Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection

Jacobson, Ira M. M.D.
McHutchison, John G. M.D.
Dusheiko, Geoffrey M.D.
Di Bisceglie, Adrian M. M.D.
Reddy, Rajender K. M.D.
Bzowej, Natalie H. M.D.
Marcellin, Patrick M.D.
Muir, Andrew J. M.D.
Ferenci, Peter M.D.
Flisiak, Robert M.D.
George, Jacob M.D.
Rizzetto, Mario M.D.
Shouval, Daniel M.D.
Sola, Ricard M.D.
Terg, Ruben A. M.D.
Yoshida, Eric M. M.D.
Adda, Nathalie M.D.
Bengtsson, Leif B.Sc.
Sankoh, Abdul J. Ph.D.
Kieffer, Tara L. Ph.D.
George, Shelley M.D.
Kauffman, Robert S. M.D., Ph.D.
Zeuzem, Stefan M.D.

From the Weill Cornell Medical College and Center for the Study of Hepatitis C, New York (I.M.J.); Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, NC (J.G.M., A.J.M.); Royal Free Hospital, Centre for Hepatology, London (G.D.); Saint Louis University School of Medicine, St. Louis (A.M.D.B.); Division of Gastroenterology, University of Pennsylvania, Philadelphia (K.R.R.); California Pacific Medical Center, San Francisco (N.H.B.); Hôpital Beaujon, Service d'Hépatologie and INSERM CRB3, Clichy, France (P.M.); University of Vienna, Vienna (P.F.); Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland (R.F.); Storr Liver Unit, Westmead Millennium Institute for Medical Research and Westmead Hospital, University of Sydney, Westmead, NSW, Australia (J.G.); Department of Gastroenterology, University of Turin, Turin, Italy (M.R.); Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel (D.S.); Hospital del Mar, Institut Municipal d'Investigació Médica, Universitat Autónoma de Barcelona, Barcelona (R.S.); Hospital de Gastroenterología Dr. Bonorino Udaondo, Buenos Aires (R.A.T.); University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada (E.M.Y.); Vertex Pharmaceuticals, Cambridge, MA (N.A., L.B., A.J.S., T.L.K., S.G., R.S.K.); and Department of Internal Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany (S.Z.).

Address reprint requests to Dr. Jacobson at the Weill Cornell Medical College and Center for the Study of Hepatitis C, 1305 York Ave., New York, NY 10021, or at [email protected].

^*The members of the ADVANCE Study Team are listed in the Supplementary Appendix, available at NEJM.org.

Supported by Vertex Pharmaceuticals and Tibotec.

Dr. Jacobson reports receiving consulting fees from Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Human Genome Sciences, Novartis, Pharmasset, Pfizer, Roche-Genentech, Sanofi-Aventis, Schering-Plough (now part of Merck), Tibotec, Vertex Pharmaceuticals, and ZymoGenetics, lecture fees from Bristol-Myers Squibb, Gilead Sciences, Roche-Genentech, and Schering-Plough (Merck), and grant support from Anadys Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlobeImmune, Human Genome Sciences, Novartis, Pfizer, Pharmasset, Roche-Genentech, Schering-Plough (Merck), Tibotec, Vertex Pharmaceuticals, and ZymoGenetics; Dr. McHutchison, being an employee of Gilead Sciences, participating in advisory committees or review panels for Abbott, Anadys Pharmaceuticals, Biolex, Gilead Sciences, National Genetics Institute, Pharmasset, Pfizer, United Therapeutics, and Vertex Pharmaceuticals, and receiving grant support from GlaxoSmithKline, GlobeImmune, Human Genome Sciences, Idera Pharmaceuticals, Intarcia Therapeutics, Medtronics, Novartis, Osiris Therapeutics, Roche-Genentech, Schering-Plough (Merck), and Vertex Pharmaceuticals; Dr. Dusheiko, receiving consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Human Genome Sciences, Novartis, Pharmasset, Pfizer, Roche-Genentech, Schering-Plough (Merck), Tibotec, Vertex Pharmaceuticals, and ZymoGenetics, travel support from Gilead Sciences, and grant support from Gilead Sciences, Novartis, Pharmasset, Hoffmann-La Roche, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals; Dr. Di Bisceglie, receiving consulting fees from Abbott, Anadys Pharmaceuticals, Bristol-Myers Squibb, GlobeImmune, Idenix Pharmaceuticals, Pharmasset, Roche-Genentech, and Vertex Pharmaceuticals, and grant support from Bristol-Myers Squibb, Gilead Sciences, GlobeImmune, Idenix Pharmaceuticals, and Roche-Genentech; Dr. Reddy, receiving consulting fees from Human Genome Sciences, Roche-Genentech, Salix Pharmaceuticals, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals and grant support from Bristol-Myers Squibb, Gilead Sciences, Roche-Genentech, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals; Dr. Bzowej, receiving consulting fees from Gilead Sciences and Vertex Pharmaceuticals and grant support from Anadys Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Human Genome Sciences, Idenix Pharmaceuticals, Johnson & Johnson, LifeCycle Pharma, Pharmasset, Roche-Genentech, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals; Dr. Marcellin, receiving consulting fees from Abbott, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, InterMune, MSD Pharmaceuticals (Merck), Novartis, Pfizer, Pharmasset, Roche-Genentech, Schering-Plough (Merck), Tibotec, Vertex Pharmaceuticals, and ZymoGenetics, lecture fees from Bristol-Myers Squibb, Gilead Sciences, InterMune, Novartis, Roche-Genentech, Schering-Plough (Merck), and Tibotec, and grant support from Echosens, Gilead Sciences, Roche-Genentech, and Schering-Plough (Merck); Dr. Muir, receiving consulting fees from Bristol-Myers Squibb, Pharmasset, Santaris Pharma, Schering-Plough (Merck), Vertex Pharmaceuticals, and ZymoGenetics and grant support from Anadys Pharmaceuticals, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Idera Pharmaceuticals, Medtronic, Pfizer, Pharmasset, Santaris Pharma, Scynexis, Three Rivers Pharmaceuticals, Schering-Plough (Merck), and Vertex Pharmaceuticals; Dr. Ferenci, receiving consulting fees from Achillion Pharmaceuticals, Boehringer Ingelheim, MSD Pharmaceuticals (Merck), Novartis, Pfizer, Rottapharm Madaus, Roche-Genentech, Tibotec, and Vertex Pharmaceuticals and grant support from Roche-Genentech; Dr. Flisiak, receiving consulting fees from Bristol-Myers Squibb, Debiopharm, Human Genome Sciences, Novartis, Pfizer, Roche, and Schering-Plough (Merck) and lecture fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Roche, and Schering-Plough (Merck); Dr. J. George, receiving consulting fees from Bristol-Myers Squibb, Gilead Sciences, MSD Pharmaceuticals (Merck), and Roche-Genentech, lecture fees from Bristol-Myers Squibb, Gilead Sciences, MSD Pharmaceuticals (Merck), Novartis, and Roche-Genentech, and grant support from MSD Pharmaceuticals (Merck) and Roche-Genentech; Dr. Rizzetto, receiving consulting fees from Bristol-Myers Squibb, Janssen-Cilag, Roche-Genentech and Schering-Plough (Merck) and lecture fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Roche-Genentech, and Schering-Plough (Merck); Dr. Shouval, receiving consulting fees from SciGen and Biotest, lecture fees from Cangene, Gilead Sciences, Roche-Genentech, and Schering-Plough (Merck), and grant support from Human Genome Sciences, Novartis, Pfizer, Roche-Genentech, and Schering-Plough (Merck); Dr. Sola, receiving consulting fees from Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche-Genentech, and Tibotec-Janssen-Cilag, lecture fees from Bristol-Myers Squibb, Gilead Sciences, Novartis, and Roche-Genentech, and grant support from Gilead Sciences, Roche-Genentech, and Schering-Plough (Merck); Dr. Terg, receiving grant support from Fundación CIDEA; Dr. Yoshida, receiving consulting fees from Cangene, Gilead Sciences, Roche-Genentech, and Schering-Plough (Merck), lecture fees from Vertex Pharmaceuticals, and grant support from Boehringer Ingelheim, Cangene, Gilead Sciences, Human Genome Sciences, Novartis, Pfizer, Roche-Genentech, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals; L. Bengtsson and Drs. Adda, Sankoh, Kieffer, S. George, and Kauffman, being employees of and owning stock in Vertex Pharmaceuticals; and Dr. Zeuzem, receiving consulting fees from Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Human Genome Sciences, iTherX, Novartis, Pfizer, Pharmasset, Roche-Genentech, Santaris Pharma, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals and lecture fees from Bristol-Myers Squibb, Gilead Sciences, Roche-Genentech, and Schering-Plough (Merck).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.

We thank the study coordinators, nurses, and patients involved in the study; the personnel at the coordinating center for the study, including Eric Zafarana, M.D. (Parexel), and Andrew J. Muir, M.D. (Duke Clinical Research Institute), for medical monitoring, Hans Tillman, M.D. (Duke Clinical Research Institute), for viral monitoring, and Ann-Marie Dunne, M.P.H. (Vertex Pharmaceuticals), for clinical project management; John Alam, M.D., and Lindsay McNair, M.D. (both former employees of Vertex Pharmaceuticals), for contribution to the design of the study; and Xiangchen Cui, Ph.D., Claude Fiset, and Min Chen, Ph.D., for statistical programming, Doug Bartels, Ph.D., and Ann Kwong, Ph.D., for virology analysis, Angela Scott, Ph.D., for data analysis, and Valérie Philippon, Ph.D., for medical writing, editorial assistance, and coordination support (all from Vertex Pharmaceuticals).

New England Journal of Medicine 364(25):p 2405-2416, June 23, 2011.

ABSTRACT

BACKGROUND

In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients.

METHODS

In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response).

RESULTS

Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.

CONCLUSIONS

Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.)