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Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial

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Abstract

Background and aims

The combination of pegylated interferon alfa/ribavirin will likely remain the treatment of choice for HCV genotype 2/3 patients in financially constrained countries for the foreseeable future. Patients with poor on-treatment response may benefit from treatment extension. This study examined the effect of 48 versus 24 weeks of peginterferon alfa-2a/ribavirin on the sustained virological response (SVR) in patients with HCV genotype 2/3 who did not achieve rapid virological response (RVR).

Methods

N-CORE was a multicentre, randomised, phase III study. HCV genotype 2/3 patients receiving peginterferon alfa-2a/ribavirin without a rapid but with an early virological response were randomised at week 24 to stop treatment (Arm A) or continue to 48 weeks (Arm B). The primary efficacy endpoint was SVR.

Results

Two hundred thirty-five patients were enrolled. End of treatment response was similar in both treatment arms. SVR24 rates were not significantly greater in the extended treatment arm compared with the standard 24-week treatment in either the intention-to-treat or the per-protocol populations (61 vs. 52 %, p = 0.1934 and 63 vs. 52 %, p = 0.1461, respectively). Serious adverse events occurred more frequently in patients receiving extended treatment duration (12 %) versus 24-week therapy (4 %).

Conclusions

It is unclear whether the extension of peginterferon alfa-2a/ribavirin treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. The study was stopped early because recruitment was slower than anticipated, and this may have limited the statistical impact of these findings.

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Acknowledgements

The authors thank the N-CORE Study Group investigators: Australia: Gerry Macquillan, Sam Galhenage, Alice Lee, Greg Dore, Stephen Pianko; Austria: Peter Ferenci, Rudolf Stauber, Michael Gschwantler, Gabriele Fischer, Andreas Maieron, Wolfgang Vogel, Christian Datz; Belgium: Jean-Pierre Mulkay, Marc Van Gossum, Peter Michielsen, Hans Van Vlierberghe, Christophe George, Jean Delwaide, Luc Lasser, Chantal De Galocsy; Brazil: Hugo Cheinquer, Fernando Wolff, Nelson Cheinquer, Edison Roberto Parise, Marcela Pezzoto Laurito, Maria Lucia Ferraz, Ivonete Souza e Silva, Arnaldo Dominici Jesus, Adalgisa Souza Paiva Ferreira, Maria Patelli Lima, Fernando José Góes Ruiz, Ligia Ruiz, Angelo Mattos, Cristiane Tovo, Fernanda De Araújo, Paulo Roberto Lerias Almeida, Gabriela Coral, Idilio Zamin Junior, Jorge Pinheiro, Sirlei Dittrich, Tania Reuter, Janaína Casotti Schneider, Waltesia Perini, Marcelo Costa, Fernando Gonçales Jr., Adilson Cavalcante, Ana Carla Silva, Catia Carpinelli, Maria Cássia Mendes-Corrêa, Virgilio Tiezzi Neto, Andresa Teixeira, Ana De Lourdes Candolo Martinelli, Marcia Villanova, Fernanda Souza, Cláudio de Figueiredo-Mendes; Canada: Stephen D. Shafran, Keith Tsoi, Alnoor Ramji, Nav Anand; Germany: Stefan Zeuzem, Eckart Schott, Peter Buggisch, Dietmar M. Klass, Christoph Eisenbach, Tobias Goeser, Christoph Berg, Bernd Möller, Ulrich Spengler, Roland M. Schmid, Peter R. Galle, Robert Thimme, Andreas Erhardt, Stefan Mauss, Rainer Günther, Jörg Schlaak, Thomas Discher, Ralph Link, Andreas Stallmach; Mexico: Ignacio Escalante Sandoval, Jose Isidro Minero Alfaro, Tomás Marcelino Morales Cadena, Alma Minerva Pérez Ríos, Nahum Mendez Sanchez, Rene Male Velazquez; Switzerland: Andreas Geier, Aref Al Deb’i, Beat Muellhaupt, Heiko Fruehauf, Joachim Mertens, Darius Moradpour, Jan Borovicka, Benedetta Terziroli, Andreas Cerny, Lorenzo Magenta, Marina Knoepfli, Rosita Dell’orto Spadacini; United States: Kimberly Beavers, Raymond Chung, Greg Everson, Norman Gitlin, Paul Pockros, Jatinder Pruthi, Alan Tice, Fernando Alemany-Lopez, Sanjeev Arora, Luis Balart, Ana Maria Corregidor, Edwin Dejesus, Adrian Dibisceglie, Christopher Williams, Tarek Hassanein, Timothy Morgan, Maribel Rodriguez-Torres, Lorenzo Rossaro, Vinod R. Rustgi, John Santoro, Arun Sanyal, Atif Zaman, Kevin Korenblat, Curtis Argo, Douglas Homoky, Robert A. Levine, Joseph Bloomer, John Phillips, Gary Poleynard, Aasim Sheikh, Hillel Tobias, Bindu Balani, Harlan Wright, Edward Piken, Sergio Rojter, Michael Fried, Neville Pimstone, Fred Poordad, Terry Box. This study was supported by F. Hoffmann-La Roche Ltd., Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Sarah Davies, Ph.D., was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Compliance with ethical requirements and Conflict of interests

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. Mitchell L Shiffman—Advisor: Achillion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gen-Probe, Gilead, Globeimmune, GlaxoSmithKline, Janssen, Merck, Novartis, Roche/Genentech, Vertex; Speaker: Bayer, Gilead, GlaxoSmithKline, Merck, Roche/Genentech, Vertex; Grant support: Abbott, Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Globeimmune, Idenix, Merck, Novartis, Roche/Genentech. Hugo Cheinquer—Advisor: Roche; Speaker: Bristol-Myers Squibb, Roche; Research Grant: Bristol-Myers Squibb, Merck, Roche. Christoph P Berg—Advisor: Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Roche; Speaker: Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche. Thomas Berg—Advisor: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Novartis, Roche, Vertex; Speaker: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Novartis, Roche, Vertex; Research Grants: Bristol-Myers Squibb, Gilead, Janssen, Novartis. Roche Cláudio de Figueiredo-Mendes—Research support: Bristol-Myers Squibb, Merck, Roche. Gregory J. Dore—Advisor: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche; Research Grants: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche, Vertex. Maria Lúcia Ferraz—Advisor: Abbott, Janssen, Merck, Roche; Speaker: Abbott, Janssen, Merck, Roche; Clinical trials: Abbott, Janssen, Merck, Roche. Maria Lúcia Ferraz—Advisor: Abbott, Janssen, Merck, Roche; Speaker: Abbott, Janssen, Merck, Roche; Clinical trials: Abbott, Janssen, Merck, Roche. Maria Cássia Mendes-Corrêa—Research support: Bristol-Myers Squibb, Janssen, Merck, Roche. Maria Patelli Lima—None to declare. Edison R. Parise—Advisor: Bristol-Myers Squibb, Merck, Roche; Speaker: Bristol-Myers Squibb, Janssen, Merck, Roche; Research support: Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck, Roche. Alma Minerva Perez Rios—None to declare. Tania Reuter—Research support: GlaxoSmithKline, Janssen, NIH, Roche; Speaker: Janssen, Roche. Arun J Sanyal—Advisor: Abbott, Galectin, Gilead, Ikaria, Immuron, Merck, Norgine, Novartis, Roche/Genentech, Salix, Takeda; Research Grants: Bayer-Onyx, Exhalenz, Genentech, Gilead, Gore, Ikaria, Intercept, Salix, Takeda, Astellas; Royalties: Up to date. Stephen D Shafran—Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Pfizer, Roche, Vertex; Research funding: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Pfizer, Roche, Vertex. Marc Hohmann—Employee of IST GmbH; IST GmbH has a contract with Roche to provide statistical support. Fernando Tatsch—Employee of AbbVie, Chicago, IL; was an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland at the time the study was conducted. George Bakalos—Employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Stefan Zeuzem—Advisor: Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, Vertex.

Author information

Author notes

  1. Fernando Tatsch

    Present address: AbbVie, Chicago, IL, USA

Authors and Affiliations

  1. Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, 5855 Bremo Road, Suite 509, Richmond, VA, 23226, USA

    Mitchell L. Shiffman

  2. Department of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    Hugo Cheinquer

  3. Department of Internal Medicine, Medizinische Universitätsklinik Tübingen, Tübingen, Germany

    Christoph P. Berg

  4. Hepatology Section, Department of Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Leipzig, Germany

    Thomas Berg

  5. Hospital Geral, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, Brazil

    Cláudio de Figueiredo-Mendes

  6. Kirby Institute, The University of New South Wales and St. Vincent’s Hospital, Sydney, NSW, Australia

    Gregory J. Dore

  7. Department of Gastroenterology, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil

    Maria Lúcia Ferraz & Edison R. Parise

  8. Infectious Diseases Research Unit, ABC Foundation Medical School, Santo André, Brazil

    Maria Cássia Mendes-Corrêa

  9. Medical Sciences, Pontifícia Universidade Católica de Campinas, São Paulo, Brazil

    Maria Patelli Lima

  10. Centro de Investigación Farmacéutica Especializada, Guadalajara, JAL, Mexico

    Alma Minerva Perez Rios

  11. Centre for Infectious Diseases, Universidade Federal do Espírito Santo, Vitória, Brazil

    Tania Reuter

  12. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Arun J. Sanyal

  13. Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada

    Stephen D. Shafran

  14. IST GmbH, Mannheim, Germany

    Marc Hohmann

  15. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Fernando Tatsch & George Bakalos

  16. Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany

    Stefan Zeuzem

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  1. Mitchell L. Shiffman
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Corresponding author

Correspondence to Mitchell L. Shiffman.

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Shiffman, M.L., Cheinquer, H., Berg, C.P. et al. Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial. Hepatol Int 8, 517–526 (2014). https://doi.org/10.1007/s12072-014-9555-3

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