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From genetic association studies to the biology of interleukin-28B in hepatitis C virus infection and beyond
  1. Christian M Lange
  1. Correspondence to Dr Christian M Lange, Klinikum der J. W. Goethe-Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; lange_christian1{at}yahoo.de

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Numerous studies have confirmed and extended the striking results of independent genome-wide association studies showing that single nucleotide polymorphisms (SNPs) near the IL28B gene (encoding interferon-λ3 (IFN-λ3)) are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection (reviewed in1). Most importantly, these studies have shown that good-response IL28B SNPs (eg, rs12979860 CC vs CT/TT) increase sustained virological response rates in HCV genotype 1 and 4 patients after classical treatment with pegylated interferon-α (pegIFN-α) and ribavirin by approximately twofold.1 With respect to the strength of this association, the identification of IL28B as a genetic determinant of treatment outcome and spontaneous clearance from HCV infection constitutes a remarkable exception among numerous published genome-wide association studies, which generally yielded susceptibility loci that only had a moderate impact on the investigated phenotype (see http://www.genome.gov/26525384 for a listing). However, the outstanding findings regarding IL28B and HCV infection, initially made in cohorts treated with classical pegIFN-α/ribavirin therapy, coincide with a likewise stunning progress in therapeutic opportunities to manage HCV infection. Recently approved telaprevir and boceprevir-based triple therapies, as well as numerous other directly acting antiviral agents (DAAs) currently being in advanced clinical evaluation in both pegIFN-α-based and IFN-free treatment regimens, result in a dramatically improved therapeutic repertoire to treat chronic hepatitis C.2 Consequently, the clinical value of IL28B genotyping is currently under re-evaluation.

In this regard, recent data have clearly shown that IL28B genotype is predictive for treatment outcome of many pegIFN-α-based triple therapies as well, though its impact is strongly attenuated compared with pegIFN-α/ribavirin therapy.2 Perhaps more surprisingly, IL28B genotype also appears to have a moderate impact on virological response to IFN-free, all-oral regimens.3 Regarding the completely different mode of operation of immune-modulating …

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