Higher level of Hepatitis B Surface antigen associated with delayed development of hepatocellular carcinoma in immune-tolerant patients

Abstract

Background: Active viral replication in patients with chronic HBV infection is a major risk factor for hepatocellular carcinoma (HCC). However, the HCC risk in highly viremic patients, such as immune-tolerant patients, remains unclear. This study aimed to investigate the relationship between viral factors and HCC risk in patients with chronic HBV infection, focusing on immune-tolerant patients. Patients and Methods: A total of 6,139 non-cirrhotic Taiwanese patients with chronic HBV infection were enrolled, comprising 2,666 patients from ERADICATE-B study and 3,473 patients from REVEAL-HBV study. The primary endpoint was HCC development. The relationships between viral factors and HCC risk in HBeAg-positive and HBeAg-negative patients were analyzed separately. Results: Over a median 21.7-year follow-up, 547 patients developed HCC. The relationship between viral factors and HCC risk varied depending on HBeAg status. HCC risk increased with viral load and plateaued at ≥5 log10 IU/mL in HBeAg-negative patients, while showing limited correlation in HBeAg-positive patients. Conversely, HBsAg levels were positively associated with HCC risk in HBeAg-negative patients but negatively associated in HBeAg-positive patients. Further investigation focusing on HBeAg-positive immune-tolerant patients showed that HBsAg levels ≥10,000 IU/mL (vs. <10,000 IU/mL) were associated with delayed HCC development, which was validated both internally through various subgroup analyses and externally by an independent Japanese cohort. Conclusion: Predictive roles of HBV DNA and HBsAg levels in HCC development differ between HBeAg-negative and HBeAg-positive patients. Particularly, among immune-tolerant patients, HBsAg levels ≥10,000 IU/mL showed delayed development of HCC, suggesting HBsAg as a biomarker to define genuine immune-tolerant patients.