http://www.ncbi.nlm.nih.gov/pubmed/23811112

Marcellin P, Cooper C, Balart L, Larrey D, Box T, Yoshida E, Lawitz E,Buggisch P, Ferenci P, Weltman M, Labriola-Tompkins E, Le Pogam S, Nájera I,Thomas D, Hooper G, Shulman NS, Zhang Y, Navarro MT, Lim CY, Brunda M, Terrault NA, Yetzer ES. Randomized controlled trial of danoprevir plus peginterferonalfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype1 infection. Gastroenterology.

Abstract

BACKGROUND & AIMS:

The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients.

METHODS:

Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment).

RESULTS:

Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study.

CONCLUSIONS:

The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.