title: Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy.
abstract: OBJECTIVE
  Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort.
  
  
  METHODS
  We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results.
  
  
  RESULTS
  We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication.
  
  
  CONCLUSIONS
  These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection.
authors.affiliation: Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.|INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sultanik
authors.affiliation: Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.|INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mallet
authors.affiliation: INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lagaye
authors.affiliation: The laboratory of Dendritic Cell Biology, Departement of Immunology, Institut Pasteur, INSERM U818, Paris, France.
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.affiliation: UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Dorival
authors.affiliation: UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Barthe
authors.affiliation: Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.|INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Fontaine
authors.affiliation: Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: Centre for Human Immunology, Departement of Immunology, Institut Pasteur, INSERM S20, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Mottez
authors.affiliation: Centre Hospitalier Universitaire de Nancy, Université de Lorraine, INSERM U954, Vandoeuvre-les-Nancy, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France.|Department of Public Health, Hôpital Saint-Antoine, AP-HP, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Carrat
authors.affiliation: Laboratory of Immunity and Infection, Groupe Hospitalier Pitié-Salpêtrière AP-HP, INSERM UMR-S 945, UPMC Université Paris 6, Paris, France.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Theodorou
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker branch, INSERM U1163, Paris, France.|University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.|Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New-York, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Department of Anesthesiology and Critical Care Medicine - Mobile Care Unit, Hôpital Lariboisière, AP-HP, Paris, France.|Biomarkers and cardiac diseases, Hôpital Lariboisière, INSERM U942, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Gayat
authors.affiliation: Departement of Epidemiology of Infectious Disease, Institut Pasteur, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Fontanet
authors.affiliation: Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.|INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: The laboratory of Dendritic Cell Biology, Departement of Immunology, Institut Pasteur, INSERM U818, Paris, France.|Centre for Human Immunology, Departement of Immunology, Institut Pasteur, INSERM S20, Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D005602:France; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D012372:ROC Curve; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D053482:beta 2-Glycoprotein I / Q000097:blood*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D016898:Interferon-alpha; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; D053482:beta 2-Glycoprotein I; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; 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; C100416:peginterferon alfa-2a
keywords: HCV protease inhibitor; apolipoprotein H; biomarker; chronic hepatitis C; virological response