The widespread application of interleukin (IL) inhibitors for various conditions, including gastrointestinal, rheumatologic, dermatologic and pulmonary diseases, has raised concerns regarding the potential for hepatitis B virus reactivation (HBVr). However, the precise risk of HBVr remains unclear due to inconsistencies in existing research. This systematic review aims to quantify the risk of HBVr in patients receiving IL inhibitor therapies.

This systematic review will follow Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search will be conducted in MEDLINE, PubMed, Google Scholar, CENTRAL, Scopus, Embase, Web of Science and ClinicalTrials.gov up to October 2025. Two reviewers will independently screen studies and extract data, resolving discrepancies by consensus. Eligible studies will include HBV-infected patients receiving IL inhibitors. HBVr rates will be estimated using a generalised linear mixed model with a binomial distribution, applying random-effects models to account for interstudy variability. Heterogeneity will be assessed using I², Cochran’s Q and ². Leave-one-out sensitivity analyses will evaluate robustness. Subgroup analyses will consider HBV serostatus, IL inhibitor type and study characteristics. Studies including patients on antiviral prophylaxis will be excluded from the primary analysis. A secondary analysis will assess prophylaxis efficacy in preventing HBVr according to hepatitis B surface antigen status. Publication bias will be evaluated using Doi plots and the Luis Furuya-Kanamori index.

This study does not require ethics approval as it involves no patient-specific data. Findings will be disseminated at gastroenterology conferences and through peer-reviewed publications.

The protocol is registered in PROSPERO (CRD42024614179).