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      Geno2pheno [HCV] – A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents

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          Abstract

          The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in 2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2pheno [HCV] (g2p [HCV]) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2p [HCV] aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2p [HCV] offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients’ virus variants.

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          Most cited references62

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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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            EASL Recommendations on Treatment of Hepatitis C 2015.

            (2015)
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              Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.

              To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 10(12) virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.
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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
                19 May 2016
                2016
                : 11
                : 5
                : e0155869
                Affiliations
                [1 ]German Center for Infection Research (DZIF)–Saarbrücken Partner Site, Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123, Saarbrücken, Germany
                [2 ]German Center for Infection Research (DZIF)–Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany
                [3 ]German Center for Infection Research (DZIF)–Heidelberg Partner Site, Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120, Heidelberg, Germany
                [4 ]Institute for Virology, University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany
                [5 ]MVZ Medizinisches Infektiologiezentrum Berlin (MIB), 13353, Berlin, Germany
                Centro de Biología Molecular Severo Ochoa (CSIC-UAM), SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PK EK SS TL MNF EH RK. Performed the experiments: PK AMS DR BB RB TL. Analyzed the data: PK EK SS BB AW JT HW MO RB TL. Wrote the paper: PK BB SS.

                Article
                PONE-D-16-06645
                10.1371/journal.pone.0155869
                4873220
                27196673
                be7e5bd4-b7d7-4234-8f34-83afc7313904
                © 2016 Kalaghatgi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 February 2016
                : 5 May 2016
                Page count
                Figures: 3, Tables: 2, Pages: 16
                Funding
                Funded by: DZIF, grant no. 8000 802-3; DZIF-TTU Hepatitis 05.805
                Award Recipient :
                Funded by: HIV-GRADE e.V
                Award Recipient :
                Funded by: Resina HIV-HEP-MASTER (IIA5-2013-2514AUK375)
                Award Recipient :
                Funded by: the MSD-PEPSI Project
                Award Recipient :
                The development of geno2pheno[HCV] is funded by the German Center for Infection Research (DZIF, grant no. 8000 802-3; DZIF-TTU Hepatitis 05.805), HIV-GRADE e.V; Resina HIV-HEP-MASTER (IIA5-2013-2514AUK375); and the MSD-PEPSI Project.
                Categories
                Research Article
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Sequencing Techniques
                Sequence Analysis
                Sequence Alignment
                Research and Analysis Methods
                Molecular Biology Techniques
                Sequencing Techniques
                Sequence Analysis
                Sequence Alignment
                Biology and Life Sciences
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                Microbial Control
                Antimicrobial Resistance
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                Split-Decomposition Method
                Multiple Alignment Calculation
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                Custom metadata
                All relevant data are within the paper and its Supporting Information files. Additional sequence data can be found under the GenBank Accession numbers KP409203-KP409213.

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