TNF-α Inhibitors and HBV Reactivation Risk in HBsAg-/Anti-HBc+ Patients: A Systematic Review and Meta-Analysis.

BACKGROUND

Tumour necrosis factor-α (TNF-α) inhibitors are integral in the treatment of immune-mediated inflammatory diseases but may precipitate hepatitis B virus reactivation (HBVr) in HBsAg-/anti-HBc+ patients. APASL guidance presumes a greater risk with higher-potency agents, but the evidence is limited and conflicting. We conducted a systematic review and meta-analysis to assess whether TNF-α inhibitor potency alters HBVr risk in HBsAg-/anti-HBc+ individuals and to identify predictors.

METHODS

PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched on May 29, 2025. Eligible cohort studies and randomised trials reported HBVr under TNF-α inhibitor treatment in HBsAg-/anti-HBc+ patients. The risk of bias was assessed via the Newcastle-Ottawa Scale and the RoB 2.0. Random-effects meta-analysis was used to pool the HBV incidence and risk ratios (RRs), and subgroup analyses were used to explore heterogeneity.

RESULTS

Thirteen cohorts (1492 patients) reported 37 HBVr events, yielding a pooled incidence of 2.3% (95% CI 1.1%-4.8%; I2 = 56%). The incidence was 3.9% (95% CI 2.1%-7.0%; I2 = 34%) with high-potency agents and 3.6% (95% CI 2.2%-5.8%; I2 = 0%) with low-potency agents. High- and low-potency TNF-α inhibitors were associated with comparable HBVr risk (RR 0.92, 95% CI 0.47-1.79; I2 = 0%). Agent-specific incidences ranged from 3.6% to 5.4%, without significant differences compared with etanercept. Anti-HBs seronegativity conferred a greater risk (incidence, 8.2% vs. 3.1%; RR 2.77, 95% CI 1.42-5.39). The reactivation risk did not vary by geography, age, indication, follow-up, design, or bias rating.

CONCLUSION

In HBsAg-/anti-HBc+ patients, TNF-α inhibitor potency did not significantly alter the already low risk of HBVr. Continued surveillance is warranted, particularly in anti-HBs-negative individuals.

TRIAL REGISTRATION: INPLASY202570100.