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      Vitamin D Status and Virologic Response to HCV Therapy in the HALT-C and VIRAHEP-C Trials

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          Abstract

          More than 150 million people worldwide are chronically infected with hepatitis C virus (HCV) and face higher risk of cirrhosis and hepatocellular carcinoma. Highly effective HCV treatments have recently been developed; however, they are costly and therefore poorly suited for application in resource-limited settings where HCV burden is high. Pegylated-interferon alpha (PEG-IFNα) and ribavirin (RBV) therapy is far less costly, but also less effective. Vitamin D supplementation has been proposed as an inexpensive adjuvant to treatment, however, prior epidemiological evidence on its effectiveness is inconsistent, with little data available among African Americans who naturally have lower vitamin D concentrations. We thus evaluated associations between baseline vitamin D status, measured by circulating 25-hydroxyvitamin D (25(OH)D), which is considered to be the best marker of vitamin D status in humans, and subsequent response to PEG-IFNα/RBV therapy in two large clinical trials that together included 1292 patients infected with HCV genotype 1. We used race-stratified logistic regression models to evaluate multivariable-adjusted associations of 25(OH)D with early virologic response (EVR; 2-log 10 HCV RNA decline at week 12) and sustained virologic response (SVR). Among African Americans, we saw no associations. Among European Americans, we saw no association with low vitamin D (≤20 ng/mL) versus sufficient concentrations (20-<30 ng/mL). However, patients with 25(OH)D ≥30 ng/mL were actually less likely to attain EVR (OR = 0.64, 95% CI = 0.43–0.94) than those with sufficient concentrations, with a similar but non-significant association observed for SVR (OR = 0.49, 95% CI = 0.20–1.17).

          Conclusion

          Higher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV.

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          Most cited references34

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          Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence.

          In efforts to inform public health decision makers, the Global Burden of Diseases, Injuries, and Risk Factors 2010 (GBD2010) Study aims to estimate the burden of disease using available parameters. This study was conducted to collect and analyze available prevalence data to be used for estimating the hepatitis C virus (HCV) burden of disease. In this systematic review, antibody to HCV (anti-HCV) seroprevalence data from 232 articles were pooled to estimate age-specific seroprevalence curves in 1990 and 2005, and to produce age-standardized prevalence estimates for each of 21 GBD regions using a model-based meta-analysis. This review finds that globally the prevalence and number of people with anti-HCV has increased from 2.3% (95% uncertainty interval [UI]: 2.1%-2.5%) to 2.8% (95% UI: 2.6%-3.1%) and >122 million to >185 million between 1990 and 2005. Central and East Asia and North Africa/Middle East are estimated to have high prevalence (>3.5%); South and Southeast Asia, sub-Saharan Africa, Andean, Central, and Southern Latin America, Caribbean, Oceania, Australasia, and Central, Eastern, and Western Europe have moderate prevalence (1.5%-3.5%); whereas Asia Pacific, Tropical Latin America, and North America have low prevalence (<1.5%). The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to secondary and tertiary prevention to reduce the burden of chronic liver disease and to improve survival for those who already have evidence of liver disease. Copyright © 2012 American Association for the Study of Liver Diseases.
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            Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

            A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.
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              A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.

              Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 November 2016
                2016
                : 11
                : 11
                : e0166036
                Affiliations
                [1 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
                [2 ]Department of Medicine, Howard University College of Medicine, Washington, DC, United States of America
                [3 ]Heartland Assays, Ames, IA, United States of America
                [4 ]VA Long Beach Healthcare System, Long Beach, CA, United States of America
                Taipei Veterans General Hospital, TAIWAN
                Author notes

                Competing Interests: The affiliation of RH with Heartland Assays does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: EL TRO NDF.

                • Formal analysis: EL RMP.

                • Funding acquisition: NDF.

                • Investigation: CDH RH TRM.

                • Methodology: EL TRO RMP NDF.

                • Project administration: EL NDF.

                • Resources: CDH RH TRM.

                • Software: EL RMP.

                • Supervision: TRO NDF.

                • Visualization: EL.

                • Writing – original draft: EL TRO RMP LPO SJW DA NDF.

                • Writing – review & editing: EL TRO RMP CDH RH LPO SJW DA TRM NDF.

                Article
                PONE-D-16-15163
                10.1371/journal.pone.0166036
                5104464
                27832143
                3d7686d3-b74e-40fa-b21f-4b3a8e2b8071

                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.

                History
                : 14 April 2016
                : 11 October 2016
                Page count
                Figures: 2, Tables: 5, Pages: 17
                Funding
                Funded by: Intramural Research Program of the National Institutes of Health
                Award Recipient :
                This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. Heartland Assays provided support in the form of salaries for author [RH], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Physical sciences
                Chemistry
                Chemical compounds
                Organic compounds
                Vitamins
                Vitamin D
                Physical sciences
                Chemistry
                Organic chemistry
                Organic compounds
                Vitamins
                Vitamin D
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
                Viral pathogens
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis C virus
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis C virus
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Hepatitis viruses
                Hepatitis C virus
                People and places
                Population groupings
                Ethnicities
                African Americans
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Cirrhosis
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Custom metadata
                Due to legal restrictions, data are made available upon request from the NIDDK Central Repository for the HALT-C Study and the VIRAHEP-C Study. Researchers can access the Data Request Form at: https://www.niddkrepository.org/wayf/?next=/requests/data-request/. To contact the NIDDK Central Repository please visit https://www.niddkrepository.org/contact/ or e-mail niddk-cr@ 123456imsweb.com .

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