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Meta-Analysis
. 2022 Dec;77(6):1670-1689.
doi: 10.1016/j.jhep.2022.07.003. Epub 2022 Jul 16.

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

George V Papatheodoridis  1 , Vasileios Lekakis  1 , Thodoris Voulgaris  1 , Pietro Lampertico  2 , Thomas Berg  3 , Henry L Y Chan  4 , Jia-Horng Kao  5 , Norah Terrault  6 , Anna S Lok  7 , K Rajender Reddy  8
Affiliations
Meta-Analysis

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

George V Papatheodoridis et al. J Hepatol. 2022 Dec.

Abstract

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: Antiviral prophylaxis; Biologics; Chemotherapy; Hepatitis flares; Immunotherapy.

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Conflict of interest statement

Conflict of interest George Papatheodoridis has received research grants from Abbvie and Gilead, and has served as advisor/lecturer for Abbvie, Albireo, Dicerna, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche and Takeda. Vasileios Lekakis and Thodoris Voulgaris have nothing to disclose. Pietro Lampertico has served as speaking bureau/advisor for Abbvie, Eiger, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck/Merck Sharp & Dohme, MYR Pharma, Roche, Vir, Antios and Aligos. Thomas Berg has received grant support from Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Norgine, Novartis, Orphalan, Sequana Medica Honoraria, served as a consultant for Abbvie, Alexion, Bayer, Gilead, GSK, Eisai, Enyo Pharma, Falk Foundation, HepaRegeniX GmbH, Humedics, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, Orphalan, Roche, Sequana Medical, SIRTEX, SOBI, Shionogi, and has served in the speakers bureau for Abbvie, Alexion, Bayer, Gilead, Eisai, Intercept, Ipsen, Janssen, MedUpdate GmbH, MSD/Merck, Novartis, Orphalan, Sequana Medica, SIRTEX, and SOBI. Henry Chan has served as an advisor for AbbVie, Aligos, Arbutus, Gilead Sciences, GlaxoSmithKline, Hepion, Roche, Vaccitech, Vir Biotechnology, Virion Therapeutics and as a lecturer for Gilead Sciences, Roche, Viatris. Jia-Horng Kao has served as advisor/consultant to Abbvie, Arbutus, BMS, Gilead, and Roche. Norah Terrault has received grant support (paid to the institution) from Gilead, GSK, Helio Health, Roche-Genentech and serves as an advisor Moderna and GSK. Anna Lok has received research grants (paid to institution) from Gilead and TARGET, and serves as advisor/consultant to Arbutus, ClearB, Enanta, Enochian, GNI, GlaxoSmithKline, Janssen, Novo Nordisk (DSMB), TARGET (unpaid), and Virion. K. Rajender Reddy has received grant support (paid to the institution) from BMS, Gilead, Merck, Intercept, Sequana, Grifols, BioVie, HCC-TARGET, HCV-TARGET, NASH-TARGET, EXACT Sciences and serves as an advisor to Spark Therapeutics, Mallinckrodt and DSMB-Novartis. Please refer to the accompanying ICMJE disclosure forms for further details.

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