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Genetics of IL28B and HCV—response to infection and treatment

Abstract

The IL28B locus attracted the attention of HCV researchers after a series of genome-wide association studies independently identified a strong association between common IL28B polymorphisms and the outcome of PEG-IFN-α plus ribavirin combination therapy in patients chronically infected with HCV genotype 1. This association was subsequently replicated for other HCV genotypes and has been linked to spontaneous eradication of HCV, development of steatosis and biochemical changes (such as altered levels of γ-glutamyl transpeptidase and LDL). Despite the introduction of direct-acting antiviral drugs, IL28B genetics are likely to play a part in patient selection and treatment decisions—moving towards a personalized approach to therapy. In HCV-infected patients with the so-called favourable IL28B genotype (rs12979860 CC; associated with better treatment response), hepatic expression levels of IL28B and interferon-stimulated genes seem to be reduced at baseline, but are induced more strongly after IFN-α administration, perhaps resulting in more effective elimination of the virus. Clarification of the mechanisms underlying these biological phenomena will lead to improved understanding of the antiviral effects of IFN-λ and, ideally, to the development of better therapies against HCV infection. This Review summarizes current understanding of the role of IL28B in HCV infection and response to therapy.

Key Points

  • The 130–170 million people chronically infected with HCV have an increased risk of cirrhosis, hepatocellular carcinoma and liver failure

  • Several single nucleotide polymorphisms upstream of the IL28B gene are associated with spontaneous clearance of HCV and improved response to PEG-IFN-α plus ribavirin combination therapy

  • In patients with the so-called favourable IL28B allele (rs12979860 CC), associated with better response to therapy, HCV RNA levels decline rapidly with treatment and IFN-α therapy induces strong interferon-stimulated gene (ISG) expression

  • In patients with unfavourable IL28B genotypes (rs12979860 CC/TT), ISG expression tends to be refractory to further IFN stimulation, resulting in poor response to IFN therapy

  • IL28B genotype might also predict response to telaprevir triple therapy, although it might not be as effective at predicting the treatment response in this scenario as with PEG-IFN-α plus ribavirin combination therapy

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Figure 1: The IL28–IL29 locus on chromosome 19.
Figure 2: Potential role of the favourable IL28B genotype in the response to interferon therapy.
Figure 3: Potential role of the unfavourable IL28B genotype in the response to interferon therapy.

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Acknowledgements

This work was supported in part by Grants-in-Aid for scientific research and development from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare, Government of Japan.

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All authors contributed equally to researching data for the article, discussion of content and reviewing and/or editing the manuscript before submission. C. N. Hayes and K. Chayama wrote the article.

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Correspondence to Kazuaki Chayama.

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Hayes, C., Imamura, M., Aikata, H. et al. Genetics of IL28B and HCV—response to infection and treatment. Nat Rev Gastroenterol Hepatol 9, 406–417 (2012). https://doi.org/10.1038/nrgastro.2012.101

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