PROPOSAL

Proposal



Interleukin-28B Polymorphisms- Proposal

Background & Aims

A substantial proportion of hepatitis C virus genotype 1 (HCV-1) patients will achieve a sustained virological response (SVR, HCV RNA sero negative throughout 24 weeks of post-treatment follow-up) after 24 weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen.

Introduction

Genome-wide association studies have recently identified single nucleotide polymorphisms in proximity to the interleukin-28B (IL-28B) gene that can predict sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection who are undergoing therapy with pegylated interferon (IFN) a and ribavirin. IL-28B encodes IFN-?3, a type III IFN involved in host antiviral immunity. Favorable variants of the 2 most widely studied IL-28B polymorphisms, rs12979860 and rs8099917, are strong pretreatment predictors of early viral clearance and SVR in patients with genotype 1 HCV infection. Variations in the distribution of IL-28B alleles may partly explain differences in SVR rates among ethnic groups. Further investigations have implicated IL-28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL-28B may be a key factor involved in host immunity against HCV. Clinical trials of IFN-? as a therapeutic agent for chronic HCV infection are currently underway. The use of IL-28B polymorphisms as a predictive tool will have a major impact on treatment strategies for chronic HCV infection, particularly in the context of emerging therapies and direct-acting antiviral agents.

Studies based on genome-wide associated studies (GWAS) have showed that single nucleotide polymorphisms (SNPs) at and/or near the interleukin28B (IL-28B) gene play a crucial role in the management of HCV infection. A growing body of evidence has shown that favorable genetic variants of IL-28B might enhance the treatment outcome in HCV-1 infected patients receiving standard 48 weeks of treatment , , , and . However, little is known about the role of IL-28B genetic polymorphisms in the outcome in HCV-1 patients with an abbreviated regimen. Instead of the on-treatment factor of RVR, whether the pretreatment factor of IL-28B genetic variants could serve as a surrogate marker to guide treatment duration in the clinical practice needs to be studied. Taiwan is an endemic area of not only hepatitis B but also hepatitisC. The current study aimed to explore the impact of the genetic variations in IL-28B in predicting treatment response of HCV-1 patients to an abbreviated 24-week peginterferon/ribavirin in a well-characterized Asian cohort.

Literature Review

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, affecting over 4 million people and accounting for the majority of newly diagnosed cases of chronic liver disease.1,2 Advanced liver disease resulting from chronic HCV infection is a major cause of liver-related mortality and is expected to increase in prevalence over the next decade.3,4 Pegylated interferon (pegIFN) a-2a or pegIFN a-2b in combination with ribavirin (RBV) was the standard- of-care treatment for chronic hepatitis C—prior to the recent licensure of boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex) in the United States—and sustained virologic response (SVR) occurred in only approximately half of ...