. In the SPRINT-2 trial, all patients received peginterferon and ribavirin during a 4-week lead-in phase before boceprevir (or placebo) was added. There were three treatment groups. The first received a standard regimen of peginterferon and ribavirin for 44 weeks after the lead-in period (control). The second received response-guided triple therapy consisting of boceprevir plus peginterferon–ribavirin for 24 weeks, after which patients with undetectable HCV RNA levels between weeks 8 and 24 after the lead-in period could stop all treatment. The third received fixedduration triple therapy for 44 weeks after the lead-in period. In both nonblack and black cohorts, the use of boceprevir achieved a substantial and significant increase in the rate of a sustained virologic response. In the combined cohorts of black and nonblack patients, the rate of a sustained virologic response was 38% among controls, 66% among patients receiving 48 weeks of triple therapy, and 63% among patients receiving response-guided triple therapy. Patients with advanced fibrosis represented 7 to 11% of the SPRINT-2 patients and had lower rates of a sustained virologic response than those with less fibrosis. Anemia and dysgeusia were among the most common adverse events associated with boceprevir, occurring in approximately 49% and 40% of boceprevir-treated patients, respectively. In HCV RESPOND-2, boceprevir was tested in patients with HCV genotype 1 infection who had previously received treatment with peginterferon–ribavirin, with an outcome of relapse or nonresponse. Importantly, the study excluded patients in whom 12 weeks of the prior therapy resulted in a reduction in the HCV RNA level of less than 2 log10 IU per milliliter. Similar to the SPRINT-2 study, HCV RESPOND-2 included a 4-week lead-in phase and studied both fixed-duration and response-guided therapy. The most important find-