July 10, 2013

Gastroenterology

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

Abstract

Background

& 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.

Methods

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).

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 [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.

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 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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