title: Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients.
abstract: OBJECTIVE
  MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of HCC. Miravirsen targets miR-122 and resulted in a dose dependent and prolonged decrease of HCV RNA levels in chronic hepatitis C patients. The aim of this study was to establish the sustained virological response rate to peginterferon (P) and ribavirin (R) following miravirsen dosing and to assess long-term safety in patients treated with miravirsen.
  
  
  METHODS
  In this multicenter, retrospective follow-up study we included 36 treatment naïve patients with chronic hepatitis C genotype 1 who received five weekly subcutaneous injections with miravirsen or placebo over a 29-day period in a phase 2a study. Patients were offered PR therapy 3weeks (3mg/kg group) or 6weeks (5 or 7mg/kg group) after completion of miravirsen or placebo dosing.
  
  
  RESULTS
  PR therapy was started in 14/36 patients of whom 12 had received miravirsen. SVR was achieved in 7/12 patients previously dosed with miravirsen. All patients dosed with 7mg/kg miravirsen who were subsequently treated with PR achieved SVR. One patient had a prolonged undetectable HCV RNA period from week 14 to week 29 after baseline without subsequent antiviral therapy and relapsed thereafter. None of the patients treated with anti-miR-122 developed HCC or other liver-related complications.
  
  
  CONCLUSIONS
  No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Meike H
authors.initials: MH
authors.lastname: van der Ree
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Adriaan J
authors.initials: AJ
authors.lastname: van der Meer
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Bruijne
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Raoel
authors.initials: R
authors.lastname: Maan
authors.affiliation: PRA International, Zuidlaren, The Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: van Vliet
authors.affiliation: J.W. Goethe University Hospital, Frankfurt, Germany.
authors.forename: Tania M
authors.initials: TM
authors.lastname: Welzel
authors.affiliation: J.W. Goethe University Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.affiliation: Fundacion de Investigacion, San Juan, Porto Rico.
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: Department of Internal Medicine, Derer's Hospital, University Hospital Bratislava, Slovakia.
authors.forename: Viera
authors.initials: V
authors.lastname: Kupcova
authors.affiliation: Medical University of Warsaw, Warsaw Hospital for Infectious Diseases, Warsaw, Poland.
authors.forename: Alcija
authors.initials: A
authors.lastname: Wiercinska-Drapalo
authors.affiliation: Santaris Pharma A/S, San Diego, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hodges
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands; Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: h.w.reesink@amc.uva.nl.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C581159:miravirsen
keywords: Anti-miRNA treatment; Hepatitis C virus; MicroRNA’s; miR-122