[Do Interleukin-28B (IL-28B) Polymorphisms Play a Role in Immune Defense against Hepatitis C Cirus?]

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ACKNOWLEDGEMENT

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DECLARATION

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ABSTRACT

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.

Table of Contents

ABSTRACT1

CHAPTER I: INTRODUCTION4

Background & Aims4

Introduction4

Discovery of IL-28B Polymorphisms6

CHAPTER II: LITERATURE REVIEW8

Background8

Prior Studies10

Sustained Virologic Response15

Genotype 115

Genotypes 2 and 320

Early Viral Clearance20

Role of IL-28B Polymorphisms in Liver Transplantation21

CHAPTER III: METHODOLOGY23

Epidemiology23

Association with Spontaneous Viral Clearance23

Study population25

HCV RNA kinetics day 0-2826

Study endpoints26

SNP rs12979860 genotyping27

IL-28B genotyping and statistical analyses27

CHAPTER IV: RESULTS & DISCUSSION29

Results29

Patient profiles and virological responses29

Interferon-? and Hepatitis C Virus Infection29

IL-28B and Treatment Strategies31

Characteristics of patients with SNP rs8099917 and its impact on treatment responses36

Patient Profiles and Virological Responses.38

Factors Associated With RVR and SVR.39

Characteristics of Patients With SNP rs8099917 and Its Impact on Treatment Responses.40

Discussion41

CHAPTER V: CONCLUSION45

REFERENCES48

CHAPTER I: INTRODUCTION

Background & Aims

A substantial proportion of hepatitisCvirus genotype 1 (HCV-1) patients will achieve a sustained virological response (SVR, HCV RNA seronegative 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

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 stan-dard-of-care treatment for chronic hepatitis C—prior to the recent licensure of boceprevir (Victrelis, Merck) and ...