Role of IL28B for Chronic Hepatitis C Treatment Toward Personalized Medicine

Kentaro Matsuura; Tsunamasa Watanabe; Yasuhito Tanaka

Disclosures

J Gastroenterol Hepatol. 2014;29(2):241-249. 

In This Article

Abstract and Introduction

Abstract

Genome-wide association studies recently revealed that certain interleukin-28B (IL28B) polymorphisms are strongly associated with responses to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients chronically infected with hepatitis C virus (HCV) genotype 1, as well as with spontaneous clearance of HCV. Subsequent reports revealed that IL28B genotypes also affect treatment efficacy in chronic infection with other HCV genotypes. Furthermore, there have been several reports that implicate IL28B genotypes in inflammatory status, progression of fibrosis and adverse clinical outcomes in chronic hepatitis C (CHC). Therapy of CHC recently entered a new era with the deployment of direct-acting antivirals. These include nonstructural 3/4A protease inhibitors which have shown promise in combination with PEG-IFN/RBV in several clinical trials. IFN-free therapy is expected to be useful especially in IFN-resistant patients and may become the standard of care in the future. Several clinical trials have revealed an association between IL28B genotype and treatment efficacy in triple therapy or IFN-free regimens. On the other hand the mechanism of the effect of IL28B on HCV infection has not yet been elucidated. Recently, it was shown that the polymorphism of IFN-lambda 4 (IFNL4) is in high linkage disequilibrium with that of near IL28B, and more strongly associated with spontaneous or treatment-induced HCV clearance than IL28B genotypes, especially in individuals of African ancestry. This finding provides new insights into the genetic regulation of HCV clearance and its clinical management. IL28B genotyping will be also useful for personalized CHC treatment in the forthcoming era of direct-acting antivirals.

Introduction

Chronic hepatitis C virus (HCV) infection represents a significant health problem worldwide with approximately 170 million people infected.[1] Over 70% of individuals acutely infected with HCV go on to develop chronic infection and are at significant risk of progressive liver fibrosis and subsequent liver cirrhosis and hepatocellular carcinoma (HCC). Antiviral treatment has been shown to improve liver histology and decrease the incidence of HCC in chronic hepatitis C (CHC).[2,3] Until 2011, the standard treatment for chronic HCV infection was weekly pegylated interferon (PEG-IFN) in combination with daily doses of ribavirin (RBV); however, less than 50% of patients infected with HCV genotype 1 treated in this way achieve a sustained virological response (SVR).[4,5] In 2009, genome-wide association studies (GWAS), including our study of HCV infection,[6] showed that a single nucleotide polymorphism (SNP) near the interleukin-28B (IL28B) gene is strongly associated with response to PEG-IFN/RBV therapy for chronic HCV genotype 1 infection.[6–11] As a result, prediction of treatment outcome, especially nonresponsiveness to PEG-IFN/RBV, has been greatly improved by genotyping for the IL28B SNP, enabling personalized medicine to be developed for CHC. Newly developed treatments involving direct-acting antivirals (DAAs), including nonstructural (NS) 3/4A protease inhibitors have shown promising outcomes in combination with PEG-IFN/RBV in several clinical trials, wherein > 70% of patients infected with HCV genotype 1 achieved SVR.[12–14] Several clinical trials have revealed an association between IL28B genotype and treatment efficacy in triple therapy or IFN-free regimens. This review focuses on the role of IL28B in CHC treatment.

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