Increased Risk of Hepatitis B Virus Reactivation in Patients with Resolved Hepatitis B Virus Infection Receiving Combination Immunosuppressive Therapy: The Role of Anti-HBs Status

Abstract

Background/Aims: Patients with prior exposure to hepatitis B virus (HBV) (HBsAg [Hepatitis B surface antigen]-negative/anti-HBc [Hepatitis B core] immunoglobulin G (IgG)-positive) who receive immunosuppressive therapy (IST) remain susceptible to HBV reactivation (HBVr). Current clinical guidelines generally estimate HBVr risk according to the immunosuppressive potential of individual agents. However, evidence regarding the cumulative risk associated with the concurrent use of multiple agents within the same risk category remains limited. The current study investigated the effect of frequently used moderate risk IST combinations on the development of HBVr.

Materials and Methods: A total of 406 HBsAg-negative/anti-HBc IgG-positive patients treated with moderate-risk IST were retrospectively analyzed. Patients were classified according to the treatment regimen into monotherapy (n = 178) and combination therapy (n = 228). HBVr was defined as either HBsAg seroconversion or the detection of HBV DNA during follow-up. The incidence of HBVr was compared between groups.

Results: No significant differences were observed between the groups in baseline demographic and clinical features, including age, sex, and IST-related risk profiles. Among patients receiving combination therapy (58.7% female; mean age 62.8 ± 10.2 years), HBVr occurred in 6 patients, including 4 cases with HBV flare, whereas no reactivation occurred in the monotherapy group (62.3% female; mean age 63.6 ± 10.1 years). All patients who developed HBVr were anti-HBs-negative at baseline. HBVr occurred significantly more frequently among patients receiving combination therapy (P < .05).

Conclusion: The use of combination IST and baseline anti-HBs negativity were identified as 2 important factors associated with increased risk of HBVr in HBsAg-negative/anti-HBc IgG-positive patients. In this subgroup, a clinical approach favoring antiviral prophylaxis may be considered. Further prospective studies with larger sample sizes are needed to fully elucidate this association.

Cite this article as: Sadeçolak M, Düzenli T, Durak İ, et al. Increased risk of hepatitis B virus reactivation in patients with resolved hepatitis B virus infection receiving combination immunosuppressive therapy: The role of anti-HBs status. Turk J Gastroenterol. 2026;37(7):793-801.