Higher level of HBsAg associated with delayed development of HCC in immune-tolerant patients

Active viral replication in patients with chronic HBV infection is a major risk factor for 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.

A total of 6139 non-cirrhotic Taiwanese patients with chronic HBV infection were enrolled, comprising 2666 patients from the ERADICATE-B study and 3473 patients from the 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. 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 log 10  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.

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.