Association Between Hepatitis B Surface Antigen Positivity and Tumor Incidence: A Large Prospective Cohort Study in Southern China

Background: Hepatitis B virus (HBV) infection is a major global health concern and has been implicated in carcinogenesis. However, evidence regarding the association between hepatitis B surface antigen (HBsAg) positivity and the risk of overall and site-specific tumors remains limited. This study aimed to investigate the association between HBsAg positivity and tumor incidence in a large prospective cohort. Methods: This prospective cohort study included 538,573 participants recruited in southern China between 2009 and 2015. Newly recorded tumor diagnoses were identified by linkage to a hospital discharge database available through December 2022. Missing covariate values were addressed using five multiple imputations, and propensity score matching was performed separately within each dataset. Cox model estimates were combined using Rubin’s rules. Time-varying and landmark analyses were also performed. Results: Baseline HBsAg positivity was associated with increased risks of all-site tumors (pooled hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.79–2.27), digestive system malignancies (pooled HR, 4.28; 95% CI, 3.51–5.22), and benign tumors (pooled HR, 1.52; 95% CI, 1.27–1.82). Strong associations were observed for liver and intrahepatic bile duct malignancies (pooled HR, 15.49; 95% CI, 8.99–26.67) and hepatocellular carcinoma (pooled HR, 19.78; 95% CI, 7.19–54.44). In contrast, the association with extrahepatic digestive system malignancies was not statistically significant. The associations generally attenuated over follow-up but persisted after excluding tumor events recorded within the first 1 and 2 years. Stronger associations with all-site tumors were observed among men and participants aged ≥45 years. Conclusions: Baseline HBsAg positivity was associated with an increased risk of overall and site-specific tumors, particularly digestive system malignancies. The associations were stronger among men and older adults. These findings support further clinical evaluation of HBsAg-positive individuals and guideline-based liver cancer surveillance when clinically indicated.