Volume 139, Issue 1 , Pages 120-129.e18, July 2010
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. Ghalib, Bradley 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
Received 31 December 2009; accepted 8 April 2010. published online 19 April 2010.
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.
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).
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).
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.
Keywords: Genetics, IL-28B, Interferon-Lambda, Peg-Interferon-Alfa
Abbreviations used in this paper: ALT, alanine aminotransferase, BMI, body mass index, cEVR, complete early virologic response, CI, confidence interval, EVR, early virologic response, HCV, hepatitis C virus, HCV-1, hepatitis C virus genotype 1, IL, interleukin, ITT, intention-to-treat, pegIFN, pegylated-interferon, RBV, ribavirin, RVR, rapid virologic response, SNP, single nucleotide polymorphism, SVR, sustained virologic response