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Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: A systematic review, meta-analysis, and expert opinion

  • Author Footnotes
    † Co-first authors.
    George V. Papatheodoridis
    Footnotes
    † Co-first authors.
    Affiliations
    Academic Department of Gastroenterology, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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  • Author Footnotes
    † Co-first authors.
    Vasileios Lekakis
    Footnotes
    † Co-first authors.
    Affiliations
    Academic Department of Gastroenterology, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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  • Author Footnotes
    † Co-first authors.
    Thodoris Voulgaris
    Footnotes
    † Co-first authors.
    Affiliations
    Academic Department of Gastroenterology, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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  • Pietro Lampertico
    Affiliations
    Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy

    CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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  • Thomas Berg
    Affiliations
    Division of Hepatology, Department of Medicine, Leipzig University Hospital, Leipzig, Germany
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  • Henry L.Y. Chan
    Affiliations
    Division of Gastroenterology and Hepatology, Union Hospital and Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
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  • Jia-Horng Kao
    Affiliations
    Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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  • Norah Terrault
    Affiliations
    Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California, USA
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  • Author Footnotes
    # Co-senior authors.
    Anna S. Lok
    Correspondence
    University of Michigan, 1500 East Medical Center Drive, 3912 Taubman Center, Ann Arbor, MI 48109, United States.
    Footnotes
    # Co-senior authors.
    Affiliations
    Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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  • Author Footnotes
    # Co-senior authors.
    K. Rajender Reddy
    Correspondence
    Corresponding authors. Addresses: University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Philadelphia, PA 19104, United States; Tel.: 215-662-431.
    Footnotes
    # Co-senior authors.
    Affiliations
    Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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  • Author Footnotes
    † Co-first authors.
    # Co-senior authors.

      Summary

      HBV reactivation (HBVr) can be prevented by nucleos(t)ide analogues (NAs). We conducted a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressive and immunomodulatory therapies and developed guidance on NA prophylaxis. An expert panel reviewed the data and categorised the risk of HBVr associated with each class of drugs into low (<1%), intermediate (1-10%), and high (>10%). Our search uncovered 59 studies, including 3,424 HBsAg+ and 5,799 HBsAg-/anti-HBc+ patients, which met our eligibility criteria. Based on medium-high quality evidence, immune checkpoint inhibitors, tyrosine kinase inhibitors, cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids were associated with high HBVr risk in HBsAg+ patients; cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids with intermediate risk in HBsAg-/anti-HBc+ patients; and anti-tumour necrosis factor agents and immune checkpoint inhibitors with low risk in HBsAg-/anti-HBc+ patients. Provisional recommendations are provided for drugs with low quality evidence. NA prophylaxis is recommended when using drugs associated with a high HBVr risk, while monitoring with on-demand NAs is recommended for low-risk drugs – either approach may be appropriate for intermediate-risk drugs. Consensus on definitions and methods of reporting HBVr, along with inclusion of HBsAg+, and HBsAg-/anti-HBc+ patients in clinical trials, will be key to gathering reliable data on the risk of HBVr associated with immunosuppressive or immunomodulatory therapies.

      Keywords

      Linked Article

      Introduction

      HBV reactivation (HBVr) is a serious event which can result in liver failure and death, but it is preventable.
      • Loomba R.
      • Liang T.J.
      Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions.
      HBVr occurs when the immune response of patients with HBV infection is suppressed. It is more common in patients with chronic HBV infection (hepatitis B surface antigen positive [HBsAg+]), but it can also occur in those with past HBV infection regardless of the presence or absence of hepatitis B surface antibody (HBsAg negative, IgG hepatitis B core antibody positive [HBsAg-/anti-HBc+]) because of the persistent presence of HBV DNA in the liver even after serologic recovery.
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      Hepatitis B virus persistence and reactivation.
      ,
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      Reactivation of hepatitis B.
      HBVr was first described in patients receiving chemotherapy for malignancies. It has since been reported to be associated with other immunosuppressive therapies including biologics used in a variety of non-malignant diseases, as well as targeted therapies for malignancies. The incidence of HBVr associated with each class of immunosuppressant or immunomodulator is highly varied due to a lack of consensus regarding definitions, and variations in study design and patient selection. Current literature show that B-cell-depleting agents, such as rituximab, are associated with the highest risk of HBVr.
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      Reactivation of hepatitis B.
      Many comprehensive reviews have been published on the risk of HBVr associated with each class of immunosuppressive therapy, but few have included a meta-analysis of the published studies. Since the publication of the meta-analysis organised by the American Gastroenterological Association in 2015,
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      American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.
      new classes of immunosuppressants and immunomodulators have been approved for clinical use. Data on the risk of HBVr with these new therapies are sparse. Several professional society guidelines provided recommendations on the prevention of HBVr associated with new classes of immunosuppressants and immunomodulators, but these guidelines focused on select therapies commonly prescribed for diseases within that specialty and most were not accompanied by a systematic review of the published literature.
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      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
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      • Chang K.M.
      • Hwang I.P.
      • Jonas M.M.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      We performed a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressants and immunomodulators used for a broad spectrum of diseases; we also analysed the impact of prophylactic HBV antiviral therapy in reducing that risk and provide guidance to physicians across a wide range of specialties. In addition, we reviewed data on 2 commonly prescribed immunosuppressants, corticosteroids and anti-tumour necrosis factor (anti-TNF) agents, to provide updated guidance on risk of HBVr associated with these therapies and indications for prophylactic antiviral therapy.

      Methods

      Literature search

      The literature search was developed in collaboration with an information specialist. All search results were collected using the bibliographic software EndNote. The search was conducted by separately combining HBVr terms with search terms for each drug class in both PubMed and EMBASE. The following search terms were used for HBVr: hepatitis B, hepatitis B virus, hepatitis B surface antigen, hepatitis B antibody, HBV, HBsAg, anti-HBc, anti-HBs, virus activation, virus reactivation, recurrence, recurrent infection, prophylaxis, reactivation, prophylactic, and preempt. The following drug classes were searched: corticosteroids, anti-proliferative agents or antimetabolites, alkylating agents, anti-TNF agents, calcineurin inhibitors, immune checkpoint inhibitors, tyrosine kinase inhibitors, cytokine inhibitors (not including anti-TNF agents), proteasome inhibitors, Janus kinase inhibitors, T cell-depleting agents, adoptive (chimeric antigen receptor [CAR] T-cell) immunotherapy, mammalian target of rapamycin (mTOR) inhibitors, phosphodiesterase inhibitors, integrin inhibitors, chemokine inhibitors, and anti-androgens. The search terms for each drug class included the name of the drug class, the drugs’ mechanisms of action and the names of applicable generic drugs within the class. To filter the search results, the drug class search terms were limited, such that only results where the drug class terms could be found in the title, abstract or keywords were collected.
      A systematic review and meta-analysis of new classes of immunosuppressants and immunomouldators was performed to assess risk of HBVr.
      For all drug classes, except for anti-TNF agents, the search was performed from 2010 to 2021. This timeframe was chosen because the focus was on new drugs and new drug classes. For anti-TNF agents, the search extended from 2005 to 2021 to ensure that any search results not captured in the previous review would be included in the present search. After importing all the results into Endnote, de-duplication screening was conducted.

      Selection criteria and data extraction

      Studies published in English as full papers were included, if they fulfilled all of the following criteria: (1) observational studies (case-control, cross-sectional or cohort) or randomised trials, (2) included patients who were HBsAg+ and/or HBsAg-/anti-HBc+ receiving any of the aforementioned drug classes, except for anti-TNF for which only HBsAg-/anti-HBc+ patients were included, (3) included patients or subgroups of patients receiving only one drug class and not combinations of >1 drug class, (4) provided data on HBVr based on virological and/or biochemical definitions, and (5) provided data on HBVr separately for each drug class. For drug classes with <5 studies, studies with <5 patients/study were excluded; for drug classes with 5-10 studies, studies with ≤10 patients/study were excluded; and for drug classes with >10 studies, studies with ≤20 patients/study were excluded.
      Each study in the list of papers identified by the information specialist was evaluated by 2 independent reviewers (VL, TV) to determine whether it fulfilled all the inclusion criteria. These 2 reviewers extracted data from the selected papers according to a predefined form. The 2 data summary tables were compared for concordance and discrepancies were discussed and arbitrated by a third reviewer (GP). This meta-analysis was conducted based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P).

      Statistical analysis

      The outcomes of interest were incidence of HBVr with or without associated hepatitis (biochemical exacerbation), according to the definitions used in each study. For outcomes of HBVr-associated hepatitis, hepatic decompensations, and deaths, events were attributed to HBVr unless otherwise stated. Results were analysed separately for each drug class in patients who did or did not receive prophylactic nucleos(t)ide analogue (NA) therapy, whenever data were available.
      Meta-analysis was performed using a generalized linear mixed model.
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      Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data.
      Two-sided confidence intervals for the single proportions of each individual study were calculated using the Clopper and Pearson method.
      ES CCP
      The use of confidence or fiducial limits illustrated in the case of the binomial.
      The between-study variance component (τ2) was estimated applying the maximum likelihood method, based on marginal distribution.
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      A likelihood approach to meta-analysis with random effects.
      Heterogeneity was quantified using I2 which describes the percentage of total variation across studies that is due to heterogeneity rather than chance.
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      Measuring inconsistency in meta-analyses.
      The test statistic was based on a weighted linear regression of the treatment effect on the inverse of the total sample size with weights reciprocal to the variance of the average event probability and followed a t distribution with number of studies -2 degrees of freedom.
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      Comparison of two methods to detect publication bias in meta-analysis.
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      A random effects or fixed effect model was applied depending on the existence or not of significant heterogeneity across studies, respectively. Analysis was conducted in R v4.1.2 using meta-packages and metaprop functions.
      Team RC

      Results

      The initial search produced 1,752 total results. De-duplication screening removed 760 results, producing 992 total unique search results. The drug classes with the highest number of search results included anti-TNF agents, cytokine inhibitors, corticosteroids, and alkylating agents. The searches did not produce any results for integrin inhibitors, chemokine inhibitors and anti-androgens, while there was no study using proteasome or phosphodiesterase inhibitors as the only immunosuppressive agent. Nine-hundred and thirty four studies were excluded: 925 for not fulfilling the inclusion criteria and 9 because the sample sizes were too small, while 1 study was identified through manual search. Thus, 59 studies with a total of 9,223 (3,424 HBsAg+ and 5,799 HBsAg-/anti-HBc+) patients were finally included in this systematic review with 1 study
      • Tokmak S.
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      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      having subgroups of patients receiving 4 and another study
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      • Fukae J.
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      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      having subgroups of patients receiving 2 different classes of agents (Fig. S1). The definitions of virological reactivation or HBVr were variable for HBsAg+ patients, from serum HBV DNA increase by >1-2 log10 IU/ml from baseline to HBV DNA levels >103-5 IU/ml, while they were usually based on detection of HBV DNA and/or HBsAg seroreversion for HBsAg-/anti-HBc+ patients. The definitions of HBVr-associated hepatitis also varied, with most studies using an alanine aminotransferase (ALT) cut-off of >upper limit of normal (ULN) or >3-fold ULN or >100 U/L. Details of the studies, patient characteristics, incidence of HBVr with and without prophylactic NA are provided separately for each drug class.

      Anti-TNF agents

      There were 18 studies including 1,640 HBsAg-/anti-HBc+ patients receiving anti-TNF agents, 76 of whom received NA prophylaxis (Table 1).
      • Tokmak S.
      • Gümürdülü Y.
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      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
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      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
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      • et al.
      Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective analysis of 32 patients.
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      Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection.
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      Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases.
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      • et al.
      Anti-tumor necrosis factor treatment in occult hepatitis B virus infection: a retrospective analysis of 62 patients with psoriatic disease.
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      Patients with core antibody positive and surface antigen negative Hepatitis B (anti-HBc+, HBsAg−) on anti-TNF therapy have a low rate of reactivation.
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      Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study.
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      Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
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      Incidence of hepatitis B virus reactivation and hepatotoxicity in patients receiving long-term treatment with tumor necrosis factor Antagonists.
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      • et al.
      Reactivation rates in patients using biological agents, with resolved HBV infection or isolated anti-HBc IgG positivity.
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      • et al.
      Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts.
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      Anti-TNF therapy in patients with HBV infection-analysis of 87 patients with inflammatory arthritis.
      The pooled HBVr rate was 1% (95% CI 1-2%; heterogeneity, p = 0.35/0.28) overall as well as in the 1,564 patients not receiving NA prophylaxis (Fig. 1A). HBVr was not observed in any of 76 patients receiving NA prophylaxis in 6 studies.
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      • Conigliaro P.
      • Chimenti M.S.
      • Kroegler B.
      • Di Muzio G.
      • Guarino M.D.
      • et al.
      Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective analysis of 32 patients.
      ,
      • Clarke W.T.
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      • Feuerstein J.D.
      • Cheifetz A.S.
      Patients with core antibody positive and surface antigen negative Hepatitis B (anti-HBc+, HBsAg−) on anti-TNF therapy have a low rate of reactivation.
      ,
      • Fidan S.
      • Capkın E.
      • Arıca D.A.
      • Durak S.
      • Okatan I.E.
      Risk of hepatitis B reactivation in patients receiving anti-tumor necrosis factor-α therapy.
      ,
      • Lee J.M.
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      • Ye B.D.
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      • et al.
      Clinical course of hepatitis B viral infection in patients undergoing anti-tumor necrosis factor α therapy for inflammatory bowel disease.
      ,
      • Solay A.H.
      • Acar A.
      • Eser F.
      • Kuşco F.
      • Tütüncü E.E.
      • Kul G.
      • et al.
      Reactivation rates in patients using biological agents, with resolved HBV infection or isolated anti-HBc IgG positivity.
      ,
      • Tamori A.
      • Koike T.
      • Goto H.
      • Wakitani S.
      • Tada M.
      • Morikawa H.
      • et al.
      Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts.
      Only 1/1,481 (0.07%) patient not receiving NA prophylaxis developed HBVr-associated hepatitis (pooled rate: 0%, 95% CI 0-0.5%; heterogeneity, p = 1.00) and no patient developed hepatic decompensation or died (Table 2).
      Table 1Main characteristics of studies providing data on HBVr in HBsAg-, anti-HBc+ patients receiving treatment with anti-tumour necrosis factor agents.
      StudyStudy designMe(di)an age, yearsPatients, nHBsAg-, anti-HBc+ patients, nProphylactic NAs, nFollow-up, monthsDefinition of HBVrDefinition of HBVr-associated hepatitis
      TotalAnti-HBs-Anti-HBs+
      Caporali 2010
      • Caporali R.
      • Bobbio-Pallavicini F.
      • Atzeni F.
      • Sakellariou G.
      • Caprioli M.
      • Montecucco C.
      • et al.
      Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases.
      R5767673928043HBV DNA detectable and/or HBsAg positiven.a.
      Cassano 2011
      • Cassano N.
      • Mastrandrea V.
      • Principi M.
      • Loconsole F.
      • De Tullio N.
      • Di Leo A.
      • et al.
      Anti-tumor necrosis factor treatment in occult hepatitis B virus infection: a retrospective analysis of 62 patients with psoriatic disease.
      R5462621250048HBV DNA detectable and/or HBsAg positiven.a.
      Mori 2011
      • Mori S.
      Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs.
      Rn.a.3131n.a.n.a.0n.a.HBV DNA detectableALT >2xULN
      Tamori 2011
      • Tamori A.
      • Koike T.
      • Goto H.
      • Wakitani S.
      • Tada M.
      • Morikawa H.
      • et al.
      Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts.
      Rn.a.4242834124HBV DNA ≥1 log increase or >2.1 log cp/mlALT ≥10xULN
      Papa 2013
      • Papa A.
      • Felice C.
      • Marzo M.
      • Andrisani G.
      • Armuzzi A.
      • Covino M.
      • et al.
      Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents.
      R542222n.a.n.a.0n.a.n.a.n.a.
      Ballanti 2014
      • Ballanti E.
      • Conigliaro P.
      • Chimenti M.S.
      • Kroegler B.
      • Di Muzio G.
      • Guarino M.D.
      • et al.
      Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective analysis of 32 patients.
      R632525124227HBsAg positiven.a.
      Ye 2014
      • Ye H.
      • Zhang X.W.
      • Mu R.
      • Fang L.K.
      • Gu J.R.
      • Lin J.
      • et al.
      Anti-TNF therapy in patients with HBV infection-analysis of 87 patients with inflammatory arthritis.
      R4650501040012HBV DNA-detectable or >1 log increasen.a.
      Barone 2015
      • Barone M.
      • Notarnicola A.
      • Lopalco G.
      • Viggiani M.T.
      • Sebastiani F.
      • Covelli M.
      • et al.
      Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection.
      Rn.a.1461460146056n.a.n.a.
      Nakamura 2016
      • Nakamura J.
      • Nagashima T.
      • Nagatani K.
      • Yoshio T.
      • Iwamoto M.
      • Minota S.
      Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      Rn.a.4848n.a.n.a.018HBV DNA >2 log cp/mln.a.
      Giannitti 2017
      • Giannitti C.
      • Lopalco G.
      • Vitale A.
      • Rigante D.
      • Anelli M.G.
      • Fabbroni M.
      • et al.
      Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study.
      R61131131n.a.n.a.075HBV DNA detectable and/or HBsAg positiven.a.
      Clarke 2018
      • Clarke W.T.
      • Amin S.S.
      • Papamichael K.
      • Feuerstein J.D.
      • Cheifetz A.S.
      Patients with core antibody positive and surface antigen negative Hepatitis B (anti-HBc+, HBsAg−) on anti-TNF therapy have a low rate of reactivation.
      R5612012032883715HBV DNA detectablen.a.
      Papalopoulos 2018
      • Papalopoulos I.
      • Fanouriakis A.
      • Kougkas N.
      • Flouri I.
      • Sourvinos G.
      • Bertsias G.
      • et al.
      Liver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: an observational, controlled, long-term study.
      Rn.a.1111112982024HBV DNA ≥1 log increase or reappearanceALT >2-3xULN
      Pauly 2018
      • Pauly M.P.
      • Tucker L.Y.
      • Szpakowski J.L.
      • Ready J.B.
      • Baer D.
      • Hwang J.
      • et al.
      Incidence of hepatitis B virus reactivation and hepatotoxicity in patients receiving long-term treatment with tumor necrosis factor Antagonists.
      R5417817869109036HBV DNA detectable or >2000 IU/ml and/or HBsAg positiven.a.
      Solay 2018
      • Solay A.H.
      • Acar A.
      • Eser F.
      • Kuşco F.
      • Tütüncü E.E.
      • Kul G.
      • et al.
      Reactivation rates in patients using biological agents, with resolved HBV infection or isolated anti-HBc IgG positivity.
      Rn.a.2222n.a.n.a.3n.a.HBV DNA detectable and/or HBsAg positiveALT >5xULN
      Watanabe 2019
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      Rn.a.98981086015HBV DNA detectablen.a.
      Tokmak 2021
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      Rn.a.1111116645024HBV DNA-detectable and/or HBsAg positiven.a.
      Fidan 2021
      • Fidan S.
      • Capkın E.
      • Arıca D.A.
      • Durak S.
      • Okatan I.E.
      Risk of hepatitis B reactivation in patients receiving anti-tumor necrosis factor-α therapy.
      R52272272312413133HBV DNA detectable or ≥1 log increase and/or HBsAg positiven.a.
      Lee 2021
      • Lee J.M.
      • Wei S.C.
      • Lee K.M.
      • Ye B.D.
      • Mao R.
      • Kim H.S.
      • et al.
      Clinical course of hepatitis B viral infection in patients undergoing anti-tumor necrosis factor α therapy for inflammatory bowel disease.
      Rn.a.10410417872n.a.HBV DNA detectable or ≥2 log increaseALT >2xULN
      Anti-HBC+, anti-hepatitis B core antibody positive; anti-HBs+/-, anti-hepatitis B surface antibody positive/negative; HBVr, HBV reactivation; NA, nucleos(t)ide analogue; n.a., not available; P, prospective; R, retrospective; ULN, upper limit of normal.
      Figure thumbnail gr1
      Fig. 1Pooled rates of HBV reactivation in HBsAg-/anti-HBc+ patients receiving treatments in the absence of NA prophylaxis.
      (A) Treatment with anti-tumour necrosis factor agents, (B) immune checkpoint inhibitors, (C) cytokine inhibitors or (D) CAR T-cell immunotherapy. CAR, chimeric antigen receptor; NA, nucleos(t)ide analogue.
      Table 2HBVr in HBsAg-, anti-HBc+ patients receiving treatment with anti-tumour necrosis factor agents.
      StudyPatients with HBVr, n/NHBVr in relation to prophylactic NA, n/NPatients with HBVr-associated hepatitis, n/NHBVr-associated hepatitis in relation to prophylactic NA, n/NLiver decompensation, n/NDeath, n/N
      NANo NANANo NA
      Caporali 2010
      • Caporali R.
      • Bobbio-Pallavicini F.
      • Atzeni F.
      • Sakellariou G.
      • Caprioli M.
      • Montecucco C.
      • et al.
      Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases.
      0/67-0/670/67-0/670/670/67
      Cassano 2011
      • Cassano N.
      • Mastrandrea V.
      • Principi M.
      • Loconsole F.
      • De Tullio N.
      • Di Leo A.
      • et al.
      Anti-tumor necrosis factor treatment in occult hepatitis B virus infection: a retrospective analysis of 62 patients with psoriatic disease.
      1/62-1/620/62-0/620/620/62
      Mori 2011
      • Mori S.
      Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs.
      1/31-1/310/31-0/310/310/31
      Tamori 2011
      • Tamori A.
      • Koike T.
      • Goto H.
      • Wakitani S.
      • Tada M.
      • Morikawa H.
      • et al.
      Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts.
      0/420/10/410/420/10/410/420/42
      Papa 2013
      • Papa A.
      • Felice C.
      • Marzo M.
      • Andrisani G.
      • Armuzzi A.
      • Covino M.
      • et al.
      Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents.
      0/220/220/22-0/220/220/22
      Ballanti 2014
      • Ballanti E.
      • Conigliaro P.
      • Chimenti M.S.
      • Kroegler B.
      • Di Muzio G.
      • Guarino M.D.
      • et al.
      Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective analysis of 32 patients.
      0/250/20/230/250/20/230/250/25
      Ye 2014
      • Ye H.
      • Zhang X.W.
      • Mu R.
      • Fang L.K.
      • Gu J.R.
      • Lin J.
      • et al.
      Anti-TNF therapy in patients with HBV infection-analysis of 87 patients with inflammatory arthritis.
      0/50-0/500/50-0/500/500/50
      Barone 2015
      • Barone M.
      • Notarnicola A.
      • Lopalco G.
      • Viggiani M.T.
      • Sebastiani F.
      • Covelli M.
      • et al.
      Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection.
      0/146-0/1460/146-0/1460/1460/146
      Nakamura 2016
      • Nakamura J.
      • Nagashima T.
      • Nagatani K.
      • Yoshio T.
      • Iwamoto M.
      • Minota S.
      Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      1/48-1/480/48-0/480/480/48
      Giannitti 2017
      • Giannitti C.
      • Lopalco G.
      • Vitale A.
      • Rigante D.
      • Anelli M.G.
      • Fabbroni M.
      • et al.
      Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study.
      0/131-0/1310/131-0/1310/1310/131
      Clarke 2018
      • Clarke W.T.
      • Amin S.S.
      • Papamichael K.
      • Feuerstein J.D.
      • Cheifetz A.S.
      Patients with core antibody positive and surface antigen negative Hepatitis B (anti-HBc+, HBsAg−) on anti-TNF therapy have a low rate of reactivation.
      4/1200/374/83n.a.n.a.n.a.0/1200/120
      Papalopoulos 2018
      • Papalopoulos I.
      • Fanouriakis A.
      • Kougkas N.
      • Flouri I.
      • Sourvinos G.
      • Bertsias G.
      • et al.
      Liver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: an observational, controlled, long-term study.
      0/111-0/1110/111-0/1110/1110/111
      Pauly 2018
      • Pauly M.P.
      • Tucker L.Y.
      • Szpakowski J.L.
      • Ready J.B.
      • Baer D.
      • Hwang J.
      • et al.
      Incidence of hepatitis B virus reactivation and hepatotoxicity in patients receiving long-term treatment with tumor necrosis factor Antagonists.
      0/178-0/1780/178-0/1780/1780/178
      Solay 2018
      • Solay A.H.
      • Acar A.
      • Eser F.
      • Kuşco F.
      • Tütüncü E.E.
      • Kul G.
      • et al.
      Reactivation rates in patients using biological agents, with resolved HBV infection or isolated anti-HBc IgG positivity.
      4/220/34/190/220/30/190/220/22
      Watanabe 2019
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      3/98-3/980/98-0/980/980/98
      Tokmak 2021
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      0/111-0/1110/111-0/1110/1110/111
      Fidan 2021
      • Fidan S.
      • Capkın E.
      • Arıca D.A.
      • Durak S.
      • Okatan I.E.
      Risk of hepatitis B reactivation in patients receiving anti-tumor necrosis factor-α therapy.
      1/2720/311/2410/2720/310/2410/2720/272
      Lee 2021
      • Lee J.M.
      • Wei S.C.
      • Lee K.M.
      • Ye B.D.
      • Mao R.
      • Kim H.S.
      • et al.
      Clinical course of hepatitis B viral infection in patients undergoing anti-tumor necrosis factor α therapy for inflammatory bowel disease.
      1/1040/21/1021/1040/21/1020/1040/104
      Anti-HBC+, anti-hepatitis B core antibody positive; NA, nucleos(t)ide analogue.

      Immune checkpoint inhibitors

      There were 8 studies with 2,183 patients receiving immune checkpoint inhibitors (Table 3).
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      • Lee P.C.
      • Chao Y.
      • Chen M.H.
      • Lan K.H.
      • Lee I.C.
      • Hou M.C.
      • et al.
      Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.
      • Ng K.Y.Y.
      • Wong L.W.J.
      • Ang A.J.S.
      • Tan S.H.
      • Choo S.P.
      • Tai D.W.
      • et al.
      Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian Center.
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      All 8 studies included HBsAg+ patients; HBVr was observed in 18/1,057 (1.7%) patients. The pooled HBVr rate was 3% overall (95% CI 1-9%; heterogeneity, p <0.01), 2% (95% CI 0-7%; heterogeneity, p <0.01) in 1,001 patients receiving (Fig. 2A) and 11% (95% CI 5-22%; heterogeneity, p = 0.34) in 56 patients not receiving NA prophylaxis (Fig. 2B) (Table 4). In 6 studies providing such data,
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      • Lee P.C.
      • Chao Y.
      • Chen M.H.
      • Lan K.H.
      • Lee I.C.
      • Hou M.C.
      • et al.
      Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.
      • Ng K.Y.Y.
      • Wong L.W.J.
      • Ang A.J.S.
      • Tan S.H.
      • Choo S.P.
      • Tai D.W.
      • et al.
      Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian Center.
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      ,
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      HBVr-associated hepatitis was observed in 7/644 (1.1%) patients (pooled rate: 1%, 95% CI 1-2%; heterogeneity, p = 0.66) without substantial differences between patients receiving or not receiving NA prophylaxis (4/590 or 0.7% vs. 3/54 or 0.6%). None of 660 HBsAg+ patients experienced liver decompensation or died (Table 4). HBsAg clearance was observed in 3 (0.3%) patients all of whom received NA prophylaxis.
      Table 3Main characteristics of studies providing data on HBVr in HBsAg+ and/or anti-HBc+ patients receiving treatment with immune checkpoint inhibitors∗.
      StudyStudy designMe(di)an age, yearsPatients, nHBsAg+ patients, nHBsAg-, anti-HBc+ patients, nProphylactic NAs, nFollow-up, monthsDefinition of HBVrDefinition of HBVr-associated hepatitis
      TotalAnti-HBs-Anti-HBs+
      Shah 2019
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      Rn.a.1688449n.a.n.a.n.a.
      Byeon 2020
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      R62321616n.a.n.a.143n.a.n.a.
      Chan 2020
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      R6842835n.a.n.a.16n.a.HBV DNA ≥2 log increase
      For patients with detectable HBV DNA at baseline.
      or ≥3 log
      For patients with undetectable HBV DNA at baseline.
      or ≥4 log IU/ml
      For patients with unknown HBV DNA levels at baseline.
      or detectable
      For patients with negative HBsAg at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      n.a.
      Ng 2020
      • Ng K.Y.Y.
      • Wong L.W.J.
      • Ang A.J.S.
      • Tan S.H.
      • Choo S.P.
      • Tai D.W.
      • et al.
      Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian Center.
      #
      Rn.a.62557n.a.n.a.57n.a.HBV DNA ≥1 log increase
      For patients with detectable HBV DNA at baseline.
      or detectable
      For patients with undetectable HBV DNA at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      ALT ≥3xULN
      Lee 2020
      • Lee P.C.
      • Chao Y.
      • Chen M.H.
      • Lan K.H.
      • Lee I.C.
      • Hou M.C.
      • et al.
      Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.
      R-P6160600n.a.n.a.544-10HBV DNA ≥1 log increase
      For patients with detectable HBV DNA at baseline.
      or ≥3 log IU/ml
      For patients with undetectable HBV DNA at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      ALT ≥3xULN & >100 U/L
      Pertejo-Fernandez 2020
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      ˆ
      R5616214n.a.n.a.320n.a.n.a.
      Wong 2021
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      #
      Rn.a.879397482n.a.n.a.474n.a.HBV DNA ≥2 log increasen.a.
      Yoo 2021
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      #
      Rn.a.1,075511564n.a.n.a.497n.a.HBV DNA ≥2 log increase
      For patients with detectable HBV DNA at baseline.
      or ≥3 log
      For patients with undetectable HBV DNA at baseline.
      or ≥4 log IU/ml
      For patients with unknown HBV DNA levels at baseline.
      or detectable
      For patients with negative HBsAg at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      ALT >ULN (according to clinicians)
      Anti-HBC+, anti-hepatitis B core antibody positive; anti-HBs+/-, anti-hepatitis B surface antibody positive/negative; HBVr, HBV reactivation; NA, nucleos(t)ide analogue; n.a., not available; P, prospective; R, retrospective; ULN, upper limit of normal.
      ∗PD-1 inhibitors; ˆPD-1 or PD-L1 inhibitors, #PD-1 or PD-L1 or CTLA-4 inhibitors.
      1 For patients with detectable HBV DNA at baseline.
      2 For patients with undetectable HBV DNA at baseline.
      3 For patients with unknown HBV DNA levels at baseline.
      4 For patients with negative HBsAg at baseline.
      Figure thumbnail gr2
      Fig. 2Pooled rates of HBV reactivation in HBsAg+ patients receiving treatment in the absence/presence of NA prophylaxis.
      (A,B) Treatment with immune checkpoint inhibitors with (A) or without (B) NA prophylaxis; (C) tyrosine kinase inhibitors without NA prophylaxis, (D) cytokine inhibitors without NA prophylaxis, or (E) CAR T-cell immunotherapy with NA prophylaxis. CAR, chimeric antigen receptor; NA, nucleos(t)ide analogue.
      Table 4HBVr in HBsAg+ and/or anti-HBc+ patients receiving treatment with immune checkpoint inhibitors.
      StudyPatients with HBVr, n/NHBVr in relation to prophylactic NA, n/NPatients with HBVr-associated hepatitis, n/NHBVr-associated hepatitis in relation to prophylactic NA, n/NLiver decompensation, n/NDeath, n/N
      NANo NANANo NA
      HBsAg+ patients
      Shah 2019
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      0/80/8-0/80/8-0/80/8
      Byeon 2020
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      3/162/141/2n.a.n.a.n.a.0/160/16
      Chan 2020
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      2/81/71/10/80/70/10/80/8
      Ng 2020
      • Ng K.Y.Y.
      • Wong L.W.J.
      • Ang A.J.S.
      • Tan S.H.
      • Choo S.P.
      • Tai D.W.
      • et al.
      Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian Center.
      5/555/55-2/552/550/550/55
      Lee 2020
      • Lee P.C.
      • Chao Y.
      • Chen M.H.
      • Lan K.H.
      • Lee I.C.
      • Hou M.C.
      • et al.
      Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.
      1/600/541/61/600/541/60/600/60
      Pertejo-Fernandez 2020
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      0/20/2-0/20/2-0/20/2
      Wong 2021
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      2/3972/397-n.a.n.a.-n.a.n.a.
      Yoo 2021
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      5/5112/4643/474/5112/4642/470/5110/511
      HBsAg-, anti-HBc+ patients
      Byeon 2020
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      0/16-0/16n.a.n.a.n.a.0/160/16
      Shah 2019
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      0/80/10/70/80/10/70/80/8
      Chan 2020
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      0/350/60/290/350/60/290/350/35
      Ng 2020
      • Ng K.Y.Y.
      • Wong L.W.J.
      • Ang A.J.S.
      • Tan S.H.
      • Choo S.P.
      • Tai D.W.
      • et al.
      Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian Center.
      1/70/21/5n.a.n.a.n.a.0/70/7
      Pertejo-Fernandez 2020
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      0/140/10/130/140/10/130/140/14
      Wong 2021
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      1/4820/771/405n.a.n.a.n.a.n.a.n.a.
      Yoo 2021
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      0/5640/330/5310/5640/330/5640/5640/564
      Anti-HBC+, anti-hepatitis B core antibody positive; HBVr, HBV reactivation; NA, nucleos(t)ide analogue, n.a., not available.
      In 7 studies including HBsAg-/anti-HBc+ patients,
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      ,
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      ,
      • Ng K.Y.Y.
      • Wong L.W.J.
      • Ang A.J.S.
      • Tan S.H.
      • Choo S.P.
      • Tai D.W.
      • et al.
      Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian Center.
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      HBVr developed in only 2/1,126 (0.2%) patients overall (pooled rate: 0%, 95% CI 0-1%; heterogeneity, p = 0.18): 0/120 (0%) in those receiving and 2/1,006 (0.2%) in those not receiving NA prophylaxis (Fig. 1B). HBVr-associated hepatitis, liver decompensation or death was not observed in >600 patients in whom these outcomes were reported (Table 4).

      Tyrosine kinase inhibitors

      Four studies including 268 patients treated with tyrosine kinase inhibitors were identified (Table 5).
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      • Sorà F.
      • Ponziani F.R.
      • Laurenti L.
      • Chiusolo P.
      • Autore F.
      • Gasbarrini A.
      • et al.
      Low risk of hepatitis B virus reactivation in patients with resolved infection and chronic myeloid leukemia treated with tyrosine kinase inhibitors.
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      • Yao Z.H.
      • Liao W.Y.
      • Ho C.C.
      • Chen K.Y.
      • Shih J.Y.
      • Chen J.S.
      • et al.
      Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients.
      In 3 studies with 196 HBsAg+ patients of whom 189 did not receive NA prophylaxis,
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      ,
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      ,
      • Yao Z.H.
      • Liao W.Y.
      • Ho C.C.
      • Chen K.Y.
      • Shih J.Y.
      • Chen J.S.
      • et al.
      Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients.
      the pooled rates of HBVr and HBVr-associated hepatitis were 11% (95% CI 7-16%; heterogeneity, p = 0.10/0.08) (Fig. 2C) and 8% (95% CI 5-13%; heterogeneity, p = 0.49), respectively. Only 7 patients received NA prophylaxis,
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      of whom 1 experienced HBVr and none had HBVr-associated hepatitis (Table 6).
      Table 5Main characteristics of studies providing data on HBVr in HBsAg+ and/or anti-HBc+ patients receiving treatment with tyrosine kinase or cytokine inhibitors.
      StudyStudy designMe(di)an age, yearsPatients, nHBsAg+ patients, nHBsAg-, anti-HBc+ patients, nProphylactic NAs, nFollow-up, monthsDefinition of HBVrDefinition of HBVr-associated hepatitis
      TotalAnti-HBs-Anti-HBs+
      Tyrosine kinase inhibitors
      Orlandi 2017
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      R5332626n.a.n.a.1112HBV DNA >2 log increase or reappearancen.a.
      Sora 2017
      • Sorà F.
      • Ponziani F.R.
      • Laurenti L.
      • Chiusolo P.
      • Autore F.
      • Gasbarrini A.
      • et al.
      Low risk of hepatitis B virus reactivation in patients with resolved infection and chronic myeloid leukemia treated with tyrosine kinase inhibitors.
      ˆ
      R651001019046HBV DNA reappearance & ALT >ULNALT >3xULN or >100 U/L
      Wang 2019
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      #
      R48551936n.a.n.a.644HBV DNA >1 log increase or reappearance or >20,000 IU/ml
      In patients with detectable baseline HBV DNA.
      ALT >100 U/L
      Yao 2019
      • Yao Z.H.
      • Liao W.Y.
      • Ho C.C.
      • Chen K.Y.
      • Shih J.Y.
      • Chen J.S.
      • et al.
      Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients.
      !
      R621711710--026HBV DNA >1 log increase or >105 IU/ml & ALT >ULNALT ≥2-fold increase
      Cytokine inhibitors
      Chiu 2013
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      R401411312410HBV DNA >1 log increase
      In patients with detectable baseline HBV DNA.
      or >6 log
      In patients with detectable baseline HBV DNA.
      or detectable
      In patients with undetectable baseline HBV DNA.
      n.a.
      Ahn 2018
      • Ahn S.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Park J.Y.
      • Lee S.W.
      Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience.
      ˆ
      R571501531209HBV DNA detectablen.a.
      Chiu 2018
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      #
      P55492524111339HBV DNA >1 log increase
      In patients with detectable baseline HBV DNA.
      or detectable
      In patients with undetectable baseline HBV DNA.
      or HBeAg seroreversion
      ALT >3-fold increase or >100 U/L
      Ting 2018
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      P45541044638224HBV DNA >2 log increase
      In patients with detectable baseline HBV DNA.
      or >20,000
      In patients with detectable baseline HBV DNA.
      or >100
      In patients with undetectable baseline HBV DNA.
       IU/ml
      ALT >2xULN
      Chen 2019
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      ˆ
      P4648741932220HBV DNA >1 log increase
      In patients with detectable baseline HBV DNA.
      or detectable
      In patients with undetectable baseline HBV DNA.
      or HBsAg/HBeAg seroreversion
      n.a.
      Lin 2019
      • Lin C.T.
      • Huang W.N.
      • Hsieh C.W.
      • Chen Y.M.
      • Chen D.Y.
      • Hsieh T.Y.
      • et al.
      Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - a three-year study in Taiwan.
      ˆ
      R5911110--1136HBV DNA >1 log increase or >2.6 log cp/mlALT >3-fold increase or >100 U/L
      Watanabe 2019
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      ˆ
      R6825025421015HBV DNA detectablen.a.
      Kuo 2021
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      ˆ
      R6471764n.a.n.a.4108HBV DNA >2 log increase
      In patients with detectable baseline HBV DNA.
      or >4 log
      In patients with detectable baseline HBV DNA.
      or >3 log
      In patients with undetectable baseline HBV DNA.
      IU/ml
      ALT >3-fold increase and >100 U/L
      Rodríguez-Tajes 2021
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      ˆ!
      P6752052n.a.n.a.332HBV DNA detectable or HBsAg positiven.a.
      Anti-HBC+, anti-hepatitis B core antibody positive; anti-HBs+/-, anti-hepatitis B surface antibody positive/negative; HBVr, HBV reactivation; NA, nucleos(t)ide analogue; n.a., not available; P, prospective; R, retrospective; ULN, upper limit of normal.
      Tyrosine kinase inhibitors: Imatinib, dasatinib, nilotinib or combinations, ˆimatinib or nilotinib, #ponatinib, imatinib, dasatinib, nilotinib or combinations, !osimertinib, gefitinib, afitinib or erlotinib.
      Cytokine inhibitors: Ustekinumab, ˆtocilizumab, #secukinumab, !siltuximab.
      1 In patients with detectable baseline HBV DNA.
      2 In patients with undetectable baseline HBV DNA.
      Table 6HBVr in HBsAg+ and/or anti-HBc+ patients receiving treatment with tyrosine kinase or cytokine inhibitors.
      StudyPatients with HBVr, n/NHBVr in relation to prophylactic NA, n/NPatients with HBVr-associated hepatitis, n/NHBVr-associated hepatitis in relation to prophylactic NA, n/NLiver decompensation, n/NDeath, n/N
      NANo NANANo NA
      Tyrosine kinase inhibitors – HBsAg+ patients
      Orlandi 2017
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      0/60/10/50/60/10/50/60/6
      Wang 2019
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      5/191/64/133/190/63/13n.a.0/19
      Yao 2019
      • Yao Z.H.
      • Liao W.Y.
      • Ho C.C.
      • Chen K.Y.
      • Shih J.Y.
      • Chen J.S.
      • et al.
      Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients.
      16/171-16/17113/171-13/171n.a.0/171
      Tyrosine kinase inhibitorsHBsAg-, anti-HBc+ patients
      Orlandi 2017
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      0/26-0/260/26-0/260/260/26
      Sora 2017
      • Sorà F.
      • Ponziani F.R.
      • Laurenti L.
      • Chiusolo P.
      • Autore F.
      • Gasbarrini A.
      • et al.
      Low risk of hepatitis B virus reactivation in patients with resolved infection and chronic myeloid leukemia treated with tyrosine kinase inhibitors.
      0/10-0/100/10-0/10n.a.0/10
      Wang 2019
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      0/36-0/360/36-0/36n.a.0/36
      Cytokine inhibitors – HBsAg+ patients
      Chiu 2013
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      2/110/42/70/110/40/70/110/11
      Chiu 2018
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      6/250/36/220/250/30/220/250/25
      Ting 2018
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      2/100/22/80/100/20/80/100/10
      Chen 2019
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      3/70/23/50/70/20/5n.a.0/7
      Lin 2019
      • Lin C.T.
      • Huang W.N.
      • Hsieh C.W.
      • Chen Y.M.
      • Chen D.Y.
      • Hsieh T.Y.
      • et al.
      Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - a three-year study in Taiwan.
      0/110/11-0/110/11-0/110/11
      Kuo 2021
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      3/70/43/33/70/43/30/70/7
      Cytokine inhibitorsHBsAg-, anti-HBc+ patients
      Chiu 2013
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      0/3-0/30/3-0/30/30/3
      Ahn 2018
      • Ahn S.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Park J.Y.
      • Lee S.W.
      Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience.
      0/15-0/150/15-0/150/150/15
      Chiu 2018
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      1/24-1/240/24-0/240/240/24
      Ting 2018
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      1/44-1/441/44-1/440/440/44
      Chen 2019
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      0/41-0/410/41-0/410/410/41
      Watanabe 2019
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      1/25-1/250/25-0/250/250/25
      Kuo 2021
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      1/64-1/640/64-0/640/640/64
      Rodríguez-Tajes 2021
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      2/520/332/190/520/330/190/520/52
      Anti-HBC+, anti-hepatitis B core antibody positive; HBVr, HBV reactivation; NA, nucleos(t)ide analogue; n.a., not available.
      In 3 studies with 72 HBsAg-/anti-HBc+ patients
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      • Sorà F.
      • Ponziani F.R.
      • Laurenti L.
      • Chiusolo P.
      • Autore F.
      • Gasbarrini A.
      • et al.
      Low risk of hepatitis B virus reactivation in patients with resolved infection and chronic myeloid leukemia treated with tyrosine kinase inhibitors.
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      (Table 5), none of whom received NA prophylaxis, no HBVr was reported (Table 6).
      No patient treated with tyrosine kinase inhibitors developed HBVr-related hepatic decompensation or died (Table 6).
      A panel of experts categorized the risk as low (<1 %), intermediate (1-10 %), or high (>10 %) and proposed standardized definitions for HBVr and reporting.

      Cytokine inhibitors

      There were 9 studies including 339 patients receiving only cytokine inhibitors (Table 5).
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      ,
      • Ahn S.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Park J.Y.
      • Lee S.W.
      Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience.
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      • Lin C.T.
      • Huang W.N.
      • Hsieh C.W.
      • Chen Y.M.
      • Chen D.Y.
      • Hsieh T.Y.
      • et al.
      Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - a three-year study in Taiwan.
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      In 6 studies with 71 HBsAg+ patients,
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      • Lin C.T.
      • Huang W.N.
      • Hsieh C.W.
      • Chen Y.M.
      • Chen D.Y.
      • Hsieh T.Y.
      • et al.
      Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - a three-year study in Taiwan.
      ,
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      the pooled HBVr rate was 23% overall (95% CI 14-34%; heterogeneity, p = 0.78): 0/26 patients receiving and 16/45 (35.5%) not receiving NA prophylaxis (pooled rate: 36%, 95% CI 23-50%; heterogeneity, p = 0.73) (Fig. 2D). In the same 6 studies, HBVr-associated hepatitis was observed in 3/71 patients overall (pooled rate: 4%, 95% CI 1-12%; heterogeneity, p = 1.00), and in 3/45 in the subgroup not receiving NA prophylaxis (pooled rate: 7%, 95% CI 2-19%; heterogeneity, p = 1.00) (Table 6).
      In 8 studies including 268 HBsAg-/anti-HBc+ patients,
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      ,
      • Ahn S.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Park J.Y.
      • Lee S.W.
      Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience.
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      ,
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      ,
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      the pooled HBVr rate was 2% overall (95% CI 1-5%; heterogeneity, p = 1.00): 0/33 patients receiving NA prophylaxis in 1 study
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      and 6/235 patients not receiving NA prophylaxis in 8 studies (pooled rate: 3%, 95% CI 1-6%; heterogeneity, p = 0.87) (Fig. 1C).
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      ,
      • Ahn S.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Park J.Y.
      • Lee S.W.
      Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience.
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      ,
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      ,
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      In the latter subgroup, HBVr-associated hepatitis occurred in only 1/235 patients (pooled rate: 0%, 95% CI 0-3%; heterogeneity, p = 1.00) (Table 6).
      No HBVr-related liver decompensation or death was observed among HBsAg+ or HBsAg-/anti-HBc+ patients treated with cytokine inhibitors (Table 6).

      T cell-depleting agents

      Four studies including 97 HBsAg+ patients treated with T cell-depleting agents were included (Table 7).
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Kim P.S.
      • Ho G.Y.
      • Prete P.E.
      • Furst D.E.
      Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      • Zappulo E.
      • Nicolini L.A.
      • Di Grazia C.
      • Dominietto A.
      • Lamparelli T.
      • Gualandi F.
      • et al.
      Efficacy of lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with resolved infection undergoing allogeneic SCT and receiving rituximab.
      In 2 studies,
      • Kim P.S.
      • Ho G.Y.
      • Prete P.E.
      • Furst D.E.
      Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.
      ,
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      HBVr was observed in 4/59 (6.8%) patients, 0/17 receiving and 4/42 (9.5%) not receiving NA prophylaxis (Table 8). In 1 study,
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      0/51 patients, of whom13 received and 38 did not receive NA prophylaxis, developed HBVr-associated hepatitis.
      Table 7Main characteristics of studies providing data on HBVr in HBsAg+ and/or anti-HBc+ patients receiving T cell-depleting agents or CAR T-cell immunotherapy.
      StudyStudy designMe(di)an age, yearsPatients, nHBsAg+ patients, nHBsAg-, anti-HBc+ patients, nProphylactic NAs, nFollow-up, monthsDefinition of HBVrDefinition of HBVr-associated hepatitis
      TotalAnti-HBs-Anti-HBs+
      T cell-depleting agents
      Kim 2012
      • Kim P.S.
      • Ho G.Y.
      • Prete P.E.
      • Furst D.E.
      Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.
      R58880--419HBV DNA ≥1-log increaseALT ≥3-fold increase
      Padovan 2016
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      R63725121n.a.n.a.1724HBV DNA >2,000 IU/ml or HBsAg seroreversionn.a.
      Zappulo 2019
      • Zappulo E.
      • Nicolini L.A.
      • Di Grazia C.
      • Dominietto A.
      • Lamparelli T.
      • Gualandi F.
      • et al.
      Efficacy of lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with resolved infection undergoing allogeneic SCT and receiving rituximab.
      ˆ
      R396060607.5n.a.n.a.
      Tokmak 2021
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      P6011011n.a.n.a.025HBV DNA reappearancen.a.
      CAR T-cell immunotherapy
      Cao 2020
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      R28-35561937532214HBV DNA ≥2 log increase
      For patients with detectable HBV DNA at baseline.
      or ≥3 log IU/ml
      For patients with undetectable HBV DNA at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      ALT >5xULN or bilirubin >3xULN
      Liu 2020
      • Liu W.
      • Huang W.
      • Wang M.
      • Lv R.
      • Li J.
      • Wang Y.
      • et al.
      Risk of hepatitis B reactivation is controllable in patients with B-cell lymphoma receiving anti-CD19 CAR T cell therapy.
      R53176111101110HBV DNA >1,000 IU/ml and/or HBsAg seroreversionn.a.
      Wang 2020
      • Wang Y.
      • Liu Y.
      • Tan X.
      • Pan B.
      • Ge J.
      • Qi K.
      • et al.
      Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection.
      P46411229326129HBV DNA >1 log increase
      For patients with detectable HBV DNA at baseline.
      or detectable
      For patients with undetectable HBV DNA at baseline.
      or >2000 IU/ml
      For patients with unknown HBV DNA levels at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      ALT ≥3xULN or >100 U/L
      Yang 2020
      • Yang C.
      • Xie M.
      • Zhang K.
      • Liu H.
      • Liang A.
      • Young K.H.
      • et al.
      Risk of HBV reactivation post CD19-CAR-T cell therapy in DLBCL patients with concomitant chronic HBV infection.
      R56151500015n.a.HBV DNA >1 log increase
      For patients with detectable HBV DNA at baseline.
      or detectable
      For patients with undetectable HBV DNA at baseline.
      ALT >100 U/L
      Li 2021
      • Li P.
      • Zhou L.
      • Ye S.
      • Zhang W.
      • Wang J.
      • Tang X.
      • et al.
      Risk of HBV reactivation in patients with resolved HBV infection receiving anti-CD19 chimeric antigen receptor T cell therapy without antiviral prophylaxis.
      P5930030921012HBV DNA ≥100 IU/ml on 2 consecutive measurementsALT 3×ULN
      Cui 2021
      • Cui R.
      • Lyu C.
      • Li Q.
      • Jiang Y.
      • Mou N.
      • Yang Z.
      • et al.
      Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.
      P3120515411810HBV DNA ≥2 log increase
      For patients with detectable HBV DNA at baseline.
      or ≥3 log IU/ml
      For patients with undetectable HBV DNA at baseline.
      or HBV DNA ≥4 log IU/ml
      For patients with unknown HBV DNA levels at baseline.
      or HBV DNA detectable
      For patients with negative HBsAg at baseline.
      or HBsAg seroreversion
      For patients with negative HBsAg at baseline.
      ALT ≥3xULN and >100 U/L
      Anti-HBC+, anti-hepatitis B core antibody positive; anti-HBs+/-, anti-hepatitis B surface antibody positive/negative; CAR, chimeric antigen receptor; HBVr, HBV reactivation; NA, nucleos(t)ide analogue; n.a., not available; P, prospective; R, retrospective; ULN, upper limit of normal.
      T cell-depleting agents: ∗Abatacept, ˆalemtuzumab.
      1 For patients with detectable HBV DNA at baseline.
      2 For patients with undetectable HBV DNA at baseline.
      3 For patients with negative HBsAg at baseline.
      4 For patients with unknown HBV DNA levels at baseline.
      Table 8HBVr in HBsAg+ and/or anti-HBc+ patients receiving T cell-depleting agents or CAR T-cell immunotherapy.
      StudyPatients with HBVr, n/NHBVr in relation to prophylactic NA, n/NPatients with HBVr-associated hepatitis, n/NHBVr-associated hepatitis in relation to prophylactic NA, n/NLiver decompensation, n/NDeath, n/N
      NANo NANANo NA
      T cell-depleting agents – HBsAg+ patients
      4/80/44/4n.a.0/8
      0/510/130/380/510/130/380/510/51
      T cell-depleting agents – HBsAg-, anti-HBc+ patients
      Padovan 2016
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      0/210/40/170/210/40/170/210/21
      Zappulo 2019
      • Zappulo E.
      • Nicolini L.A.
      • Di Grazia C.
      • Dominietto A.
      • Lamparelli T.
      • Gualandi F.
      • et al.
      Efficacy of lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with resolved infection undergoing allogeneic SCT and receiving rituximab.
      0/6-0/60/6-0/60/60/6
      Tokmak 2021
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      0/11-0/110/11-0/110/110/11
      CAR T-cell immunotherapy – HBsAg+ patients
      Cao 2020
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      1/191/19-1/191/19-0/190/19
      Liu 2020
      • Liu W.
      • Huang W.
      • Wang M.
      • Lv R.
      • Li J.
      • Wang Y.
      • et al.
      Risk of hepatitis B reactivation is controllable in patients with B-cell lymphoma receiving anti-CD19 CAR T cell therapy.
      0/60/6-0/60/6-0/60/6
      Wang 2020
      • Wang Y.
      • Liu Y.
      • Tan X.
      • Pan B.
      • Ge J.
      • Qi K.
      • et al.
      Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection.
      2/122/12-0/120/80/40/120/12
      Yang 2020
      • Yang C.
      • Xie M.
      • Zhang K.
      • Liu H.
      • Liang A.
      • Young K.H.
      • et al.
      Risk of HBV reactivation post CD19-CAR-T cell therapy in DLBCL patients with concomitant chronic HBV infection.
      3/153/15-0/150/15-0/150/15
      Cui 2021
      • Cui R.
      • Lyu C.
      • Li Q.
      • Jiang Y.
      • Mou N.
      • Yang Z.
      • et al.
      Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.
      0/50/5-0/50/50/50/5
      CAR T-cell immunotherapy – HBsAg-, anti-HBc+ patients
      Cao 2020
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      0/370/20/350/370/20/350/370/37
      Liu 2020
      • Liu W.
      • Huang W.
      • Wang M.
      • Lv R.
      • Li J.
      • Wang Y.
      • et al.
      Risk of hepatitis B reactivation is controllable in patients with B-cell lymphoma receiving anti-CD19 CAR T cell therapy.
      0/110/50/60/110/50/60/110/11
      Wang 2020
      • Wang Y.
      • Liu Y.
      • Tan X.
      • Pan B.
      • Ge J.
      • Qi K.
      • et al.
      Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection.
      1/29-1/290/29-1/290/290/29
      Li 2021
      • Li P.
      • Zhou L.
      • Ye S.
      • Zhang W.
      • Wang J.
      • Tang X.
      • et al.
      Risk of HBV reactivation in patients with resolved HBV infection receiving anti-CD19 chimeric antigen receptor T cell therapy without antiviral prophylaxis.
      2/30-2/301/30-1/300/300/30
      Cui 2021
      • Cui R.
      • Lyu C.
      • Li Q.
      • Jiang Y.
      • Mou N.
      • Yang Z.
      • et al.
      Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.
      1/150/31/121/150/31/121/151/15
      Anti-HBC+, anti-hepatitis B core antibody positive; CAR, chimeric antigen receptor; HBVr, HBV reactivation; NA, nucleos(t)ide analogue; n.a., not available.
      In 3 studies including 38 HBsAg-/anti-HBc+ patients, of whom 4 received and 34 did not receive NA prophylaxis,
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      ,
      • Zappulo E.
      • Nicolini L.A.
      • Di Grazia C.
      • Dominietto A.
      • Lamparelli T.
      • Gualandi F.
      • et al.
      Efficacy of lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with resolved infection undergoing allogeneic SCT and receiving rituximab.
      no HBVr was detected (Table 8).

      CAR T-cell immunotherapy

      There were 6 studies in patients receiving only CAR T-cell immunotherapy (Table 7).
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      • Cui R.
      • Lyu C.
      • Li Q.
      • Jiang Y.
      • Mou N.
      • Yang Z.
      • et al.
      Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.
      • Li P.
      • Zhou L.
      • Ye S.
      • Zhang W.
      • Wang J.
      • Tang X.
      • et al.
      Risk of HBV reactivation in patients with resolved HBV infection receiving anti-CD19 chimeric antigen receptor T cell therapy without antiviral prophylaxis.
      • Liu W.
      • Huang W.
      • Wang M.
      • Lv R.
      • Li J.
      • Wang Y.
      • et al.
      Risk of hepatitis B reactivation is controllable in patients with B-cell lymphoma receiving anti-CD19 CAR T cell therapy.
      • Wang Y.
      • Liu Y.
      • Tan X.
      • Pan B.
      • Ge J.
      • Qi K.
      • et al.
      Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection.
      • Yang C.
      • Xie M.
      • Zhang K.
      • Liu H.
      • Liang A.
      • Young K.H.
      • et al.
      Risk of HBV reactivation post CD19-CAR-T cell therapy in DLBCL patients with concomitant chronic HBV infection.
      In 5 studies,
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      ,
      • Cui R.
      • Lyu C.
      • Li Q.
      • Jiang Y.
      • Mou N.
      • Yang Z.
      • et al.
      Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.
      ,
      • Liu W.
      • Huang W.
      • Wang M.
      • Lv R.
      • Li J.
      • Wang Y.
      • et al.
      Risk of hepatitis B reactivation is controllable in patients with B-cell lymphoma receiving anti-CD19 CAR T cell therapy.
      • Wang Y.
      • Liu Y.
      • Tan X.
      • Pan B.
      • Ge J.
      • Qi K.
      • et al.
      Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection.
      • Yang C.
      • Xie M.
      • Zhang K.
      • Liu H.
      • Liang A.
      • Young K.H.
      • et al.
      Risk of HBV reactivation post CD19-CAR-T cell therapy in DLBCL patients with concomitant chronic HBV infection.
      HBVr was observed in 6/57 HBsAg+ patients who received NA prophylaxis (pooled rate: 11%, 95% CI 5-22%; heterogeneity, p = 0.81) (Fig. 2E). One of these 57 (1.8%) patients experienced HBVr-associated hepatitis, and none developed hepatic decompensation or died (Table 8).
      In 5 studies,
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      • Cui R.
      • Lyu C.
      • Li Q.
      • Jiang Y.
      • Mou N.
      • Yang Z.
      • et al.
      Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.
      • Li P.
      • Zhou L.
      • Ye S.
      • Zhang W.
      • Wang J.
      • Tang X.
      • et al.
      Risk of HBV reactivation in patients with resolved HBV infection receiving anti-CD19 chimeric antigen receptor T cell therapy without antiviral prophylaxis.
      • Liu W.
      • Huang W.
      • Wang M.
      • Lv R.
      • Li J.
      • Wang Y.
      • et al.
      Risk of hepatitis B reactivation is controllable in patients with B-cell lymphoma receiving anti-CD19 CAR T cell therapy.
      • Wang Y.
      • Liu Y.
      • Tan X.
      • Pan B.
      • Ge J.
      • Qi K.
      • et al.
      Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection.
      HBVr was observed in 4/122 (3.3%) HBsAg-/anti-HBc+ patients (pooled rate: 3%, 95% CI 1-8%; heterogeneity, p = 0.99): 0/10 receiving and 4/112 (3.6%) not receiving NA prophylaxis (Fig. 1D). Two of the 112 patients not receiving NA prophylaxis experienced HBVr-associated hepatitis (pooled rate: 2%, 95% CI 1-6%; heterogeneity, p = 0.99) and 1 patient developed liver decompensation and died (Table 8).

      Corticosteroids

      There were 6 studies including 3,866 patients receiving only corticosteroids (Table S1A).
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Hatano M.
      • Mimura T.
      • Shimada A.
      • Noda M.
      • Katayama S.
      Hepatitis B virus reactivation with corticosteroid therapy in patients with adrenal insufficiency.
      • Kim T.W.
      • Kim M.N.
      • Kwon J.W.
      • Kim K.M.
      • Kim S.H.
      • Kim W.
      • et al.
      Risk of hepatitis B virus reactivation in patients with asthma or chronic obstructive pulmonary disease treated with corticosteroids.
      • Notsumata K.
      • Nomura Y.
      • Tanaka A.
      • Nomura Y.
      • Ueda T.
      • Sanada T.
      • et al.
      Efficient prophylactic management of HBV reactivation by an information technology encoding system: results of a 6-year prospective cohort study.
      • Wong G.L.
      • Wong V.W.
      • Yuen B.W.
      • Tse Y.K.
      • Yip T.C.
      • Luk H.W.
      • et al.
      Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure.
      • Yang S.S.
      • Hung C.T.
      • Li S.F.
      • Lee H.M.
      • Chung Y.C.
      • Chen H.H.
      • et al.
      Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: a population-based study.
      Two studies included 1,728 HBsAg+ patients. In 1 study,
      • Kim T.W.
      • Kim M.N.
      • Kwon J.W.
      • Kim K.M.
      • Kim S.H.
      • Kim W.
      • et al.
      Risk of hepatitis B virus reactivation in patients with asthma or chronic obstructive pulmonary disease treated with corticosteroids.
      8/72 (11%) patients not receiving NA prophylaxis developed HBVr and all 8 patients were reported to have HBVr-associated hepatitis as well, but none developed liver decompensation or died. In the second study,
      • Yang S.S.
      • Hung C.T.
      • Li S.F.
      • Lee H.M.
      • Chung Y.C.
      • Chen H.H.
      • et al.
      Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: a population-based study.
      which only assessed mortality, 36/1,447 (2.5%) patients not receiving but 0/209 receiving NA prophylaxis were reported to have died due to HBVr (Table S2A1). In 4 studies including 2,138 HBsAg-/anti-HBc+ patients, none of whom received NA prophylaxis
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Hatano M.
      • Mimura T.
      • Shimada A.
      • Noda M.
      • Katayama S.
      Hepatitis B virus reactivation with corticosteroid therapy in patients with adrenal insufficiency.
      ,
      • Notsumata K.
      • Nomura Y.
      • Tanaka A.
      • Nomura Y.
      • Ueda T.
      • Sanada T.
      • et al.
      Efficient prophylactic management of HBV reactivation by an information technology encoding system: results of a 6-year prospective cohort study.
      ,
      • Wong G.L.
      • Wong V.W.
      • Yuen B.W.
      • Tse Y.K.
      • Yip T.C.
      • Luk H.W.
      • et al.
      Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure.
      (Table S1A), the pooled HBVr rate was 3% (95% CI 1-6%; heterogeneity, p <0.01), and no patient died. In 3 of the latter studies providing such data,
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Hatano M.
      • Mimura T.
      • Shimada A.
      • Noda M.
      • Katayama S.
      Hepatitis B virus reactivation with corticosteroid therapy in patients with adrenal insufficiency.
      ,
      • Notsumata K.
      • Nomura Y.
      • Tanaka A.
      • Nomura Y.
      • Ueda T.
      • Sanada T.
      • et al.
      Efficient prophylactic management of HBV reactivation by an information technology encoding system: results of a 6-year prospective cohort study.
      only 1/338 (0.3%) patients experienced HBVr-associated hepatitis (pooled rate: 0%, 95% CI 0-2%; heterogeneity, p = 1.00) and no patient developed decompensation (Table S2A2).
      Dose and duration of corticosteroids appear to influence the probability of HBVr, but a proper meta-analysis could not be performed due to the heterogeneity of corticosteroid dose groups among studies. In 1 study including 1,800 HBsAg-/anti-HBc+ patients,
      • Wong G.L.
      • Wong V.W.
      • Yuen B.W.
      • Tse Y.K.
      • Yip T.C.
      • Luk H.W.
      • et al.
      Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure.
      the probability of HBsAg seroreversion was not associated with corticosteroid dose and duration but the risk of hepatitis flare started to increase in patients receiving corticosteroids at peak daily doses of 20–40 mg or >40 mg prednisolone equivalents given for <7 days (adjusted hazard ratio compared to prednisolone <20 mg for <7 days: 2.19/2.11, p = 0.048/0.015, respectively) and increased further with treatment durations of 7–28 days and >28 days (adjusted hazard ratio 2.02–3.85; p <0.001–0.012). However, the cause of hepatitis flares was not examined in this study and many flares may not be related to HBVr.

      Anti-proliferative agents

      There were only 2 studies including 87 patients treated with anti-proliferative agents (Table S1B).
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Chen M.H.
      • Chen M.H.
      • Liu C.Y.
      • Tsai C.Y.
      • Huang D.F.
      • Lin H.Y.
      • et al.
      Hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologics treatment.
      One study
      • Chen M.H.
      • Chen M.H.
      • Liu C.Y.
      • Tsai C.Y.
      • Huang D.F.
      • Lin H.Y.
      • et al.
      Hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologics treatment.
      included 50 HBsAg+ patients, none of whom received NA prophylaxis; 9 (18%) experienced HBVr, while data on HBVr-associated hepatitis was not provided (Table S2B1). The second study
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      included 37 HBsAg-/anti-HBc+ patients, none of whom received NA prophylaxis; none developed HBVr (Table S2B2).

      Alkylating agents

      There were only 2 studies including 141 patients treated with alkylating agents (Table S1C).
      • Karaca M.
      • Tural D.
      • Akar E.
      • Çil I.
      • Bayrak S.
      • Ozet G.
      • et al.
      Hepatitis B reactivation rate is higher undergoing some cytotoxic chemotherapy in patients with solid tumors: a large retrospective study.
      ,
      • Watanabe M.
      • Shibuya A.
      • Takada J.
      • Tanaka Y.
      • Minamino T.
      • Okuwaki Y.
      • et al.
      Entecavir can reduce the incidence and severity of hepatitis B virus reactivation.
      One study included 133 HBsAg+ patients,
      • Karaca M.
      • Tural D.
      • Akar E.
      • Çil I.
      • Bayrak S.
      • Ozet G.
      • et al.
      Hepatitis B reactivation rate is higher undergoing some cytotoxic chemotherapy in patients with solid tumors: a large retrospective study.
      none of whom received NA prophylaxis, HBVr was reported in 17 (12.7%) patients all of whom experienced HBVr-associated hepatitis (Table S2C1). In another study including 8 HBsAg-/anti-HBc+ patients who did not receive NA prophylaxis,
      • Watanabe M.
      • Shibuya A.
      • Takada J.
      • Tanaka Y.
      • Minamino T.
      • Okuwaki Y.
      • et al.
      Entecavir can reduce the incidence and severity of hepatitis B virus reactivation.
      no HBVr was observed (Table S2C2).
      Immune checkpoint inhibitors, tyrosine kinase inhibitors, cytokine inhibitors, CAR T-cell immunotherapies, and corticosteroids were categorized as high risk in HBsAg+ patients.

      Calcineurin inhibitors

      There were only 2 studies including 145 patients treated exclusively with calcineurin inhibitors (Table S1D).
      • Chen M.
      • Zhuang J.
      • Zhou D.
      • Xu Y.
      • Zhao Y.
      • Wang S.
      • et al.
      Outcome of anti-thymocyte immunoglobulin plus cyclosporine A for severe aplastic anaemia with chronic hepatitis B virus infection.
      ,
      • Mikulska M.
      • Nicolini L.
      • Signori A.
      • Rivoli G.
      • Del Bono V.
      • Raiola A.M.
      • et al.
      Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome.
      In 1 study of HBsAg+ patients, HBVr was reported in 0/4 patients receiving and in 1/4 not receiving NA prophylaxis (Table S2D2).
      • Chen M.
      • Zhuang J.
      • Zhou D.
      • Xu Y.
      • Zhao Y.
      • Wang S.
      • et al.
      Outcome of anti-thymocyte immunoglobulin plus cyclosporine A for severe aplastic anaemia with chronic hepatitis B virus infection.
      In the second study of 137 HBsAg-/anti-HBc+ patients, none of whom received NA prophylaxis, HBVr was observed in 14 (10.2%), HBVr-associated hepatitis in 6 (4.4%), and liver decompensation and death in 3 (2.2%) patients (Table S2D2).
      • Mikulska M.
      • Nicolini L.
      • Signori A.
      • Rivoli G.
      • Del Bono V.
      • Raiola A.M.
      • et al.
      Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome.

      mTOR inhibitors

      There was only 1 study on mTOR inhibitors, which included 27 HBsAg+ patients (Table S1E).
      • Shiah H.S.
      • Chen C.Y.
      • Dai C.Y.
      • Hsiao C.F.
      • Lin Y.J.
      • Su W.C.
      • et al.
      Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma.
      HBVr-associated hepatitis was observed in 4/26 patients who did not receive NA prophylaxis; HBV DNA testing showed that all 4 patients had HBVr. None developed decompensation or died (Table S1F).

      Janus kinase inhibitors

      There was no study on Janus kinase inhibitor monotherapy in HBsAg+ patients and only 1 study in HBsAg-/anti-HBc+ patients. None of the 213 patients in this study received NA prophylaxis (Table S1F).
      • Harigai M.
      • Winthrop K.
      • Takeuchi T.
      • Hsieh T.Y.
      • Chen Y.M.
      • Smolen J.S.
      • et al.
      Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis.
      HBVr was observed in 30 (14.1%) patients, but none developed HBVr-associated hepatitis or liver decompensation (Table S2F).

      Discussion

      HBVr can be associated with a wide spectrum of immunosuppressants and immunomodulators. Because HBsAg+ and often HBsAg-/anti-HBc+ patients are excluded from clinical trials of immunosuppressants and immunomodulators, the incidence of HBVr associated with these therapies is unknown. Yet, when new immunosuppressants and immunomodulators are approved, they are used in patients with chronic or past HBV infection. While universal use of NA prophylaxis might prevent most if not all cases of HBVr, its use may not be necessary if the risk of HBVr is low. We conducted a systematic review of available publications up to 2021, and when possible meta-analyses to provide an estimate of the risk of HBVr associated with new classes of immunosuppressants and immunomodulators to guide the use of NA prophylaxis.
      In the 2015 systematic review organised by the American Gastroenterological Association,
      • Perrillo R.P.
      • Gish R.
      • Falck-Ytter Y.T.
      American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.
      ,
      • Reddy K.R.
      • Beavers K.L.
      • Hammond S.P.
      • Lim J.K.
      • Falck-Ytter Y.T.
      American Gastroenterological Association
      American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.
      the risk of HBVr associated with anti-TNF agents in HBsAg-/anti-HBc+ patients was rated as moderate. Our updated meta-analysis including 18 studies and 1,564 HBsAg-/anti-HBc+ patients receiving anti-TNF agents and no NA prophylaxis yielded a pooled HBVr risk of 1% (95% CI 1-2%) (Fig. 1A). While the pooled risk of 1% would marginally categorise the risk of HBVr as intermediate, HBVr-associated hepatitis developed in <0.1% (1/1481) of such patients without NA prophylaxis and no patient developed hepatic decompensation or died. In addition, data from recent large (>100 patients) studies indicate that the risk of HBVr associated with anti-TNF agents in HBsAg-/anti-HBc+ patients should be categorised as low. Specifically, 5 studies with a total of 677 patients (111-178 in each study) reported no HBVr,
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Barone M.
      • Notarnicola A.
      • Lopalco G.
      • Viggiani M.T.
      • Sebastiani F.
      • Covelli M.
      • et al.
      Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection.
      ,
      • Giannitti C.
      • Lopalco G.
      • Vitale A.
      • Rigante D.
      • Anelli M.G.
      • Fabbroni M.
      • et al.
      Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study.
      ,
      • Papalopoulos I.
      • Fanouriakis A.
      • Kougkas N.
      • Flouri I.
      • Sourvinos G.
      • Bertsias G.
      • et al.
      Liver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: an observational, controlled, long-term study.
      ,
      • Pauly M.P.
      • Tucker L.Y.
      • Szpakowski J.L.
      • Ready J.B.
      • Baer D.
      • Hwang J.
      • et al.
      Incidence of hepatitis B virus reactivation and hepatotoxicity in patients receiving long-term treatment with tumor necrosis factor Antagonists.
      and 2 studies with 102 and 241 patients reported HBVr in 1 patient each.
      • Fidan S.
      • Capkın E.
      • Arıca D.A.
      • Durak S.
      • Okatan I.E.
      Risk of hepatitis B reactivation in patients receiving anti-tumor necrosis factor-α therapy.
      ,
      • Lee J.M.
      • Wei S.C.
      • Lee K.M.
      • Ye B.D.
      • Mao R.
      • Kim H.S.
      • et al.
      Clinical course of hepatitis B viral infection in patients undergoing anti-tumor necrosis factor α therapy for inflammatory bowel disease.
      We did not evaluate the risk of HBVr associated with anti-TNF agents in HBsAg+ patients, which was rated as moderate in the 2015 systematic review,
      • Perrillo R.P.
      • Gish R.
      • Falck-Ytter Y.T.
      American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.
      ,
      • Reddy K.R.
      • Beavers K.L.
      • Hammond S.P.
      • Lim J.K.
      • Falck-Ytter Y.T.
      American Gastroenterological Association
      American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.
      though recent studies showed that risk is high and most experts agree that NA prophylaxis is indicated.
      • Lau G.
      • Yu M.L.
      • Wong G.
      • Thompson A.
      • Ghazinian H.
      • Hou J.L.
      • et al.
      APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.
      ,
      • Menter A.
      • Strober B.E.
      • Kaplan D.H.
      • Kivelevitch D.
      • Farley Prater E.
      • Stoff B.
      Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics.
      Immune checkpoint inhibitors have revolutionised the treatment of a wide variety of malignancies. While their primary action is to remove immune blockade hence enabling the immune destruction of tumour cells, it is unclear if immune checkpoint inhibitors can cause HBVr. A review of 8 studies including 1,001 HBsAg+ patients receiving NA prophylaxis
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      • Lee P.C.
      • Chao Y.
      • Chen M.H.
      • Lan K.H.
      • Lee I.C.
      • Hou M.C.
      • et al.
      Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.
      ,
      • Pertejo-Fernandez A.
      • Ricciuti B.
      • Hammond S.P.
      • Marty F.M.
      • Recondo G.
      • Rangachari D.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      ,
      • Cao W.
      • Wei J.
      • Wang N.
      • Xu H.
      • Xiao M.
      • Huang L.
      • et al.
      Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy.
      showed that the pooled rate of HBVr was 2% (95% CI 0-7%) overall but only 0.5% (4/861) when data were limited to 2 large studies.
      • Wong G.L.
      • Wong V.W.
      • Hui V.W.
      • Yip T.C.
      • Tse Y.K.
      • Liang L.Y.
      • et al.
      Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection.
      ,
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      The risk of HBVr among HBsAg+ patients not receiving NA prophylaxis was higher, with a pooled rate of 11% (95% CI 5-22%) but there were only 4 studies
      • Byeon S.
      • Cho J.H.
      • Jung H.A.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • et al.
      PD-1 inhibitors for non-small cell lung cancer patients with special issues: real-world evidence.
      • Chan G.H.
      • Gwee Y.X.
      • Low J.L.
      • Huang Y.
      • Chan Z.Y.
      • Choo J.R.
      • et al.
      Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: experience from a single Asian centre.
      • Lee P.C.
      • Chao Y.
      • Chen M.H.
      • Lan K.H.
      • Lee I.C.
      • Hou M.C.
      • et al.
      Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.
      ,
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      with a total of 56 patients and the risk was 6% (3/47) in the largest study.
      • Yoo S.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment.
      While the studies analysed indicated that the patients received immune checkpoint inhibitors only, given the frequent occurrence of immune-mediated adverse events necessitating high dose corticosteroids, it is unclear if all cases of HBVr can be solely attributed to immune checkpoint inhibitors. Moreover, most patients in these studies had advanced stage solid cancers and possible immune impairment from previous therapies or advanced malignancies, and many had hepatocellular carcinoma. Nonetheless, until further data are available, NA prophylaxis should be recommended in HBsAg+ patients who will be receiving immune checkpoint inhibitors. By contrast, only 2/1,006 (0.2%) HBsAg-/anti-HBc+ patients receiving immune checkpoint inhibitors and no NA prophylaxis were observed to have HBVr (Fig. 1B) suggesting that monitoring and on-demand NA therapy suffice for these patients.
      Many kinase inhibitors have been approved for treatment of malignancies in the last 30 years, with many more in clinical trials. We found only 4 studies
      • Orlandi E.M.
      • Elena C.
      • Bono E.
      Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia.
      • Sorà F.
      • Ponziani F.R.
      • Laurenti L.
      • Chiusolo P.
      • Autore F.
      • Gasbarrini A.
      • et al.
      Low risk of hepatitis B virus reactivation in patients with resolved infection and chronic myeloid leukemia treated with tyrosine kinase inhibitors.
      • Wang Y.H.
      • Liang J.D.
      • Sheng W.H.
      • Tien F.M.
      • Chen C.Y.
      • Tien H.F.
      Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-Experience in 142 adult patients with chronic myeloid leukemia.
      • Yao Z.H.
      • Liao W.Y.
      • Ho C.C.
      • Chen K.Y.
      • Shih J.Y.
      • Chen J.S.
      • et al.
      Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients.
      of patients receiving tyrosine kinase inhibitors alone, with pooled rates of HBVr of 11% (95% CI 7-16%) in 189 HBsAg+ patients not receiving NA prophylaxis (Fig. 2C), while no cases of HBVr were reported in 72 HBsAg-/anti-HBc+ patients not receiving NA prophylaxis, suggesting a need for NA prophylaxis in HBsAg+ but not in HBsAg-/anti-HBc+ patients.
      Several cytokine inhibitors have been approved for treatment of rheumatologic, gastrointestinal, and dermatologic conditions in recent years. We found 9 studies reporting on HBVr in patients receiving cytokine inhibitors alone,
      • Watanabe T.
      • Fukae J.
      • Fukaya S.
      • Sawamukai N.
      • Isobe M.
      • Matsuhashi M.
      • et al.
      Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.
      ,
      • Ahn S.S.
      • Jung S.M.
      • Song J.J.
      • Park Y.B.
      • Park J.Y.
      • Lee S.W.
      Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience.
      • Chen Y.M.
      • Chen H.H.
      • Huang W.N.
      • Chen Y.H.
      • Hsieh T.Y.
      • Yang S.S.
      • et al.
      Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: a long-term, real-world observation.
      • Chiu H.Y.
      • Chen C.H.
      • Wu M.S.
      • Cheng Y.P.
      • Tsai T.F.
      The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.
      • Chiu H.Y.
      • Hui R.C.Y.
      • Huang Y.H.
      • Huang R.Y.
      • Chen K.L.
      • Tsai Y.C.
      • et al.
      Safety profile of secukinumab in treatment of patients with psoriasis and concurrent hepatitis B or C: a multicentric prospective cohort study.
      • Kuo M.H.
      • Tseng C.W.
      • Lu M.C.
      • Tung C.H.
      • Tseng K.C.
      • Huang K.Y.
      • et al.
      Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab-containing treatment.
      • Lin C.T.
      • Huang W.N.
      • Hsieh C.W.
      • Chen Y.M.
      • Chen D.Y.
      • Hsieh T.Y.
      • et al.
      Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - a three-year study in Taiwan.
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      • Ting S.W.
      • Chen Y.C.
      • Huang Y.H.
      Risk of hepatitis B reactivation in patients with psoriasis on ustekinumab.
      but the number of patients in each study was small (range 3-64). Thus, while the pooled rate of HBVr of 36% (95% CI 23-50%) in HBsAg+ patients not receiving NA prophylaxis (Fig. 2D) suggest an indication for NA prophylaxis in HBsAg+ patients, more data are needed. By contrast, the pooled rate of HBVr was lower: 3% (95% CI 1-6%) in 235 HBsAg-/anti-HBc+ patients not receiving NA prophylaxis with 1 study of 19 patients accounting for 40% of HBVr cases,
      • Rodríguez-Tajes S.
      • Miralpeix A.
      • Costa J.
      • López-Suñé E.
      • Laguno M.
      • Pocurull A.
      • et al.
      Low risk of hepatitis B reactivation in patients with severe COVID-19 who receive immunosuppressive therapy.
      suggesting NA prophylaxis may not be necessary (Fig. 1C).
      Janus kinase inhibitors are used in the treatment of many immune-mediated and inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis as well as hematologic disorders such as myelofibrosis and graft-versus-host disease. We found only 1 study with HBVr in 30/213 (14%) HBsAg-/anti-HBc+ patients not receiving NA prophylaxis,
      • Harigai M.
      • Winthrop K.
      • Takeuchi T.
      • Hsieh T.Y.
      • Chen Y.M.
      • Smolen J.S.
      • et al.
      Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis.
      but none experienced HBVr-associated hepatitis, hepatic decompensation, or death.
      Cytokine inhibitors, CAR T-cell immunotherapies, and corticosteroids were categorized as intermediate risk in HBsAg-/anti-HBc+ patients.
      T cell-depleting agents are used in rheumatologic conditions. Only 4 studies reporting on HBVr were found.
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.
      ,
      • Kim P.S.
      • Ho G.Y.
      • Prete P.E.
      • Furst D.E.
      Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      • Zappulo E.
      • Nicolini L.A.
      • Di Grazia C.
      • Dominietto A.
      • Lamparelli T.
      • Gualandi F.
      • et al.
      Efficacy of lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with resolved infection undergoing allogeneic SCT and receiving rituximab.
      HBVr was observed in only 1 study where all 4 HBsAg+ patients not receiving NA prophylaxis had HBVr,
      • Kim P.S.
      • Ho G.Y.
      • Prete P.E.
      • Furst D.E.
      Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.
      but HBVr was not observed in 38 HBsAg+ patients in another study
      • Padovan M.
      • Filippini M.
      • Tincani A.
      • Lanciano E.
      • Bruschi E.
      • Epis O.
      • et al.
      Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection.
      or in 34 HBsAg-/anti-HBc+ patients not receiving NA prophylaxis in 3 studies.
      • Tokmak S.
      • Gümürdülü Y.
      • Taş D.A.
      • Kara I.O.
      • Güzel A.B.
      What is the risk of reactivation in patients with Resolved and Past HBV Infection during immunosuppressive therapy if HBV-DNA Negative before treatment?.