Impact of IFNL4 Genetic Variants on Sustained Virologic Response and Viremia in Hepatitis C Virus Genotype 3 Patients

Vincent Pedergnana,John Mclauchlan,Stop-Hcv Consortium ,William L Irving,Eleanor Barnes,Chris C.A Spencer

doi:10.1089/jir.2019.0013

Abstract

Hepatitis C virus (HCV) genotype 3 is very prevalent in Europe and Asia and is associated with worst outcomes than other genotypes. Genetic factors have been associated with HCV infection; however, no extensive genome-wide study has been performed among HCV genotype 3 patients. In this study, using a large cohort of 1,759 patients infected with HCV genotype 3, we explore the role of genetic variants on the response to interferon (IFN) and direct-acting antiviral (DAA) regimens and viremia in a combined candidate gene and genome-wide analysis. We show that genetic variants within the IFN lambda 4 (IFNL4) locus are the major factors associated with the studied traits, accordingly with observations in other HCV genotypes and with comparable effect sizes. In particular, the functional dinucleotide polymorphism rs368234815 was associated with IFN-based sustained virologic response (SVR) [odds ratio (OR) = 1.5, P = 2.3 × 10−7], viremia (beta = −0.23, P = 8.8 × 10−10), and also DAA-based SVR (OR = 1.7; P = 4.2 × 10−4). Our results provide evidence for a role of genetic variants on HCV viremia and SVR, notably DAA-based, in patients infected with HCV genotype 3.

Highlights

Chronic hepatitis C (CHC) infection affects more than 71 million people worldwide (WHO 2017)
We describe the evidence for association at 38 previously reported genetic variants located at 33 loci, and in particular within the IFNL3-IFN lambda 4 (IFNL4) locus
We studied 3 different traits relating to Hepatitis C virus (HCV) infection (Table 1): (1) viral load measured before the treatment was administered, we used the normalized log10 value [log10(PTVL)]; (2) the response to peg-IFN-a and Ribavirin treatment (IFNRB_SVR); and (3) the response to direct-acting antiviral (DAA) treatment (DAA_SVR)

Summary

Introduction

Chronic hepatitis C (CHC) infection affects more than 71 million people worldwide (WHO 2017). In a combined cohort of 1,759 patients infected by HCV genotype 3, we performed an epidemiological study of demographic and clinical variables for 3 different traits related to HCV infection, ie, pretreatment viral load (PTVL), response to IFN therapy, and response to DAA therapy.

Results

Conclusion