IL28B : its role in the therapeutic response of antiviral therapy in hepatitis C virus infected patients

Abstract

The hepatitis C virus (HCV) is a bloodborne pathogen commonly transmitted via percutaneous contact with blood from an HCV-infected individual, targeting the liver and resulting in inflammation which can lead to severe progressive liver disease. Failure to spontaneously clear the virus results in the development of chronic hepatitis C (CHC). Thus, standard combination therapy is carried out using pegylated interferon (peg-IFNα) and ribavirin (RBV), with a sustained viral response (SVR) being attained after 24–48 weeks. Treatment success was however found to be influenced not only by the HCV genotype but also by host factors – specifically genetic variants which regulate interleukin 28B (IL28B) expression. IL28B encodes Interferon Lambda 3 (IFNλ3), which is involved in mediating the response to interferon therapy and subsequently in HCV clearance. A gene coding for Interferon Lambda 4 (IFNλ4) protein, determined by the ΔG allele of the rs368234815 TT/ΔG dinucleotide variant, was found to impair the action of IFNλ3 and other interferons. Since genotyping of this variant has been identified as a strong predictor of SVR, this raises the question of the genotype frequencies of the rs368234815 TT/ΔG variant within the Maltese population of CHC-infected individuals. In this study, DNA was extracted from a cohort of 26 blood samples collected from treatment-naïve chronic HCV-infected individuals. A chelating ion-exchanging resin-based extraction technique was utilised and extracted DNA was spectrophotometrically tested to ensure optimal concentration and purity for genotyping via a real-time quantitative PCR array. In the tested Maltese HCV-positive cohort, the rs368234815 genotype proportions were observed to be 38.5% homozygous TT (TT/TT), 50% heterozygous (TT/ΔG), and 11.5% homozygous ΔG (ΔG/ΔG). In terms of allele frequencies, the IFNL4-TT allele frequency was 63.5%, while the IFNL4-ΔG allele frequency was 36.5%. These results suggest that the Maltese HCV-infected population’s genetic predisposition for clearing HCV or responding to interferon therapy is intermediate to favourable, since although the IFNL4-TT was found to be the major allele in the Maltese population, the heterozygous genotype TT/ΔG, rather than the favourable TT/TT genotype, is the most prevalent. The integration of such genetic insights into national HCV elimination strategies in Malta could improve efficiency, reduce costs, and enhance the overall success of efforts to eliminate HCV.