Re-treatment of Patients With Chronic Hepatitis C Who Do Not Respond to Peginterferon-α2b
A Randomized Trial
- Donald M. Jensen, MD;
- Patrick Marcellin, MD;
- Bradley Freilich, MD;
- Pietro Andreone, MD;
- Adrian Di Bisceglie, MD;
- Carlos E. Brandão-Mello, MD, PhD;
- K. Rajender Reddy, MD;
- Antonio Craxi, MD;
- Antonio Olveira Martin, MD;
- Gerlinde Teuber, MD;
- Diethelm Messinger, MS;
- James A. Thommes, MD; and
- Andreas Tietz, MD
- From the Center for Liver Diseases, University of Chicago Hospitals, Chicago, Illinois; Centre de Recherche Biologique Bichat-Beaujon CRB3, Hôpital Beaujon, Clichy, France; Liver and Pancreas Institute of Kansas City, Kansas City, Missouri; University of Bologna, Bologna, Italy; Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri; University of Rio de Janeiro, Rio de Janeiro, Brazil; University of Pennsylvania, Philadelphia, Pennsylvania; University of Palermo, Palermo, Italy; Hospital La Paz, Madrid, Spain; J.W. Goethe University Hospital, Frankfurt, Germany; IST, Mannheim, Germany; Roche, Nutley, New Jersey; and Roche, Basel, Switzerland.
Abstract
Background: Many patients with chronic hepatitis C have not responded to therapy with pegylated interferon plus ribavirin.
Objective: To evaluate use of peginterferon-α2a plus ribavirin to re-treat nonresponders to peginterferon-α2b plus ribavirin.
Design: Randomized, parallel-group trial conducted between September 2003 and February 2007. Patients and researchers were not blinded to intervention assignment. Random assignment was centralized, computer-generated, and stratified by geographic region, hepatitis C virus (HCV) genotype, and histologic diagnosis.
Setting: 106 international centers.
Patients: 950 nonresponders to 12 or more weeks of therapy with peginterferon-α2b plus ribavirin.
Intervention: Peginterferon-α2a, 360 µg/wk, for 12 weeks, then 180 µg/wk to complete 72 weeks (group A) or 48 weeks (group B), or peginterferon-α2a, 180 µg/wk for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200 mg/d.
Measurements: Sustained virologic response (SVR), defined as undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment.
Results: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively.
Limitation: Nonresponders to peginterferon-α2a plus ribavirin were not evaluated.
Conclusion: Re-treating nonresponders to therapy with peginterferon-α2b plus ribavirin for 72 weeks significantly increases SVR rates compared with re-treating them for 48 weeks. The overall SVR rate was low, but patients who are most likely to respond to re-treatment can be identified at week 12.
Primary Funding Source: Roche.
Article and Author Information
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Note: Drs. Jensen and Marcellin contributed equally to this work.
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Acknowledgment: The authors thank all of the patients who volunteered to participate in this study and all of the investigators and other health care professionals who ensured the successful completion of the study. They also thank Blair Jarvis for providing editorial assistance.
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Grant Support: By Roche, Basel, Switzerland.
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Potential Financial Conflicts of Interest: Employment: D. Messinger (IST [provides various services for sponsor]), J.A. Thommes (Roche), A. Tietz (Roche). Consultancies: D.M. Jensen (Roche, Abbott, Boehringer Ingelheim, Vertex, Novartis, AstraZeneca, HGS), P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Vertex, Idenix-Novartis, Valeant, HGS, Pharmasset, Cytheris, Intermune, Wyeth, Tibotec), A. Di Bisceglie (Roche, Schering), K.R. Reddy (Roche, Gilead, Idenix, Vertex), D. Messinger (Roche). Honoraria: P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Idenix-Novartis), K.R. Reddy (Roche, Gilead, Idenix, Vertex), G. Teuber (Roche). Grants received: D.M. Jensen (Roche, Vertex, Boehringer Ingelheim), P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Vertex, Idenix-Novartis, Valeant, HGS, Pharmasset, Cytheris, Intermune, Wyeth, Tibotec), A. Di Bisceglie (Roche), K.R. Reddy (Roche, Schering, Human Genomics, Novartis). Grants pending: K.R. Reddy (Boehringer Ingelheim, Pharmasset).
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Reproducible Research Statement: Study protocol: Available at http://www.roche-trials.com/patient/trials/trial120.html. Statistical code: Not available. Data set: Available at http://www.roche-trials.com/patient/trialresults/stur124.html.
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Requests for Single Reprints: Donald M. Jensen, MD, Center for Liver Diseases, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637; e-mail, djensen{at}medicine.bsd.uchicago.edu.
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Current Author Addresses: Dr. Jensen: Center for Liver Diseases, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637.
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Dr. Marcellin: Service d'Hepatologie and Centre de Recherches Biologiques Bichat Beaujon (INSERM CRB3), Hôpital Beaujon, Clichy 92110, France.
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Dr. Freilich: Liver and Pancreas Institute of Kansas City, 6675 Holmes, Suite 425, Kansas City, MO 64131.
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Dr. Andreone: Department of Internal Medicine, Cardiology, and Hepatology, Ospedale S. Orsola-Malpighi, Universita di Bologna, Via Massarenti 9-40138, Bologna, Italy.
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Dr. Di Bisceglie: Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Boulevard, Saint Louis, MO 63110-0250.
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Dr. Brandão-Mello: University of Rio de Janeiro Medical School, Internal Medicine Department, Liver and Gastroenterology Unit, Gaffree e Guinle University Hospital, Rua Mariz e Barros 775, 20270-004 Rio de Janeiro, Brazil.
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Dr. Reddy: Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104.
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Dr. Craxi: Instituto Di Clinica Medica Policlinico, Divisione Di Gastroenterologia, Piazzale Delle Cliniche 2, Palermo 90127, Italy.
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Dr. Olveira Martin: Digestive Diseases (Servicio Aparato Digestivo), Hospital La Paz, Paseo de la Castellana 261, Madrid 28046, Spain.
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Dr. Teuber: J.W. Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
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Mr. Messinger: IST GmbH, Soldnerstrasse 1, 68219 Mannheim, Germany.
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Dr. Thommes: Roche Pharmaceuticals, 340 Kingsland Street, Nutley, NJ 07110.
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Dr. Tietz: Pharmaceuticals Division, F. Hoffmann-La Roche, Building 074/3O.202, CH-4070 Basel, Switzerland.
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Author Contributions: Conception and design: P. Marcellin, K.R. Reddy, D. Messinger, J.A. Thommes, A. Tietz.
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Analysis and interpretation of the data: D.M. Jensen, P. Marcellin, A. Di Bisceglie, K.R. Reddy, A. Craxi, D. Messinger, J.A. Thommes, A. Tietz.
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Drafting of the article: D.M. Jensen, P. Marcellin, A. Di Bisceglie, K.R. Reddy, J.A. Thommes, A. Tietz.
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Critical revision of the article for important intellectual content: D.M. Jensen, P. Marcellin, P. Andreone, A. Di Bisceglie, C.E. Brandão-Mello, K.R. Reddy, A. Craxi, G. Teuber, D. Messinger, J.A. Thommes, A. Tietz.
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Final approval of the article: D.M. Jensen, P. Marcellin, B. Freilich, P. Andreone, A. Di Bisceglie, C.E. Brandão-Mello, K.R. Reddy, A. Craxi, A. Olveira Martin, G. Teuber, J.A. Thommes, A. Tietz.
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Provision of study materials or patients: D.M. Jensen, P. Marcellin, P. Andreone, A. Di Bisceglie, K.R. Reddy, A. Craxi, A. Olveira Martin, G. Teuber.
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Statistical expertise: A. Craxi, D. Messinger.
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Collection and assembly of data: D.M. Jensen, C.E. Brandão-Mello.
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ClinicalTrials.gov registration number: NCT00087646.
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