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      Pretreatment prediction of the outcome of response-guided peginterferon-α and ribavirin therapy for chronic hepatitis C

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          Abstract

          Background and Aim

          The accuracy for predicting virological outcomes of peginterferon-α and ribavirin therapy in patients with chronic hepatitis C is limited to approximately 80%, even with IL28B genotyping. Our in vitro study revealed that the numbers of (TA) dinucleotide repeats [(TA)n] of rs72258881, which is located in the promoter region of IL28B gene, might regulate IL28B transcription. We aimed to evaluate the usefulness of these host factors for predicting virological outcomes of this therapy in response-guided clinical settings.

          Methods

          A nationwide, multi-center prospective study in Japan determined IL28B (rs8099917) genotype, (TA)n of rs72258881, and amino acid substitutions of hepatitis C virus and used these for multivariate analysis together with other parameters at pretreatment.

          Results

          After enrolling 215 patients with genotype 1 and high viral load from 23 hospitals between October 2009 and February 2011, intent-to-treat analysis identified 202 patients in whom the final virological outcomes could be determined. Non-virological response by non-TT genotype was predicted with 79.7% accuracy. When combined with the (TA)n, the incidences of virological response tended to be higher in the longer (TA)n group, regardless of rs8099917 genotype. Multivariate logistic regression analysis revealed that rs8099917 non-TT genotype ( P < 0.001), shorter (TA)n ( P = 0.011), mutation of amino acid 70 in the virus core region ( P = 0.029), and lower levels of serum albumin ( P = 0.036) were independently associated with non-virological response.

          Conclusions

          IL28B genotype and (TA)n of rs72258881 may independently affect virological outcomes of peginterferon-α and ribavirin as host factors, even in response-guided therapy.

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          Most cited references27

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          Diagnosis, management, and treatment of hepatitis C: an update.

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            Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.

            The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).
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              Boceprevir for untreated chronic HCV genotype 1 infection.

              Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).
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                Author and article information

                Journal
                J Gastroenterol Hepatol
                J. Gastroenterol. Hepatol
                jgh
                Journal of Gastroenterology and Hepatology
                BlackWell Publishing Ltd (Oxford, UK )
                0815-9319
                1440-1746
                December 2014
                18 November 2014
                : 29
                : 12
                : 1996-2005
                Affiliations
                [* ]The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine Chiba, Japan
                []Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital Chiba, Japan
                []Department of Virology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
                [§ ]Department of Gastroenterology, NHO Kyushu Medical Center Fukuoka, Japan
                []Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital Tokyo, Japan
                [** ]Department of Gastroenterology, Juntendo University Tokyo, Japan
                [†† ]Institute of Clinical Medicine and Research, The Jikei University School of Medicine Chiba, Japan
                [‡‡ ]Department of Gastroenterology, Akita City Hospital Akita, Japan
                [§§ ]Department of Gastroenterology, Kagawa Medical University School of Medicine Kagawa, Japan
                [¶¶ ]First Department of Medicine, Yamanashi University School of Medicine Yamanashi, Japan
                [*** ]Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine Aichi, Japan
                [††† ]Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo Tokyo, Japan
                Author notes
                Correspondence, Naohiko Masaki, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan. Email: nmasaki@ 123456hospk.ncgm.go.jp

                Potential conflict of interests: Nothing to declare.

                Financial support: This study was supported by the Grant-in-Aid from the National Center for Global Health and Medicine (21A113) (N.M.). The funding source had no involvement, such as the roles of the study design, the collection, analysis, interpretation of the data, the writing of this manuscript or the decision to submit this manuscript for publication.

                Article
                10.1111/jgh.12646
                4263356
                24910341
                d789cee2-1e07-4557-8f0d-370d5e6d69ae
                © 2014 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 03 May 2014
                Categories
                Clinical Hepatology

                Gastroenterology & Hepatology
                (ta) dinucleotide repeat,chronic hepatitis c,il28b,response-guided therapy

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