title: Flares during long-term entecavir therapy in chronic hepatitis B.
abstract: OBJECTIVE
  The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB).
  
  
  METHODS
  CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as > 3× increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT > 3× ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA).
  
  
  RESULTS
  Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg (n = 3) and hepatitis B surface antigen (n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance (n = 2) and non-compliance (n = 1).
  
  
  CONCLUSIONS
  The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Heng
authors.initials: H
authors.lastname: Chi
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Pauline
authors.initials: P
authors.lastname: Arends
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jurriën G P
authors.initials: JG
authors.lastname: Reijnders
authors.affiliation: Department of Hepatology and Gastroenterology, King's College London, London, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Carey
authors.affiliation: Department of Hepatology and Gastroenterology, Imperial College London, London, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Brown
authors.affiliation: Clinic of Infectious Diseases, University of Foggia, Foggia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Fasano
authors.affiliation: Centre for Liver Research, NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mutimer
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Deterding
authors.affiliation: Centre for Liver Research, NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Ye H
authors.initials: YH
authors.lastname: Oo
authors.affiliation: Ifi Institute, Asklepios Klinik St. Georg, Hamburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Department of Hepatology, University Clinic Leipzig, Leipzig, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: van Bommel
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.affiliation: Clinic of Infectious Diseases, University of Foggia, Foggia, Italy.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Santantonio
authors.affiliation: Department of Hepatology, University Clinic Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Medizinische Klinik 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
authors.forename: Tania M
authors.initials: TM
authors.lastname: Welzel
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.affiliation: Department of Hepatology, Hospital Vall de Hebron, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Department of Hepatology, Hospices Civils de Lyon, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Pradat
authors.affiliation: Department of Hepatology, Hospices Civils de Lyon, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.|Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D004279:DNA, Viral / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; C413685:entecavir; D006147:Guanine; D000410:Alanine Transaminase
keywords: ALT; chronic hepatitis B; entecavir; flare; nucleos(t)ide analogue