Core mutations , IL 28 B polymorphisms and response to peginterferon / ribavirin treatment in Swedish patients with hepatitis C virus genotype 1 infection

Background: Patients infected with hepatitis C virus (HCV) genotype 1 respond poorly to standard treatment with 50% or less achieving sustained virologic response. Predicting outcome is essential and could help avoid unnecessary treatment and reduce health cost. Recently, an association of amino acid substitutions in the core region and treatment outcome was observed in Japanese patients. In the present study, the impact of these mutations on response kinetics and treatment outcome was explored in Caucasian patients. Methods: The core region of HCV pre-treatment samples obtained from 50 patients treated with peginterferon/ ribavirin in a previous Swedish clinical trial with genotype 1 infection were sequenced. The alleles at rs12979860, a single nucleotide polymorphism (SNP), were assessed in order to identify any co-association with this strong response predictor. Results: No association between treatment response and substitutions of core residue 91 was found. In contrast, substitutions of core residue 70 were observed in 6/21 (29%) non-responders, but only in one of 29 responders (p = 0.03), and were more common in subgenotype 1b (R70Q in 6 of 13 strains) than in 1a (R70P in 1 of 37 strains, p = 0.004). The rs12979860 SNP upstream of the IL28B gene was overall the strongest response predictor (p = 0.0001). Core 70 substitutions were associated with poorer response kinetics in patients carrying the CT genotype at rs12979860. Conclusions: The results indicate that substitutions of core residue 70 are related to treatment response in Caucasian patients with HCV-1b infection, but are of less importance than IL28B polymorphism. Background Hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular cancer affecting approximately 170 million persons worldwide [1]. Combination therapy with pegylated interferon and ribavirin (PegIFN/RBV), given for 24 to 72 weeks, may eradicate the infection and stop progression of liver damage [2-4], but many patients do not achieve sustained virologic response (SVR). For this reason, and in light of high costs and frequent side effects, it is important to identify factors that can predict the likelihood of response. Several host factors such as age, stage of liver fibrosis, body mass index (BMI), liver steatosis, insulin resistance and ethnicity, as well as viral genotype influence the treatment outcome [5]. While the impact on outcome by genotype is undisputed, with 80% of patients with genotype 2 or 3 achieving SVR as compared with 50% for genotype 1, the importance of subtypes [6], regional variability or mutations are controversial. In 1995 it was reported from Japan that mutations in a part of the NS5A region were associated with treatment response in genotype 1b patients. The association between * Correspondence: erik.alestig@gu.se Department of Infection and Virology, University of Gothenburg, Gothenburg, Sweden Full list of author information is available at the end of the article Alestig et al. BMC Infectious Diseases 2011, 11:124 http://www.biomedcentral. com/1471-2334/11/124 © 2011 Alestig et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. mutations in this segment of NS5A, denoted the interferon sensitivity determining region (ISDR) [7] was verified in subsequent Japanese, but not in European studies [8-10]. Several reports have described that Japanese patients carrying HCV strains with a substitution of amino acids 70 (R70Q) and 91 (L91M) respond less well to treatment [11-13], and it was suggested that preand ontreatment analysis of core region polymorphism may be useful for predicting SVR in individual patients [14]. However, the occurrence of core 70 and 91 substitutions has not been corroborated in European strains. In addition to well-known host factors like age and liver fibrosis, it was recently revealed that single nucleotide polymorphisms (SNPs) upstream of the interferon l3-encoding IL28B gene may predict which patients achieve SVR after the completion of peg-IFN/ribavirin therapy [15,16]. This observation may be relevant for investigations of how core variation influences treatment response in different populations of patients with hepatitis C, firstly because the distribution of IL28B SNP genotypes differ between ethnic groups [15,17] and secondly because SNP differences may bias the results. In this study, serum samples were drawn from 50 patients infected with HCV genotype 1a or 1b prior to treatment with peginterferon-alpha2a and ribavirin for sequencing of the core region and part of NS5A (including ISDR). The outcome of treatment was related to the core substitutions as well as to IL28B variation.