Volume 145, Issue 4 , Pages 790-800.e3, October 2013
Patrick Marcellin, Curtis Cooper, Luis Balart, Dominique Larrey, Terry Box, Eric Yoshida, Eric Lawitz, Peter Buggisch, Peter Ferenci, Martin Weltman, Emily Labriola–Tompkins, Sophie Le Pogam, Isabel Nájera, Denise Thomas, Gregory Hooper, Nancy S. Shulman, Ying Zhang, Mercidita T. Navarro, Chin Yin Lim, Michael Brunda, Norah A. Terrault, Ellen S. Yetzer
Received 3 January 2013; accepted 20 June 2013. published online 28 June 2013.
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.
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).
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.
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.
Abbreviations used in this paper: ALT, alanine aminotransferase, BMI, body mass index, CI, confidence interval, eRVR, extended rapid virologic response, HCV, hepatitis C virus, PI, protease inhibitor, SVR, sustained virologic response
Conflicts of interest The authors disclose the following: P. Marcellin is an investigator for Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, AbbVie, Boehringer Ingelheim, Pfizer, Alios BioPharma; received grant/research support from Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; and is a speaker and expert for Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, AbbVie. C. Cooper is a speaker/advisor for BMS, Merck, Roche, Vertex; an advisor for BI; and received research funding from Merck, Roche. L. Balart is on advisory committees or review panels for Genentech, Janssen, AbbVie; received grant/research support from Merck, Roche/Genentech, Bayer, Hyperion, AbbVie, Takeda, GI Dynamics, Gilead, BMS, Eisai, Vertex; and does speaking and teaching for Merck. D. Larrey D is on advisory boards for Roche, Boehringer-Ingelheim, Bristol-Myers Squibb, Janssen, MSD, AbbVie and received research grants from Roche, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, AbbVie. T. Box is on advisory committees or review panels for Genentech, Vertex, Kadmon, Gilead; received grant/research support from Genentech, Merck, AbbVie, Idenix, Gilead, Boehringer ingelheim, BMS, Salix, Sundise, Genfit; and did speaking and teaching for Genentech, Vertex, Salix. E. Yoshida received honoraria from Roche, Merck, Vertex, Gilead, Bayer; received grant/research support from Roche, Merck, Vertex, Gilead, Pfizer, Boerhinger Ingelheim, Janssen, Astellas, AbbVie, Novartis. E. Lawitz received grant/research support from Abbvie, BMS, Gilead, GSK, Medtronic, Idenix, Merck, Novartis, Roche, Pfizer, Vertex, Tibotec/Johnson and Johnson, Achillion, Boehringer Ingelheim, Santaris, Genentech. P. Buggisch does speaking and teaching for MSD, Roche, Gilead, Novartis, Janssen, BMS. P. Ferenci is on the global advisory board for Roche/Genentech, Merck, Janssen, Boehringer-Ingelheim and Rottapharm-Madaus; is an advisor for GSK, Achillion, Idenix; on the speaker's bureau for Roche, MSD Austria, Janssen Austria, BMS Austria; received an unrestricted research grant from Roche Austria and MSD Austria. M. Weltman is on the advisory committees or review panels for Roche, Janssen, MSD, Abbvie, Gilead; and does speaking and teaching for Roche, BMS, MSD, Janssen. E. Labriola-Tompkins, S. Le Pogam, I. Nájera, and M. Brunda are employees of Hoffmann-La Roche Inc. D. Thomas and G Hooper are employees of Roche Products Ltd. N. S. Shulman, M. T. Navarro, C. Y. Lim, and E. S. Yetzer are employees of Genentech. Y. Zhang was an employee of Genentech at the time that the study was conducted. N. A. Terrault does consulting for Roche/Genentech; and received grant/research support from Roche/Genentech.
Funding This research was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.
© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.