Associations among family history of hepatitis B virus, baseline hepatitis B surface antigen and surface antigen clearance

BACKGROUND Hepatitis B virus family history (HBFH) is a prominent epidemiological characteristic of chronic hepatitis B (CHB) in China and has been associated with impaired antiviral immune responses.However, it remains unclear whether HBFH is independently associated with hepatitis B surface antigen (HBsAg) clearance following pegylated interferon-α (Peg-IFNα) treatment and, if so, through which pathways this association occurs.AIM To examine whether baseline HBsAg mediates the association between HBFH and Peg-IFNα-induced HBsAg clearance in patients with CHB.METHODS In this retrospective cohort study, patients with CHB receiving Peg-IFNα at Central Hospital, Tianjin University/Tianjin Third Central Hospital (December 2021-July 2025) were consecutively enrolled and followed for ≥ 48 weeks.Patients were categorized as HBFH-positive (HBFH-P) or HBFH-negative.The endpoint was HBsAg clearance (< 0.05 IU/mL).Cox proportional hazards regression assessed the association, and the Imai framework examined baseline HBsAg as a potential mediator.An age-adjusted and sex-adjusted probit model derived an exploratory baseline HBsAg threshold for HBFH-P patients.RESULTS Of the 1334 patients included, 688 (51.57%) were HBFH-P.Cox regression analysis showed that HBFH was significantly associated with a lower hazard of HBsAg clearance after adjustment for covariates (model I: Hazard ratio = 0.714, 95%CI: 0.538-0.946,P = 0.019).Mediation analysis demonstrated a total effect of HBFH on HBsAg clearance of -0.057 (P = 0.006).The average indirect effect mediated through 5 / 36 baseline HBsAg was -0.021 (P = 0.006), accounting for 36.84% of the total effect, whereas the remaining average direct effect was independent of baseline HBsAg (average direct effect = -0.036,P = 0.038).To achieve the same probability of HBsAg clearance, HBFH-P patients required a lower baseline HBsAg level than HBFHnegative patients.CONCLUSION HBFH is associated with lower HBsAg clearance in Peg-IFNα-treated CHB patients, with approximately 37% of this association mediated by baseline HBsAg.HBFH-P patients may require a lower HBsAg level, although this warrants validation.