Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C

Abstract

AIMTo determine whether hepatitis C virus (HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients.METHODSOne hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein (BigDye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28B gene rs12979860 (Custom TaqMan 5' allelic discrimination assay; Applied Biosystems).RESULTSOf the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response (SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70 (R70Q/H) or/and position 91 (L91M). The favorable IL28B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age (P < 0.001), urban residence (P = 0.004), IL28B CC genotype (P < 0.001), absence of core mutations (P = 0.005), achievement of rapid virologic response (P < 0.001) and early virological response (P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age (P < 0.001), absence of core substitutions (P = 0.04) and IL28B CC genotype (P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%.CONCLUSIONHCV core mutations can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.

Interferon-γ inducible protein-10 and interleukin 28B gene polymorphism as predictive markers for genotype 4 hepatitis C virus treatment response

“…The meticulous biological pathways emphasizing the IL-28B gene SNP association with treatment response and viral clearance remain mysterious. Studies investigated IL28B polymorphism revealed that IL-28B polymorphism variants genotypes are linked with endogenous activation of host innate immunity (Sultana et al, 2016). As host innate immune mechanisms including IFN-γ control viral infection (Ibrahim et al, 2013).…”

Frequency of Interferon-Resistance Conferring Substitutions in Amino Acid Positions 70 and 91 of Core Protein of the Russian HCV 1b Isolates Analyzed in the T-Cell Epitopic Context

“…The presence of substitutions R to Q/H in aa position 70 of the nucleocapsid (core) of HCV 1b can help distinguish patients who can still benefit from the affordable IFN-based therapy from those who do not respond and are at an increased risk of HCC development [ 17 , 22 , 25 , 32 – 38 ]. There are also indications of the clinical significance of L to M substitution in aa position 91 of HCV 1b, although less well defined [ 18 , 19 ].…”

“… Table S1: presentation by HLA I alleles of 9-mer peptide variants derived from the region between aa 62 and 78 of the nucleocapsid (core) of HCV 1b encompassing aa 70, predicted using EPISPOT tool ( http://bio.med.ucm.es/episopt.html ; EPISPOT [ 25 ]). Nine amino acid long peptides were chosen based on the consensus amino acid sequence of nucleocapsid (core) protein of HCV 1b variants isolated in the Russian Federation.…”

“…A series of studies determined the frequency of these mutations in different population groups [ 22 – 24 ]. All, including the very recent ones, concluded that the nature of amino acid residues in aa position 70 of HCV core can help to distinguish patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards the end-stage liver disease [ 25 ]. The clinical significance of substitutions in aa position 91 of HCV 1b is less well defined [ 19 ] and for other HCV genotypes either unclear [ 19 ] or not demonstrated [ 26 – 29 ].…”

Detection of anti-protease inhibitors resistance mutations in HCV strains infecting treatment-naïve chronic patients from Romania

“…Forty-four 1b subtype HCV chronically infected Caucasian patients unexposed to any antiviral therapy were selected for study. Viral subtyping was assessed elsewhere by sequencing a fragment of core region (17). The study was approved by the Bioethics Committee of Cantacuzino National Medico-Military Institute for Research and Development and conducted in accordance with the ethical principles stated in the Declaration of Helsinki.…”