July 10, 2013

Randomized Controlled Trial of Danoprevir Plus Peginterferon Alfa-2a and Ribavirin in Treatment-Naive Patients with HCV Genotype 1 Infection


Article in Press

P. Marcellin, C. Cooper, L. Balart, D. Larrey, T. Box. E. Yoshida, E. Lawitz, P. Buggisch, P. Ferenci, M. Weltman, E. Labriola,Tompkins, S. Le, Pogam, I. N├íjera, D. Thomas, G. Hoope,N.S. Shulman, Y. Zhang, M.T. Navarro, C.Y. Lim, M. Brunda, N.A. Terrault, E.S. Yetzer

Received 3 January 2013; received in revised form 20 June 2013; accepted 20 June 2013. published online 28 June 2013.

Accepted Manuscript



& Aims: The combination of an 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.


Treatment-naive patients (n=237) were randomly assigned to groups given 12 wks of danoprevir (300 mg every 8 h; 600 mg every 12 h, and 900 mg every 12 h) 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 wks 4–20) stopped therapy at wk 24; those without an eRVR4–20 continued therapy to 48 wks. Patients who were given placebo received 48 wks of peginterferon alfa-2a and ribavirin. The primary efficacy endpoint was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 wks without treatment).


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 [CI], 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%–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 (ALT); this led to early discontinuation of the 900 mg arm of the study.


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 ALT. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway. Clinicaltrials.gov number, NCT00963885.

Keywords: danoprevir (RG7227), hepatitis C virus, sustained virologic response, response-guided therapy


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