Association between Hepatitis B Surface Antigen Levels and the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection: Systematic Review and Meta-Analysis

BACKGROUND: The role of hepatitis B surface antigen (HBsAg) levels in predicting the risk of developing hepatocellular carcinoma (HCC) has remained unclear. The aim of this study was to obtain the most up-to-date estimated measure of the association between HBsAg levels and the development of HCC in patients. METHODS: We performed a systematic review by searching for relevant studies on PubMed, Scopus, ProQuest and the Cochrane Central Register of Controlled Trials from January 2002 to November 2017. We presented the effects of HBsAg levels at each cut-off value as the odds ratios (ORs) at 95% confidence interval (CI). We also investigated HCC and its potential risk factors including HBeAg, and HBV DNA. We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42018081138. RESULTS: We selected 10 studies representing 12 541 cases. At the 100 IU/ml cut-off, the OR for HCC at the high HBsAg level versus the low level was 4.99 (95% CI, 3.01–8.29) with high inconsistency (I(2)=79%). At the 1,000 IU/ml threshold, the pooled OR for HCC at the high HBsAg versus the low level was 2.46 (95% CI, 2.15–2.83) with low variance. We also found correlations between the risk of HCC and male gender (OR=2.12), hepatitis B e-antigen positivity (OR=2.99), or hepatitis B (HBV) viral load ≥ 2,000 IU/ml (OR=4.37). CONCLUSION: Our study revealed that HBsAg levels ≥ 100 IU/ml, and notably >1,000 IU/ml, are associated with an increased risk of HCC development.