Gastroenterology
Volume 139, Issue 1 , Pages 120-129.e18 , July 2010

Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus

  • Alexander J. Thompson

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • ,
  • Andrew J. Muir

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • Duke University Medical Center, Durham, North Carolina
    • ,
  • Mark S. Sulkowski

      Affiliations

    • Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Dongliang Ge

      Affiliations

    • Center for Human Genome Variation, Duke University, Durham, North Carolina
    • ,
  • Jacques Fellay

      Affiliations

    • Center for Human Genome Variation, Duke University, Durham, North Carolina
    • ,
  • Kevin V. Shianna

      Affiliations

    • Center for Human Genome Variation, Duke University, Durham, North Carolina
    • ,
  • Thomas Urban

      Affiliations

    • Center for Human Genome Variation, Duke University, Durham, North Carolina
    • ,
  • Nezam H. Afdhal

      Affiliations

    • Beth Israel Deaconess Medical Centre, Boston, Massachusetts
    • ,
  • Ira M. Jacobson

      Affiliations

    • Weill Cornell Medical College, New York, New York
    • ,
  • Rafael Esteban

      Affiliations

    • Hospital General Universitario Valle de Hebron, Barcelona, Spain
    • ,
  • Fred Poordad

      Affiliations

    • Cedars-Sinai Medical Center, Los Angeles, California
    • ,
  • Eric J. Lawitz

      Affiliations

    • Alamo Medical Research, San Antonio, Texas
    • ,
  • Jonathan McCone

      Affiliations

    • Mt. Vernon Endoscopy Center, Alexandria, Virginia
    • ,
  • Mitchell L. Shiffman

      Affiliations

    • Liver Institute of Virginia, Newport News, Virginia
    • ,
  • Greg W. Galler

      Affiliations

    • Kelsey Research Foundation, Houston, Texas
    • ,
  • William M. Lee

      Affiliations

    • University of Texas Southwestern Medical Center, Dallas, Texas
    • ,
  • Robert Reindollar

      Affiliations

    • Piedmont Healthcare, Statesville, North Carolina
    • ,
  • John W. King

      Affiliations

    • Louisiana State University, Shreveport, Louisiana
    • ,
  • Paul Y. Kwo

      Affiliations

    • Indiana University School of Medicine, Indianapolis, Indiana
    • ,
  • Reem H. Ghalib

      Affiliations

    • The Liver Institute at Methodist Dallas Medical Center, Dallas, Texas
    • ,
  • Bradley Freilich

      Affiliations

    • Kansas City Gastroenterology and Hepatology, Kansas City, Missouri
    • ,
  • Lisa M. Nyberg

      Affiliations

    • Kaiser Permanente, San Diego, California
    • ,
  • Stefan Zeuzem

      Affiliations

    • J.W. Goethe-University Hospital, Frankfurt, Germany
    • ,
  • Thierry Poynard

      Affiliations

    • Groupe Hospitalier Pitie-Salpetriere, Paris, France
    • ,
  • David M. Vock

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • ,
  • Karen S. Pieper

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • ,
  • Keyur Patel

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • Duke University Medical Center, Durham, North Carolina
    • ,
  • Hans L. Tillmann

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • Duke University Medical Center, Durham, North Carolina
    • ,
  • Stephanie Noviello

      Affiliations

    • Schering-Plough Research Institute, Kenilworth, NJ
    • ,
  • Kenneth Koury

      Affiliations

    • Schering-Plough Research Institute, Kenilworth, NJ
    • ,
  • Lisa D. Pedicone

      Affiliations

    • Schering-Plough Research Institute, Kenilworth, NJ
    • ,
  • Clifford A. Brass

      Affiliations

    • Schering-Plough Research Institute, Kenilworth, NJ
    • ,
  • Janice K. Albrecht

      Affiliations

    • Schering-Plough Research Institute, Kenilworth, NJ
    • ,
  • David B. Goldstein

      Affiliations

    • Center for Human Genome Variation, Duke University, Durham, North Carolina
    • ,
  • John G. McHutchison

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • Duke University Medical Center, Durham, North Carolina
    • Corresponding Author InformationReprint requests Address requests for reprints to: John G. McHutchison, MD, Duke Clinical Research Institute, Duke University Medical Center, PO Box 17969, Durham, North Carolina 27715. fax: (919) 668-7164

Received 31 December 2009 ,Accepted 8 April 2010.

References 

  1. Hepatitis C fact sheet. Geneva: World Health Organization http://www.who.int/mediacentre/factsheets/fs164/en/Accessed July 13, 2009
  2. Jacobson IM, Brown RS, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971–981
  3. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965
  4. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982
  5. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–355
  6. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–593
  7. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265–2271
  8. Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470–477
  9. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401
  10. Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;
  11. Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;
  12. Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;
  13. Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure—a genome-wide association study. Gastroenterology. 2010;
  14. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–1374
  15. Thiebaut R, Jacqmin-Gadda H. Mixed models for longitudinal left-censored repeated measures. Comput Methods Programs Biomed. 2004;74:255–260
  16. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061–1069
  17. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–1838
  18. Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77
  19. Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–68
  20. Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–3854
  21. Marcello T, Grakoui A, Barba-Spaeth G, et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006;131:1887–1898
  22. Shiffman ML, et al. PEG-IFN-λ: antiviral activity and safety profile in a 4-week phase 1b study in relapsed genotype 1 hepatitis C infection. J Hepatol. 2009;50(Suppl 1):s237;(A643)

 View this article's video abstract at www.gastrojournal.org.

 Conflicts of interest The authors disclose the following: Drs McHutchison, Goldstein, Muir, Afdhal, Jacobson, Esteban, Poordad, Lawitz, McCone, Shiffman, Galler, Lee, Reindollar, King, Kwo, Ghalib, Freilich, Nyberg, Patel, Zeuzem, Poynard, and Sulkowski report having received research and grant support from Schering-Plough; Drs McHutchison, Goldstein, Muir, Afdhal, Jacobson, Esteban, Poordad, Lawitz, Shiffman, Reindollar, Kwo, Zeuzem, Poynard, and Sulkowski have received consulting fees or acted in an advisory capacity for Schering-Plough; Drs Brass, Koury, Pedicone, and Albrecht are employees of Schering-Plough (now Merck & Co, Inc) and are stockholders in this entity; Dr Noviello is a former employee of Schering-Plough and is now a consultant to Merck & Co, Inc; and Drs Goldstein, Ge, Fellay, Shianna, Urban, McHutchison, and Thompson are co-inventors of a patent application based on this finding. David Vock and Karen Pieper declare that they have had access to all data and independent statistical support to allow them to analyze the data independently of the sponsor of the study.

 Funding This study was funded by Schering-Plough Research Institute, Kenilworth, NJ; Alexander Thompson received funding support from the Duke Clinical Research Institute, the Richard B. Boebel Family Fund, the National Health and Medical Research Council of Australia, and the Gastroenterology Society of Australia and the Royal Australasian College of Physicians.Jennifer King, PhD, provided editorial assistance in preparing the manuscript; she was funded by the Duke Clinical Research Institute, Duke University. The sponsor did not provide any funding for Dr King or have any contact with her.

PII: S0016-5085(10)00574-3

doi: 10.1053/j.gastro.2010.04.013

Gastroenterology
Volume 139, Issue 1 , Pages 120-129.e18 , July 2010

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