title: Geno2pheno[HCV] - A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents.
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.
authors.affiliation: German Center for Infection Research (DZIF)-Saarbrücken Partner Site, Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123, Saarbrücken, Germany.
authors.forename: Prabhav
authors.initials: P
authors.lastname: Kalaghatgi
authors.affiliation: German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany.|German Center for Infection Research (DZIF)-Heidelberg Partner Site, Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120, Heidelberg, Germany.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Sikorski
authors.affiliation: German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Knops
authors.affiliation: German Center for Infection Research (DZIF)-Heidelberg Partner Site, Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rupp
authors.affiliation: German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany.
authors.forename: Saleta
authors.initials: S
authors.lastname: Sierra
authors.affiliation: German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Heger
authors.affiliation: German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Neumann-Fraune
authors.affiliation: German Center for Infection Research (DZIF)-Saarbrücken Partner Site, Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123, Saarbrücken, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Beggel
authors.affiliation: Institute for Virology, University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Walker
authors.affiliation: Institute for Virology, University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Timm
authors.affiliation: MVZ Medizinisches Infektiologiezentrum Berlin (MIB), 13353, Berlin, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Walter
authors.affiliation: MVZ Medizinisches Infektiologiezentrum Berlin (MIB), 13353, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Obermeier
authors.affiliation: German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, Institute of Virology, University of Cologne, 50935, Cologne, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: German Center for Infection Research (DZIF)-Heidelberg Partner Site, Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: German Center for Infection Research (DZIF)-Saarbrücken Partner Site, Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123, Saarbrücken, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
mesh_terms: D000465:Algorithms; D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D024882:Drug Resistance, Viral; D056726:Genetic Association Studies; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D020407:Internet; D009154:Mutation; D009842:Oligopeptides / Q000008:administration & dosage; D010641:Phenotype; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069616:Simeprevir / Q000008:administration & dosage; D012984:Software
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D000069616:Simeprevir