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Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis

  • Cheng-Hao Tseng
    Affiliations
    Division of Gastroenterology and Hepatology, E-DA Cancer Hospital, Kaohsiung, Taiwan

    Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan

    School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
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  • Tzu-Haw Chen
    Affiliations
    Division of Gastroenterology and Hepatology, E-DA Cancer Hospital, Kaohsiung, Taiwan

    Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan

    School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
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  • Jia-Ling Wu
    Affiliations
    Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Teng-Yu Lee
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

    School of Medicine, Chung Shan Medical University, Taichung, Taiwan
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  • John A. Borghi
    Affiliations
    Lane Medical Library & Knowledge Management Center, Stanford University, Palo Alto, CA, USA
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  • Jaw-Town Lin
    Affiliations
    Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan
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  • Mindie H. Nguyen
    Correspondence
    Corresponding author. Mindie H. Nguyen, Division of Gastroenterology and Hepatology Stanford University Medical Center; 750 Welch Road, Suite 210 
Palo Alto, CA 94304; ; TEL: (650) 498-6084; Fax: (650) 498-5692
    Affiliations
    Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA

    Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA
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  • Yao-Chun Hsu
    Correspondence
    Corresponding author. Yao-Chun Hsu, Center for Liver Diseases, E-DA Hospital, I-Shou University; No.1, Yida Rd., Yanchao District, Kaohsiung 82445, Taiwan; ; TEL: +886-7-6150011
    Affiliations
    Division of Gastroenterology and Hepatology, E-DA Cancer Hospital, Kaohsiung, Taiwan

    Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan

    School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan

    Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Division of Gastroenterology, Fu-Jen Catholic University Hospital/Fu-Jen Catholic University, New Taipei, Taiwan
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Open AccessPublished:October 27, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100617

      Highlights

      • Current literature on the safety of stopping nucleos(t)ide analogs in HBV infection is limited with important caveats.
      • Serious safety events were not often reported in small studies with short follow-up and/or unclear outcome definition.
      • Severe withdrawal flares or hepatic decompensation occurred in about 1% of overall nucleos(t)ide analog stoppers.
      • Approximately 0.3-0.4% of patients would require liver transplantation or die after stopping nucleos(t)ide analogs.
      • Patients with cirrhosis were significantly more vulnerable to serious adverse events following treatment withdrawal.

      Abstract

      Background & Aims

      The risk of serious clinical outcomes following cessation of nucleos(t)ide analogue (Nuc) in patients with chronic hepatitis B remains poorly characterized. This systematic review and meta-analysis aimed to evaluate current literature on this issue.

      Methods

      We searched PubMed, Embase, and Web of Science for Nuc stop studies that noted clinical outcomes published between January 1, 2006 and August 18, 2022. We performed meta-research analyses to examine the relationships of reported outcomes with study designs and characteristics and also pooled studies with non-overlapping populations to provide risk estimates for the proportions of (1) severe hepatitis flares or hepatic decompensation or (2) hepatitis flare-related death or liver transplantation.

      Results

      The meta-research analysis included 50 studies of highly heterogeneous designs and characteristics. We found that reporting of safety outcomes varied widely according to outcome definition, follow-up duration, and sample size. Only ten studies prespecified safety events as the study outcome, and only four had an outcome definition to include hepatic insufficiency, a follow-up duration >12 months, and a sample size >100 patients. We further pooled 15 studies with 4525 individual patients and estimated the proportion of severe hepatitis flares or decompensation at 1.21% (95% confidence interval [CI], 0.70–2.08%), with significant heterogeneity (I2 = 54%, p < 0.01), while that of hepatitis flare-related death or liver transplantation was 0.37% (95% CI, 0.20–0.67%), without significant heterogeneity (I2 = 0.00%, p = 1.00).

      Conclusions

      Current literature on the risk of serious clinical outcomes following Nuc cessation is very limited and highly heterogeneous. Pooled analyses of available data found approximately 1% of patients who stopped Nuc developed severe flares or hepatic decompensation.

      Lay summary

      Current literature for the safety concerns surrounding Nuc cessation for patients with chronic hepatitis B is limited and heterogeneous in designs and characteristics, and thus should be interpreted with great caution. Based on currently available data, the proportion of patients to develop severe hepatitis flares or hepatic decompensation was estimated at 1.21% and that of flare-related death or liver transplantation at 0.37%.

      Graphical abstract

      Keywords

      Abbreviations:

      ALT (alanine transaminase), APASL (Asian Pacific Association for the Study of the Liver), CHB (chronic hepatitis B), DNA (deoxyribonucleic acid), EASL (European Association for the Study of the Liver), ETV (entecavir), HBeAg (hepatitis B e-antigen), HBsAg (hepatitis B surface antigen), HBV (Hepatitis B virus), HCC (hepatocellular carcinoma), INR (nternational normalized ratio), Nuc (Nucleos(t)ide Analogues), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), PT (prothrombin time), TDF (tenofovir disoproxil fumarate), ULN (upper limit of normal)

      Introduction

      Hepatitis B virus (HBV) infection remains a global health problem, with 296 million infected people worldwide.

      World Health Organization. Hepatitis B. [Internet] [cited; Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b.

      Chronic hepatitis B (CHB) is the leading cause of hepatocellular carcinoma (HCC) and liver-related mortality,
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      Meanwhile, long-term or indefinite duration of treatment can be costly or unaffordable, leading to efforts to define strategies for more finite Nuc therapy. Additionally, recent data also suggested a higher HBsAg seroclearance rate after Nuc cessation comparing to continuous Nuc treatment.
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      Nevertheless, Nuc cessation may lead to serious clinical events such as severe hepatitis flares that may progress to liver failure and possibly death.
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      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      Risk estimation for serious clinical outcomes following Nuc cessation has been difficult because most of the events were reported as sporadic cases
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      , based on which quantitative analysis was challenging
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      . In order to fill in the knowledge gap, a critical appraisal of existent literature is necessary and a pooled analysis based on all available data is indispensable. Therefore, we conducted this systematic review and meta-analysis to appraise published studies that reported safety outcomes of Nuc cessation and then estimated the proportions of patients who developed serious clinical events including severe hepatitis flares, hepatic decompensation, liver-related mortality, and liver transplantation. In this analysis, we focused on Nuc cessation following entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy because older generations of Nucs are no longer in routine clinical use.
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      Methods

      Search Strategy and Study Selection

      This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Supplementary Table 1).
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      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      We searched PubMed, Embase, and Web of Science without language restriction for relevant full-text studies published between January 1, 2006, and August 18, 2022. The search strategy was developed in collaboration with a medical librarian (JAB) and involved the use of keywords related to CHB, Nuc cessation, withdrawal, stoppage, and discontinuation (details in Supplementary Table 2). Two authors (CHT and THC) independently screened the literature and extracted data using a case report form developed for this study. Discrepancies were resolved via consensus and/or discussion with two senior investigators (MHN and YCH).
      Eligible studies are full-length articles that reported virological, biochemical, and/or clinical outcomes of adult CHB patients (≥18 years) who received Nucs for at least 1 year before cessation. Studies were excluded if the sample size was <30 patients, if patients had viral coinfection (e.g., with hepatitis C virus, hepatitis D virus, or human immunodeficiency virus), if they included unique populations (e.g., patients who received organ transplants or had end-stage renal disease or rheumatic diseases), if they included patients who had achieved HBsAg seroclearance during the antiviral therapy, if patients receiving treatments with experimental drugs or interferon were included, if patients tested positive for hepatitis B e-antigen (HBeAg) at the time of treatment cessation were included, or if less than 50% of the study population received ETV or TDF.

      Data Extraction

      Study data, including baseline age, gender, pretreatment HBeAg status, the proportion of patients with cirrhosis, the types of Nuc used, treatment duration, consolidation duration, end-of-treatment HBsAg levels, follow-up duration, and criteria for Nuc cessation and retreatment, were extracted into a spreadsheet. The safety outcomes of interest included (1) severe hepatitis flares or hepatic decompensation as stated by each study, and (2) hepatitis flare-related death or liver transplantation.
      We first conducted a meta-research analysis to characterize included all articles and evaluate the relationships between study characteristics and outcomes.
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      Then we pooled aggregate data from selected studies without overlapping populations for risk estimation. The criteria for studies to be selected into data pooling were (1) studies without overlapping populations (for studies with substantial overlapping populations, we selected the one that was largest in sample size or most comprehensive in information), (2) studies not exclusively composed of special populations such as those with low HBsAg levels or prior severe acute exacerbation, and (3) studies with a mean or median follow-up duration longer than 12 months. A minimum duration of follow-up was necessary for pooling the event data because most studies reported occurrence of serious clinical events in proportions instead of in incidences. A time frame of 12 months was appropriate in that most flare-related clinical events occurred within 1–2 years after Nuc cessation
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      ,
      • Hirode G.
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      • Seto W.K.
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      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      ,
      • Liu Y.C.
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      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      .

      Statistical Analysis

      A random-effects model and the inverse variance method were adopted to pool the reported proportions of (1) severe hepatitis flares or hepatic decompensation as respectively defined in each study, and (2) hepatitis flare-related death or liver transplantation. Studies that reported zero outcomes were adjusted for in the analysis through continuity correction.
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      We evaluated between-study heterogeneity by using I2 statistics. Comparison between the studies with and those without exclusion of patients with cirrhosis is carried out using the Wald test. All tests are two-sided, and statistical significance was defined as a p value <0.05. Egger’s funnel plot was used to assess publication bias. All statistical analysis was performed using R (version 4.1.3).

      Risk-of-Bias Assessment

      Each study’s risk of bias was assessed with the modified Newcastle–Ottawa scale (NOS), which classified the quality of reporting safety issues as high (7–9 points), fair (4–6 points), or low (<4 points) (Supplementary Table 3).

      GA Wells BS, D O'Connell, J Peterson, V Welch, M Losos, P Tugwell. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [cited 2020 March 1]; Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

      Results

      We identified 6297 articles through the initial electronic database search (Supplementary Table 2). After removing duplicates and reviewing the titles and abstracts, we retrieved 160 potentially relevant articles for full-text evaluation. Ultimately, we identified 50 eligible studies which reported the events of severe hepatitis flares, hepatic decompensation, hepatitis flare-related death, or liver transplantation (Figure 1).
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      The Incidence of Hepatitis B Surface Antigen Loss Between Hepatitis B E Antigen-Negative Noncirrhotic Patients Who Discontinued or Continued Entecavir Therapy.
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      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      • Seto W.K.
      • Hui A.J.
      • Wong V.W.
      • Wong G.L.
      • Liu K.S.
      • Lai C.L.
      • et al.
      Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
      • Su T.H.
      • Yang H.C.
      • Tseng T.C.
      • Liou J.M.
      • Liu C.H.
      • Chen C.L.
      • et al.
      Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
      • Tseng T.N.
      • Hu T.H.
      • Wang J.H.
      • Kuo Y.H.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL.
      • Yao C.C.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • Wang J.H.
      • Lee C.M.
      • et al.
      Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL.
      • Chen Y.C.
      • Peng C.Y.
      • Jeng W.J.
      • Chien R.N.
      • Liaw Y.F.
      Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis.
      • Fong T.L.
      • Tien A.
      • Jo K.J.
      • Chu D.
      • Cheung E.
      • Mena E.A.
      • et al.
      Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.
      • Jeng W.J.
      • Sheen I.S.
      • Chen Y.C.
      • Hsu C.W.
      • Chien R.N.
      • Chu C.M.
      • et al.
      Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      • Liao G.
      • Ding X.
      • Xia M.
      • Wu Y.
      • Chen H.
      • Fan R.
      • et al.
      Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B.
      • Lin C.C.
      • Bair M.J.
      • Chen C.J.
      • Lee K.H.
      • Chen M.J.
      • Liu C.Y.
      • et al.
      Off-treatment efficacy of 3-year nucleos(t)ide analogues in chronic hepatitis B patients.
      • Manolakopoulos S.
      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      • Papatheodoridi M.
      • Su T.H.
      • Hadziyannis E.
      • Liao C.H.
      • Orfanidou Α.
      • Yang H.C.
      • et al.
      Hepatocellular carcinoma after treatment cessation in non-cirrhotic HBeAg-negative chronic hepatitis B: A multicentre cohort study.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Su T.H.
      • Siakavellas S.
      • Liu C.J.
      • Kourikou A.
      • et al.
      Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      • Sonneveld M.J.
      • Park J.Y.
      • Kaewdech A.
      • Seto W.K.
      • Tanaka Y.
      • Carey I.
      • et al.
      Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      • Wang C.H.
      • Chang K.K.
      • Lin R.C.
      • Kuo M.J.
      • Yang C.C.
      • Tseng Y.T.
      Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study.
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      • Xie Y.
      • Li M.
      • Ou X.
      • Zheng S.
      • Gao Y.
      • Xu X.
      • et al.
      HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation.
      • Broquetas T.
      • Hernandez J.J.
      • Garcia-Retortillo M.
      • Canillas L.
      • Puigvehí M.
      • Cañete N.
      • et al.
      On-therapy HBsAg kinetics can predict HBsAg loss after nucleos(t)ide analogues interruption in HBeAg-negative patients. The cup is half full and half empty.
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      • Chen C.H.
      • Peng C.Y.
      • Kuo Y.H.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • et al.
      Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen-Positive Patients.
      • Peng C.W.
      • Jeng W.J.
      • Yang H.I.
      • Liu Y.C.
      • Chien R.N.
      • Liaw Y.F.
      A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study.
      • Papatheodoridi M.
      • Papachristou E.
      • Moschidis Z.
      • Hadziyannis E.
      • Rigopoulou E.
      • Zachou K.
      • et al.
      Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy.
      One of the studies involved two distinct cohorts, of which one consisted exclusively of patients with prior severe acute exacerbation and the other consisted of patients who had never experienced such an event.
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      Therefore, 50 studies with 51 cohorts were included in the meta-research analysis. Results of the risk-of-bias assessment of the included studies were listed in Supplementary Table 4.
      Figure thumbnail gr1
      Figure 1Flow Chart of Study Selection
      The first part of analysis (part 1) is to characterize all the included articles and evaluate the relationships between study designs/characteristics and outcomes in a meta-research approach. The second part (part 2) is to pool data from selected studies without overlapping populations for risk estimation.
      a: criteria of study selection for pooling aggregate data: (1) no overlapping populations, (2) a mean or median follow-up duration >12 months, (3) not for special populations such as studies exclusively composed of patients with prior severe acute exacerbation or low serum HBsAg level.
      CHB: chronic hepatitis B, ETV: entecavir, HBsAg: hepatitis B surface antigen, TDF: tenofovir disoproxil fumarate.
      Data were pooled to generate risk estimates from 15 selected studies with 4525 patients overall.
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      ,
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
      • Tse Y.K.
      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      ,
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      ,
      • Ma T.L.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Chen C.H.
      Incidence and predictors of retreatment in chronic hepatitis B patients after discontinuation of entecavir or tenofovir treatment.
      ,
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      ,
      • Su T.H.
      • Yang H.C.
      • Tseng T.C.
      • Liou J.M.
      • Liu C.H.
      • Chen C.L.
      • et al.
      Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
      ,
      • Fong T.L.
      • Tien A.
      • Jo K.J.
      • Chu D.
      • Cheung E.
      • Mena E.A.
      • et al.
      Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.
      ,
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      ,
      • Manolakopoulos S.
      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      ,
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      ,
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      ,
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      ,
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      The analysis was further stratified by cirrhosis status: the non-cirrhotic subgroup analysis from 14 studies with 3731 patients,
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      ,
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
      • Tse Y.K.
      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      ,
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      ,
      • Ma T.L.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Chen C.H.
      Incidence and predictors of retreatment in chronic hepatitis B patients after discontinuation of entecavir or tenofovir treatment.
      ,
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      ,
      • Su T.H.
      • Yang H.C.
      • Tseng T.C.
      • Liou J.M.
      • Liu C.H.
      • Chen C.L.
      • et al.
      Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
      ,
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      ,
      • Manolakopoulos S.
      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      ,
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      ,
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      ,
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      ,
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      and the cirrhotic subgroup analysis from 5 studies with 744 patients.
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      ,
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
      • Tse Y.K.
      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      ,
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      The funnel plot did not detect a significant publication bias among the 15 studies (Supplementary Fig. 1).

      Meta-research Analysis

      Study Characteristics

      Major characteristics of the included studies were summarized in Table 1 and additional details were provided in Supplementary Tables 5–7. The vast majority (74.00%) of these studies were conducted in Asia, while two large international studies included cohorts from both Asia and Western countries with enrolled patients overlapped considerably in other published studies.
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      ,
      • Sonneveld M.J.
      • Park J.Y.
      • Kaewdech A.
      • Seto W.K.
      • Tanaka Y.
      • Carey I.
      • et al.
      Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).
      Table 1Characteristics of the 50 Studies Reporting the Safety Outcomes.
      Number of study (%)
      Safety outcomes as the prespecified events:
      Yes10 (20%)
      No40 (80%)
      Country:
      Asia37 (74.00%)
      Western countries8 (16.00%)
      Mixed Asia and the west5 (10.00%)
      Study design:
      Clinical cohort study -Prospective
      prospective in combination with retrospective study was classified as prospective study,
      35 (70.00%)
      Clinical cohort study -Retrospective13 (26.00%)
      Electronic health record study2 (4%)
      Criteria to define severe hepatitis flares or decompensation
      from 46 studies reporting the events of severe hepatitis flares or decompensation,
      Hyperbilirubinemia + coagulopathy, or clinical symptoms12 (26.09%)
      Hyperbilirubinemia or coagulopathy20 (43.48%)
      No clear definition14 (30.43%)
      Principle of stopping Nuc:
      International guideline / Local regulation / Others / No mention35 (70.00%) / 9 (18.00%) / 5 (10.00%) / 1 (2.00%)
      Principle of resuming Nuc:
      VR / CR / CR with a withholding period / Others / No mention4 (8.00%) / 6 (12.00%) / 29 (58.00%) / 2 (4.00%) / 9 (18.00%)
      Cirrhosis status
      Pure non-cirrhosis / Mixed / Pure cirrhosis / No mention32 (62%) / 16 (32%) / 1 (2%) / 1 (2%)
      Patient number:
      >501 / 500-101 / ≤ 1009 (18%) / 28 (56%) / 13 (26%)
      Follow-up duration (month)
      mean or median,
      ,
      from 49 studies with available follow-up duration.
      :
      ≥24 / between 12-24 / ≤1224 (48.98%) / 14 (28.57%) / 11 (22.45%)
      Pretreatment HBeAg status:
      Only HBeAg(-) / Mixed with HBeAg(+) and (-) / Only HBeAg(+)23 (46.00%) / 21 (42.00%) / 6 (12.00%)
      Studies focusing on special patient populations:
      • Lower HBsAg (<100 or 200 log IU/mL)
      3 (6.00%)
      • Seto W.K.
      • Liu K.S.
      • Mak L.Y.
      • Cloherty G.
      • Wong D.K.
      • Gersch J.
      • et al.
      Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.
      ,
      • Tseng T.N.
      • Hu T.H.
      • Wang J.H.
      • Kuo Y.H.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL.
      ,
      • Yao C.C.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • Wang J.H.
      • Lee C.M.
      • et al.
      Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL.
      • Prior severe acute exacerbation
      1 (2.00%)
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      CR: clinical relapse, EHR: electronic health record, HBeAg: hepatitis B e-antigen, Nuc: nucleos(t)ide analogue, VR: virological relapse.
      a prospective in combination with retrospective study was classified as prospective study,
      b from 46 studies reporting the events of severe hepatitis flares or decompensation,
      c mean or median,
      d from 49 studies with available follow-up duration.
      The characteristics of these studies including study sample size, follow-up duration, proportion of patients with cirrhosis, definition of safety outcomes, pretreatment HBeAg status and criteria for Nuc cessation and retreatment were all highly heterogeneous. Regarding study design, most studies were primarily designed to analyze virological and/or biochemical relapses, and only ten studies prespecified safety outcomes with a clear definition.
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
      • Tse Y.K.
      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Buti M.
      • Wong D.K.
      • Gane E.
      • Flisiak R.
      • Manns M.
      • Kaita K.
      • et al.
      Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      • Seto W.K.
      • Liu K.S.
      • Mak L.Y.
      • Cloherty G.
      • Wong D.K.
      • Gersch J.
      • et al.
      Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      ,
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      Among these ten studies, only four included manifestations of hepatic insufficiency (such as jaundice, coagulopathy, or related clinical complications), instead of a certain serum alanine aminotransferase (ALT) level alone, in the outcome definition and had a sample size more than 100 patients and a follow-up duration longer than 12 months.
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      ,
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      The other six studies relied on serum ALT levels alone to define the safety outcomes,
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
      • Tse Y.K.
      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      ,
      • Seto W.K.
      • Liu K.S.
      • Mak L.Y.
      • Cloherty G.
      • Wong D.K.
      • Gersch J.
      • et al.
      Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.
      ,
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      was small in sample size (N = 46),
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      had a short duration of follow-up (≤6 months),
      • Buti M.
      • Wong D.K.
      • Gane E.
      • Flisiak R.
      • Manns M.
      • Kaita K.
      • et al.
      Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.
      ,
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      or was exclusively composed of a special patient population (those with HBsAg <200 IU/mL
      • Seto W.K.
      • Liu K.S.
      • Mak L.Y.
      • Cloherty G.
      • Wong D.K.
      • Gersch J.
      • et al.
      Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.
      ) (Supplementary Table 8). The criteria for antiviral retreatment were also remarkably heterogeneous. In the absence of hepatic decompensation that indicated immediate retreatment, patients could resume the treatment because of virological relapse alone (4 of 50 studies, 8.00%), biochemical relapse alone or accompanied with virological relapse (6 of 50 studies, 12.00%), biochemical relapse that did not subside after an observation period to withhold immediate treatment resumption (29 of 50 studies, 58.00%), or local regulations of the participating institutions (2 of 50 studies, 4.00%). The criteria of retreatment were not mentioned at all in 9 (18.00%) studies.
      A total of 46 of 50 studies reported data of severe flares or hepatic decompensation but heterogeneously defined them as hyperbilirubinemia (without or without concurrent coagulopathy), ascites, encephalopathy, and/or variceal bleeding, in addition to abrupt elevation of serum ALT.
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      • Chen C.H.
      • Hu T.H.
      • Wang J.H.
      • Lai H.C.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Comparison of HBsAg changes between HBeAg-negative patients who discontinued or maintained entecavir therapy.
      • Chen C.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Lai H.C.
      • Hu T.H.
      • et al.
      The Incidence of Hepatitis B Surface Antigen Loss Between Hepatitis B E Antigen-Negative Noncirrhotic Patients Who Discontinued or Continued Entecavir Therapy.
      ,
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
      • Tse Y.K.
      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Buti M.
      • Wong D.K.
      • Gane E.
      • Flisiak R.
      • Manns M.
      • Kaita K.
      • et al.
      Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      ,
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      • Chen C.H.
      • Hsu Y.C.
      • Lu S.N.
      • Hung C.H.
      • Wang J.H.
      • Lee C.M.
      • et al.
      The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients.
      • Chen C.H.
      • Hung C.H.
      • Hu T.H.
      • Wang J.H.
      • Lu S.N.
      • Su P.F.
      • et al.
      Association Between Level of Hepatitis B Surface Antigen and Relapse After Entecavir Therapy for Chronic Hepatitis B Virus Infection.
      • Chen C.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Hu T.H.
      • Lee C.M.
      Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.
      • Chen H.
      • Ding X.
      • Liao G.
      • Xia M.
      • Ren Z.
      • Fan R.
      • et al.
      Hepatitis B surface antigen kinetics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B.
      • Chien N.H.
      • Huang Y.T.
      • Wu C.Y.
      • Chang C.Y.
      • Wu M.S.
      • Kao J.H.
      • et al.
      Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy.
      • Chiu S.M.
      • Kuo Y.H.
      • Wang J.H.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • et al.
      Associations of HBV Genotype B vs C Infection With Relapse After Cessation of Entecavir or Tenofovir Therapy.
      • Fang H.W.
      • Yen Y.H.
      • Hung C.H.
      • Wang J.H.
      • Hu T.H.
      • Lu S.N.
      • et al.
      Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir.
      • Hsu Y.C.
      • Mo L.R.
      • Chang C.Y.
      • Wu M.S.
      • Yang T.H.
      • Kao J.H.
      • et al.
      Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.
      • Huang P.Y.
      • Wang J.H.
      • Hung C.H.
      • Lu S.N.
      • Hu T.H.
      • Chen C.H.
      The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients.
      • Jeng W.J.
      • Chen Y.C.
      • Sheen I.S.
      • Lin C.L.
      • Hu T.H.
      • Chien R.N.
      • et al.
      Clinical Relapse After Cessation of Tenofovir Therapy in Hepatitis B e Antigen-Negative Patients.
      • Kuo M.T.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Tsai K.L.
      • et al.
      Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir.
      • Kuo Y.H.
      • Wang J.H.
      • Hung C.H.
      • Lu S.N.
      • Hu T.H.
      • Chen C.H.
      Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation.
      • Ma T.L.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Chen C.H.
      Incidence and predictors of retreatment in chronic hepatitis B patients after discontinuation of entecavir or tenofovir treatment.
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      • Seto W.K.
      • Hui A.J.
      • Wong V.W.
      • Wong G.L.
      • Liu K.S.
      • Lai C.L.
      • et al.
      Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
      • Su T.H.
      • Yang H.C.
      • Tseng T.C.
      • Liou J.M.
      • Liu C.H.
      • Chen C.L.
      • et al.
      Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
      • Tseng T.N.
      • Hu T.H.
      • Wang J.H.
      • Kuo Y.H.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL.
      • Yao C.C.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • Wang J.H.
      • Lee C.M.
      • et al.
      Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL.
      • Chen Y.C.
      • Peng C.Y.
      • Jeng W.J.
      • Chien R.N.
      • Liaw Y.F.
      Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis.
      • Fong T.L.
      • Tien A.
      • Jo K.J.
      • Chu D.
      • Cheung E.
      • Mena E.A.
      • et al.
      Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.
      • Jeng W.J.
      • Sheen I.S.
      • Chen Y.C.
      • Hsu C.W.
      • Chien R.N.
      • Chu C.M.
      • et al.
      Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      • Liao G.
      • Ding X.
      • Xia M.
      • Wu Y.
      • Chen H.
      • Fan R.
      • et al.
      Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B.
      • Lin C.C.
      • Bair M.J.
      • Chen C.J.
      • Lee K.H.
      • Chen M.J.
      • Liu C.Y.
      • et al.
      Off-treatment efficacy of 3-year nucleos(t)ide analogues in chronic hepatitis B patients.
      • Manolakopoulos S.
      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      ,
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Su T.H.
      • Siakavellas S.
      • Liu C.J.
      • Kourikou A.
      • et al.
      Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      • Sonneveld M.J.
      • Park J.Y.
      • Kaewdech A.
      • Seto W.K.
      • Tanaka Y.
      • Carey I.
      • et al.
      Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      • Wang C.H.
      • Chang K.K.
      • Lin R.C.
      • Kuo M.J.
      • Yang C.C.
      • Tseng Y.T.
      Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study.
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      • Xie Y.
      • Li M.
      • Ou X.
      • Zheng S.
      • Gao Y.
      • Xu X.
      • et al.
      HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation.
      ,
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      ,
      • Chen C.H.
      • Peng C.Y.
      • Kuo Y.H.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • et al.
      Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen-Positive Patients.
      ,
      • Papatheodoridi M.
      • Papachristou E.
      • Moschidis Z.
      • Hadziyannis E.
      • Rigopoulou E.
      • Zachou K.
      • et al.
      Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy.
      The definition of hyperbilirubinemia was also heterogeneous and could be a level of serum bilirubin ≥2 mg/dL, >3 mg/dL, and >2.5 times the upper limit of normal (ULN). Similarly, coagulopathy was heterogeneously defined by prolongation of prothrombin time (PT) >3 seconds or an international normalized ratio (INR) >1.5 (Supplementary Table 7). Of note, 14 (30.43%) of the 46 articles did not provide specific definitions for the said clinical events.
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      ,
      • Hsu Y.C.
      • Mo L.R.
      • Chang C.Y.
      • Wu M.S.
      • Yang T.H.
      • Kao J.H.
      • et al.
      Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.
      ,
      • Seto W.K.
      • Hui A.J.
      • Wong V.W.
      • Wong G.L.
      • Liu K.S.
      • Lai C.L.
      • et al.
      Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
      ,
      • Fong T.L.
      • Tien A.
      • Jo K.J.
      • Chu D.
      • Cheung E.
      • Mena E.A.
      • et al.
      Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.
      • Jeng W.J.
      • Sheen I.S.
      • Chen Y.C.
      • Hsu C.W.
      • Chien R.N.
      • Chu C.M.
      • et al.
      Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      • Liao G.
      • Ding X.
      • Xia M.
      • Wu Y.
      • Chen H.
      • Fan R.
      • et al.
      Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B.
      ,
      • Manolakopoulos S.
      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      ,
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Su T.H.
      • Siakavellas S.
      • Liu C.J.
      • Kourikou A.
      • et al.
      Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
      ,
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      ,
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      • Wang C.H.
      • Chang K.K.
      • Lin R.C.
      • Kuo M.J.
      • Yang C.C.
      • Tseng Y.T.
      Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study.
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      • Xie Y.
      • Li M.
      • Ou X.
      • Zheng S.
      • Gao Y.
      • Xu X.
      • et al.
      HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation.
      In the analysis of the relationships between the reported safety outcomes and the characteristics of the studies, we excluded four cohorts that comprised exclusively of special patient populations (3 cohorts of patients with low HBsAg levels and one cohort of only patients with prior severe acute exacerbation,
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      ,
      • Seto W.K.
      • Liu K.S.
      • Mak L.Y.
      • Cloherty G.
      • Wong D.K.
      • Gersch J.
      • et al.
      Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.
      ,
      • Tseng T.N.
      • Hu T.H.
      • Wang J.H.
      • Kuo Y.H.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL.
      ,
      • Yao C.C.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • Wang J.H.
      • Lee C.M.
      • et al.
      Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL.
      ) and included 44 cohorts reporting severe hepatitis flares or hepatic decompensation,
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      • Chen C.H.
      • Hu T.H.
      • Wang J.H.
      • Lai H.C.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Comparison of HBsAg changes between HBeAg-negative patients who discontinued or maintained entecavir therapy.
      • Chen C.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Lai H.C.
      • Hu T.H.
      • et al.
      The Incidence of Hepatitis B Surface Antigen Loss Between Hepatitis B E Antigen-Negative Noncirrhotic Patients Who Discontinued or Continued Entecavir Therapy.
      ,
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      • Wong G.L.
      • Chan H.L.
      • Yuen B.W.
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      • Luk H.W.
      • Yip T.C.
      • et al.
      The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Buti M.
      • Wong D.K.
      • Gane E.
      • Flisiak R.
      • Manns M.
      • Kaita K.
      • et al.
      Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      ,
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      • Chen C.H.
      • Hsu Y.C.
      • Lu S.N.
      • Hung C.H.
      • Wang J.H.
      • Lee C.M.
      • et al.
      The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients.
      • Chen C.H.
      • Hung C.H.
      • Hu T.H.
      • Wang J.H.
      • Lu S.N.
      • Su P.F.
      • et al.
      Association Between Level of Hepatitis B Surface Antigen and Relapse After Entecavir Therapy for Chronic Hepatitis B Virus Infection.
      • Chen C.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Hu T.H.
      • Lee C.M.
      Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.
      • Chen H.
      • Ding X.
      • Liao G.
      • Xia M.
      • Ren Z.
      • Fan R.
      • et al.
      Hepatitis B surface antigen kinetics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B.
      • Chien N.H.
      • Huang Y.T.
      • Wu C.Y.
      • Chang C.Y.
      • Wu M.S.
      • Kao J.H.
      • et al.
      Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy.
      • Chiu S.M.
      • Kuo Y.H.
      • Wang J.H.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • et al.
      Associations of HBV Genotype B vs C Infection With Relapse After Cessation of Entecavir or Tenofovir Therapy.
      • Fang H.W.
      • Yen Y.H.
      • Hung C.H.
      • Wang J.H.
      • Hu T.H.
      • Lu S.N.
      • et al.
      Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir.
      • Hsu Y.C.
      • Mo L.R.
      • Chang C.Y.
      • Wu M.S.
      • Yang T.H.
      • Kao J.H.
      • et al.
      Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.
      • Huang P.Y.
      • Wang J.H.
      • Hung C.H.
      • Lu S.N.
      • Hu T.H.
      • Chen C.H.
      The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients.
      • Jeng W.J.
      • Chen Y.C.
      • Sheen I.S.
      • Lin C.L.
      • Hu T.H.
      • Chien R.N.
      • et al.
      Clinical Relapse After Cessation of Tenofovir Therapy in Hepatitis B e Antigen-Negative Patients.
      • Kuo M.T.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Tsai K.L.
      • et al.
      Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir.
      • Kuo Y.H.
      • Wang J.H.
      • Hung C.H.
      • Lu S.N.
      • Hu T.H.
      • Chen C.H.
      Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation.
      • Ma T.L.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Chen C.H.
      Incidence and predictors of retreatment in chronic hepatitis B patients after discontinuation of entecavir or tenofovir treatment.
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      • Seto W.K.
      • Hui A.J.
      • Wong V.W.
      • Wong G.L.
      • Liu K.S.
      • Lai C.L.
      • et al.
      Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
      • Su T.H.
      • Yang H.C.
      • Tseng T.C.
      • Liou J.M.
      • Liu C.H.
      • Chen C.L.
      • et al.
      Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
      ,
      • Chen Y.C.
      • Peng C.Y.
      • Jeng W.J.
      • Chien R.N.
      • Liaw Y.F.
      Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis.
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      • Tien A.
      • Jo K.J.
      • Chu D.
      • Cheung E.
      • Mena E.A.
      • et al.
      Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.
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      • Sheen I.S.
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      • Hsu C.W.
      • Chien R.N.
      • Chu C.M.
      • et al.
      Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
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      • Park J.Y.
      • Chon Y.E.
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      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
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      • Ding X.
      • Xia M.
      • Wu Y.
      • Chen H.
      • Fan R.
      • et al.
      Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B.
      • Lin C.C.
      • Bair M.J.
      • Chen C.J.
      • Lee K.H.
      • Chen M.J.
      • Liu C.Y.
      • et al.
      Off-treatment efficacy of 3-year nucleos(t)ide analogues in chronic hepatitis B patients.
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      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      ,
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Su T.H.
      • Siakavellas S.
      • Liu C.J.
      • Kourikou A.
      • et al.
      Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
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      • Park J.Y.
      • Kaewdech A.
      • Seto W.K.
      • Tanaka Y.
      • Carey I.
      • et al.
      Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      • Wang C.H.
      • Chang K.K.
      • Lin R.C.
      • Kuo M.J.
      • Yang C.C.
      • Tseng Y.T.
      Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study.
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      • Xie Y.
      • Li M.
      • Ou X.
      • Zheng S.
      • Gao Y.
      • Xu X.
      • et al.
      HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation.
      ,
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      ,
      • Chen C.H.
      • Peng C.Y.
      • Kuo Y.H.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • et al.
      Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen-Positive Patients.
      ,
      • Papatheodoridi M.
      • Papachristou E.
      • Moschidis Z.
      • Hadziyannis E.
      • Rigopoulou E.
      • Zachou K.
      • et al.
      Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy.
      and 45 reporting hepatitis flare-related death or liver transplantation.
      • Jeng W.J.
      • Chen Y.C.
      • Chien R.N.
      • Sheen I.S.
      • Liaw Y.F.
      Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B.
      • Chen C.H.
      • Hu T.H.
      • Wang J.H.
      • Lai H.C.
      • Hung C.H.
      • Lu S.N.
      • et al.
      Comparison of HBsAg changes between HBeAg-negative patients who discontinued or maintained entecavir therapy.
      • Chen C.H.
      • Hung C.H.
      • Wang J.H.
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      • Lai H.C.
      • Hu T.H.
      • et al.
      The Incidence of Hepatitis B Surface Antigen Loss Between Hepatitis B E Antigen-Negative Noncirrhotic Patients Who Discontinued or Continued Entecavir Therapy.
      ,
      • Hsu Y.C.
      • Wu J.L.
      • Tseng C.H.
      • Nguyen M.H.
      • Lin C.W.
      • Hung C.L.
      Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice.
      ,
      • Hirode G.
      • Choi H.S.J.
      • Chen C.H.
      • Su T.H.
      • Seto W.K.
      • Van Hees S.
      • et al.
      Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).
      ,
      • Liu Y.C.
      • Jeng W.J.
      • Peng C.W.
      • Chien R.N.
      • Liaw Y.F.
      Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.
      ,
      • Buti M.
      • Wong D.K.
      • Gane E.
      • Flisiak R.
      • Manns M.
      • Kaita K.
      • et al.
      Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.
      • Lai C.Y.
      • Yang S.S.
      • Lee S.W.
      • Tsai H.J.
      • Lee T.Y.
      Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation.
      • Liem K.S.
      • Fung S.
      • Wong D.K.
      • Yim C.
      • Noureldin S.
      • Chen J.
      • et al.
      Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study).
      ,
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      • Chen C.H.
      • Hsu Y.C.
      • Lu S.N.
      • Hung C.H.
      • Wang J.H.
      • Lee C.M.
      • et al.
      The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients.
      • Chen C.H.
      • Hung C.H.
      • Hu T.H.
      • Wang J.H.
      • Lu S.N.
      • Su P.F.
      • et al.
      Association Between Level of Hepatitis B Surface Antigen and Relapse After Entecavir Therapy for Chronic Hepatitis B Virus Infection.
      • Chen C.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Hu T.H.
      • Lee C.M.
      Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.
      • Chen H.
      • Ding X.
      • Liao G.
      • Xia M.
      • Ren Z.
      • Fan R.
      • et al.
      Hepatitis B surface antigen kinetics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B.
      • Chien N.H.
      • Huang Y.T.
      • Wu C.Y.
      • Chang C.Y.
      • Wu M.S.
      • Kao J.H.
      • et al.
      Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy.
      • Chiu S.M.
      • Kuo Y.H.
      • Wang J.H.
      • Hung C.H.
      • Hu T.H.
      • Lu S.N.
      • et al.
      Associations of HBV Genotype B vs C Infection With Relapse After Cessation of Entecavir or Tenofovir Therapy.
      • Fang H.W.
      • Yen Y.H.
      • Hung C.H.
      • Wang J.H.
      • Hu T.H.
      • Lu S.N.
      • et al.
      Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir.
      • Hsu Y.C.
      • Mo L.R.
      • Chang C.Y.
      • Wu M.S.
      • Yang T.H.
      • Kao J.H.
      • et al.
      Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.
      • Huang P.Y.
      • Wang J.H.
      • Hung C.H.
      • Lu S.N.
      • Hu T.H.
      • Chen C.H.
      The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients.
      • Jeng W.J.
      • Chen Y.C.
      • Sheen I.S.
      • Lin C.L.
      • Hu T.H.
      • Chien R.N.
      • et al.
      Clinical Relapse After Cessation of Tenofovir Therapy in Hepatitis B e Antigen-Negative Patients.
      • Kuo M.T.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Tsai K.L.
      • et al.
      Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir.
      • Kuo Y.H.
      • Wang J.H.
      • Hung C.H.
      • Lu S.N.
      • Hu T.H.
      • Chen C.H.
      Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation.
      • Ma T.L.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • Lu S.N.
      • Chen C.H.
      Incidence and predictors of retreatment in chronic hepatitis B patients after discontinuation of entecavir or tenofovir treatment.
      • Papatheodoridis G.V.
      • Rigopoulou E.I.
      • Papatheodoridi M.
      • Zachou K.
      • Xourafas V.
      • Gatselis N.
      • et al.
      DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.
      • Seto W.K.
      • Hui A.J.
      • Wong V.W.
      • Wong G.L.
      • Liu K.S.
      • Lai C.L.
      • et al.
      Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.
      • Su T.H.
      • Yang H.C.
      • Tseng T.C.
      • Liou J.M.
      • Liu C.H.
      • Chen C.L.
      • et al.
      Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy.
      ,
      • Fong T.L.
      • Tien A.
      • Jo K.J.
      • Chu D.
      • Cheung E.
      • Mena E.A.
      • et al.
      Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.
      • Jeng W.J.
      • Sheen I.S.
      • Chen Y.C.
      • Hsu C.W.
      • Chien R.N.
      • Chu C.M.
      • et al.
      Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
      • Jung K.S.
      • Park J.Y.
      • Chon Y.E.
      • Kim H.S.
      • Kang W.
      • Kim B.K.
      • et al.
      Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients.
      • Liao G.
      • Ding X.
      • Xia M.
      • Wu Y.
      • Chen H.
      • Fan R.
      • et al.
      Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B.
      • Lin C.C.
      • Bair M.J.
      • Chen C.J.
      • Lee K.H.
      • Chen M.J.
      • Liu C.Y.
      • et al.
      Off-treatment efficacy of 3-year nucleos(t)ide analogues in chronic hepatitis B patients.
      • Manolakopoulos S.
      • Kranidioti H.
      • Kourikou A.
      • Deutsch M.M.
      • Triantos C.
      • Tsolias C.
      • et al.
      Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues.
      • Papatheodoridi M.
      • Su T.H.
      • Hadziyannis E.
      • Liao C.H.
      • Orfanidou Α.
      • Yang H.C.
      • et al.
      Hepatocellular carcinoma after treatment cessation in non-cirrhotic HBeAg-negative chronic hepatitis B: A multicentre cohort study.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Su T.H.
      • Siakavellas S.
      • Liu C.J.
      • Kourikou A.
      • et al.
      Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.
      • Sohn H.R.
      • Min B.Y.
      • Song J.C.
      • Seong M.H.
      • Lee S.S.
      • Jang E.S.
      • et al.
      Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
      • Sonneveld M.J.
      • Park J.Y.
      • Kaewdech A.
      • Seto W.K.
      • Tanaka Y.
      • Carey I.
      • et al.
      Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).
      • Wang C.C.
      • Tseng K.C.
      • Hsieh T.Y.
      • Tseng T.C.
      • Lin H.H.
      • Kao J.H.
      Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg.
      • Wang C.H.
      • Chang K.K.
      • Lin R.C.
      • Kuo M.J.
      • Yang C.C.
      • Tseng Y.T.
      Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study.
      • Xia M.
      • Chi H.
      • Wu Y.
      • Hansen B.E.
      • Li Z.
      • Liu S.
      • et al.
      Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment.
      • Xie Y.
      • Li M.
      • Ou X.
      • Zheng S.
      • Gao Y.
      • Xu X.
      • et al.
      HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation.
      • Broquetas T.
      • Hernandez J.J.
      • Garcia-Retortillo M.
      • Canillas L.
      • Puigvehí M.
      • Cañete N.
      • et al.
      On-therapy HBsAg kinetics can predict HBsAg loss after nucleos(t)ide analogues interruption in HBeAg-negative patients. The cup is half full and half empty.
      • Hall S.A.L.
      • Burns G.S.
      • Anagnostou D.
      • Vogrin S.
      • Sundararajan V.
      • Ratnam D.
      • et al.
      Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.
      • Chen C.H.
      • Peng C.Y.
      • Kuo Y.H.
      • Hu T.H.
      • Hung C.H.
      • Wang J.H.
      • et al.
      Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen-Positive Patients.
      • Peng C.W.
      • Jeng W.J.
      • Yang H.I.
      • Liu Y.C.
      • Chien R.N.
      • Liaw Y.F.
      A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study.
      • Papatheodoridi M.
      • Papachristou E.
      • Moschidis Z.
      • Hadziyannis E.
      • Rigopoulou E.
      • Zachou K.
      • et al.
      Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy.

      Analysis of Severe Hepatitis Flares or Hepatic Decompensation

      Supplementary Fig. 2 presents proportions of the events according to presence of cirrhosis, number of patients, and length of follow-up. The reported proportions ranged from 0 to 4.27% with a scattered distribution in the 31 studies that had a sample size less than 300
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