IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes§

Authors


  • Potential conflict of interest: Dr. Poynard owns stock in Biopredictive. He also consults for and is on the speakers' bureau of Merck. Dr. Pol consults for, advises, and is on the speakers' bureau of Boehringer Ingleheim, Abbott, and GlaxoSmithKline. He consults for, advises, is on the speakers' bureau of, and received grants from Roche, Gilead, Bristol-Myers Squibb, and MSD.

  • §

    Members of the Swiss Hepatitis C Cohort Study Group: Francesco Negro (Geneva, Chairman), Antoine Hadengue (Geneva, Chairman of Scientific Committee), Laurent Kaiser, Laura Rubbia-Brandt (Geneva); Darius Moradpour, Cristina Cellerai (Lausanne); Martin Rickenbach (Lausanne Data Center); Andreas Cerny, Gladys Martinetti (Lugano); Jean-François Dufour, Meri Gorgievski, Virginie Masserey Spicher (Berne); Markus Heim, Hans Hirsch (Basel); Beat Müllhaupt, Beat Helbling, Stephan Regenass (Zurich); Raffaele Malinverni (Neuchatel); David Semela, Guenter Dollenmaier (St Gallen); Gieri Cathomas (Liestal).

Abstract

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917—previously shown to be at risk of treatment failure—was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma. Conclusion: In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes. (HEPATOLOGY 2012)

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