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, Andrew J. Muir, Mark S. Sulkowski, Dongliang Ge, Jacques Fellay, Kevin V. Shianna, Thomas Urban, Nezam H. Afdhal, Ira M. Jacobson, Rafael Esteban, Fred Poordad, Eric J. Lawitz, Jonathan McCone, Mitchell L. Shiffman, Greg W. Galler, William M. Lee, Robert Reindollar, John W. King, Paul Y. Kwo, Reem H. GhalibBradley Freilich, Lisa M. Nyberg, Stefan Zeuzem, Thierry Poynard, David M. Vock, Karen S. Pieper, Keyur Patel, Hans L. Tillmann, Stephanie Noviello, Kenneth Koury, Lisa D. Pedicone, Clifford A. Brass, Janice K. Albrecht, David B. Goldstein, John G. McHutchison

Research output: Contribution to journalArticlepeer-review

640 Scopus citations

Abstract

Background & Aims: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. Methods: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). Results: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). Conclusions: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Original languageEnglish (US)
Pages (from-to)120-129.e18
JournalGastroenterology
Volume139
Issue number1
DOIs
StatePublished - Jul 2010

Bibliographical note

Funding Information:
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 .

Funding Information:
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.

Keywords

  • Genetics
  • IL-28B
  • Interferon-Lambda
  • Peg-Interferon-Alfa

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