title: Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes.
abstract: First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Spindelboeck
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Horvath
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Tawdrous
authors.affiliation: Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria.
authors.forename: Bianca
authors.initials: B
authors.lastname: Schmerböck
authors.affiliation: Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zettel
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Posch
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Streit
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Jurse
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lemesch
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Horn
authors.affiliation: Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
authors.forename: Gerit
authors.initials: G
authors.lastname: Wuensch
authors.affiliation: Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Stiegler
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Rudolf E
authors.initials: RE
authors.lastname: Stauber
authors.affiliation: Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Leber
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stadlbauer
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D012254:Ribavirin; 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; D019272:Leukocyte Elastase