title: Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.
abstract: OBJECTIVE
  Therapeutic duration of nucleos(t)ide analogues for chronic hepatitis B (CHB) is not indefinite in many parts of the world. Viral reactivation is common off therapy, but the risk of subsequent clinical outcome remains unclear and unpredictable. We aimed to quantify the incidence of and explore the predictors for clinical flare following virological relapse in CHB patients who discontinue entecavir therapy.
  
  
  METHODS
  This multicenter cohort study prospectively monitored 133 CHB patients who were HBeAg-negative and viral DNA-undetectable when discontinuing entecavir after at least 3 years on therapy. Following virological relapse (viral DNA >2,000 IU/mL) that occurred in 92 patients, the incidences of subsequent clinical flare and persistent (unremittent for 3 months) or severe hepatitis (with jaundice or coagulopathy) were determined, and risk factors were explored. Patients did not resume antiviral therapy until occurrence of persistent or severe hepatitis.
  
  
  RESULTS
  The cumulative incidence of clinical hepatitis 2 years after virological relapse was 61.0% (95% confidence interval [CI], 49.9-72.3%) and that of persistent or severe hepatitis was 53.0% (95% CI, 40.9-66.2%). Serum viral load at the virological relapse was associated with both clinical hepatitis (adjusted hazard ratio [HR], 1.31 per log IU/mL; 95% CI, 1.07-1.60) and persistent or severe hepatitis (adjusted HR, 1.63 per log IU/mL; 95% CI, 1.27-2.10), after adjustment for serum aminotransferase and alfa-fetoprotein levels in the multivariate analysis. Viral DNA >100 000 IU/mL predicted a nearly inevitable occurrence of clinical flare (P < 0.0001).
  
  
  CONCLUSIONS
  A high viral load at the virological relapse predicts subsequent clinical hepatitis in CHB patients who discontinue entecavir.
authors.affiliation: Center for Database Research, E-Da Hospital, Kaohsiung, Taiwan.|Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.|School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Yao-Chun
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Superintendent Office, Tainan Municipal Hospital, Tainan, Taiwan.
authors.forename: Lein-Ray
authors.initials: LR
authors.lastname: Mo
authors.affiliation: Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Chi-Yang
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Shiang
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology, Lotung Poh-Ai Hospital, Ilan, Taiwan.
authors.forename: Tzeng-Huey
authors.initials: TH
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chieh-Chang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Tai
authors.affiliation: Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.|Big Data Research Center, Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Jaw-Town
authors.initials: JT
authors.lastname: Lin
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D005544:Forecasting; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006515:Hepatitis B virus / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D011446:Prospective Studies; D012008:Recurrence; D000067251:Symptom Flare Up; D019562:Viral Load; D014775:Virus Activation; D028761:Withholding Treatment
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; C413685:entecavir; D006147:Guanine
keywords: chronic hepatitis B; hepatitis B viral DNA; nucleos(t)ide analogues; off-therapy relapse; outcome research