Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus
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.
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
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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
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
