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An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C

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      Abstract

      Background

      Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.

      Methods

      HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).

      Results

      Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST∶ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.

      Conclusion

      A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.

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      Most cited references 27

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      Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.

      Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
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        Global epidemiology of hepatitis C virus infection.

        Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.
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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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            Author and article information

            Affiliations
            [1 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America
            [2 ]Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America
            [3 ]Division of Gastroenterology, University of California Irvine, Irvine, California, United States of America
            [4 ]Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, California, United States of America
            [5 ]Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
            [6 ]Gastrointestinal Unit, Medical Services, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
            [7 ]Information Management Services, Silver Spring, Maryland, United States of America
            [8 ]Liver Institute of Virginia, Bon Secours Health System, Newport News, Virginia, United States of America
            [9 ]CSC, Rockville, Maryland, United States of America
            [10 ]Celera Corporation, Alameda, California, United States of America
            [11 ]Departments of Medicine and Molecular & Structural Biology and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, Connecticut, United States of America
            [12 ]Carolinas Medical Center, Charlotte, North Carolina, United States of America
            Karolinska Institutet, Sweden
            Author notes

            Conceived and designed the experiments: TRO JEE TRM RTC JJS HLB RMP. Performed the experiments: JEE TRM ASL RTC MLS JJE HLB. Analyzed the data: TRO JEE TRM ASL RTC YS MLS MD JJS HLB RMP. Wrote the paper: TRO JEE TRM ASL RTC MLS MD JJS HLB RMP.

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2011
            8 July 2011
            : 6
            : 7
            3132753
            21760886
            PONE-D-11-01963
            10.1371/journal.pone.0020904
            (Editor)
            This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
            Counts
            Pages: 9
            Categories
            Research Article
            Medicine
            Clinical Genetics
            Personalized Medicine
            Gastroenterology and Hepatology
            Liver Diseases
            Infectious Hepatitis
            Hepatitis C
            Infectious Diseases
            Viral Diseases
            Hepatitis
            Hepatitis C

            Uncategorized

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