title: Efficacy of Sofosbuvir and Daclatasvir in Patients With Fibrosing Cholestatic Hepatitis C After Liver Transplantation.
abstract: OBJECTIVE
  Fibrosing cholestatic hepatitis (FCH) is a life-threatening disorder that develops in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation. Until recently, therapeutic options have been limited. We evaluated the efficacy and safety of sofosbuvir- and daclatasvir-based regimens.
  
  
  METHODS
  We analyzed data from 23 patients with FCH who participated in a prospective cohort study in France and Belgium of the effects of antiviral agents in patients with recurrence of HCV infection after liver transplantation, from October 2013 through April 2014. Most of the patients had genotype 1 infections that had not responded to previous treatment; 4 patients also were infected with human immunodeficiency virus. Eight patients (37%) had ascites and 15 patients (65%) had bilirubin levels greater than 100 mmol/L; their median serum level of HCV RNA was 7 log IU/mL. The median time between transplantation and treatment initiation was 5 months. Subjects were given either sofosbuvir and daclatasvir (n = 15) or sofosbuvir and ribavirin (n = 8) for 24 weeks. The primary outcome was complete clinical response (survival without re-transplantation, bilirubin level <34 μmol/L, and no ascites or hepatic encephalopathy 36 weeks after treatment began).
  
  
  RESULTS
  All patients survived, without re-transplantation, until week 36. Rapid and dramatic improvements in clinical status were observed. The patients' median bilirubin concentration decreased from 122 μmol/L at baseline to a normal value at week 12 of treatment. Twenty-two patients (96%) had a complete clinical response at week 36. Despite the low rate of rapid virologic response, 22 patients (96%) achieved a sustained virologic response at week 12. The only relapse of HCV infection occurred in a patient with human immunodeficiency virus infection who received sofosbuvir and ribavirin. Tolerance was satisfactory, with no grade 3 or 4 adverse events related to sofosbuvir or daclatasvir and no significant interactions among drugs.
  
  
  CONCLUSIONS
  Sofosbuvir therapy with daclatasvir or ribavirin leads to major clinical improvement and high rates of sustained virologic response at week 12 in most patients with recurrence of HCV infection and FCH after liver transplantation. ClinicalTrial.gov no: NCT01944527.
authors.affiliation: Clinique Universitaire d'Hépato-Gastroentérologie, Pôle Digidune, Centre Hospitalier Universitaire de Grenoble, Grenoble, France; Unité INSERM/Université Grenoble Alpes U823, Immunologie Analytique des Pathologies Chroniques Institut Albert Bonniot, Grenoble, France. Electronic address: VLeroy@chu-grenoble.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
authors.affiliation: Hôpital Edouard Herriot, Unité de Transplantation Hépatique, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Dumortier
authors.affiliation: Assistance Publique-Hôpitaux de Paris Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, UMR-S 1193, Villejuif, France; Inserm, Unité 1193, Villejuif, France; DHU Hepatinov, Villejuif, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Coilly
authors.affiliation: Assistance Publique-Hôpitaux de Paris Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, UMR-S 1193, Villejuif, France; Inserm, Unité 1193, Villejuif, France; DHU Hepatinov, Villejuif, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Sebagh
authors.affiliation: Unit of Clinical Pharmacology, Rennes University Hospital, Rennes, France; INSERM Clinical Investigation Centre 1414, Rennes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Fougerou-Leurent
authors.affiliation: Hôpital de la Croix Rousse, Service de Transplantation Hépatique et INSERM 1052, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Radenne
authors.affiliation: Centre Hospitalier Universitaire Conception, Service d'Hépato-Gastroentérologie, Marseille, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Botta
authors.affiliation: Département d'Hépatologie, Hôpital Beaujon-Assistance Publique-Hôpitaux de Paris, Clichy, France; Université Paris Diderot et INSERM U1149, Centre de Recherche sur l'Inflammation, Clichy, France.
authors.forename: François
authors.initials: F
authors.lastname: Durand
authors.affiliation: Département d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; EA 4331, Pôle Biologie Santé, Poitiers, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Silvain
authors.affiliation: Departement of d'Hépatologie et de Gastroenterologie, Groupe Hospitalier Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lebray
authors.affiliation: Service des Maladies du Foie, Centre Hospitalier Universitaire Rennes, Rennes, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Houssel-Debry
authors.affiliation: Département de Néphrologie et de Transplantation d'Organes, Centre Hospitalier Universitaire Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1043, IFR-BMT, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.affiliation: Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Trousseau, Tours, France.
authors.forename: Louis
authors.initials: L
authors.lastname: D'Alteroche
authors.affiliation: Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France Recherche Nord and Sud Sida-HIV Hépatites FRENSH), Paris, France.
authors.forename: Ventzislava
authors.initials: V
authors.lastname: Petrov-Sanchez
authors.affiliation: Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France Recherche Nord and Sud Sida-HIV Hépatites FRENSH), Paris, France.
authors.forename: Alpha
authors.initials: A
authors.lastname: Diallo
authors.affiliation: Département d'Hépato-Gastroentérologie et de Transplantation Hépatique, Centre Hospitalier Universitaire Saint-Eloi, Montpellier, France; Université Montpellier 1, Montpellier, France.
authors.forename: Georges-Philippe
authors.initials: GP
authors.lastname: Pageaux
authors.affiliation: Assistance Publique-Hôpitaux de Paris Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, UMR-S 1193, Villejuif, France; Inserm, Unité 1193, Villejuif, France; DHU Hepatinov, Villejuif, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Duclos-Vallee
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001530:Belgium; D002219:Carbamates; D002779:Cholestasis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005602:France; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use; D000069474:Sofosbuvir / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir
keywords: Cirrhosis; DAA; NS5b Polymerase Inhibitor; Re-infection