Potential of ultra-highly sensitive immunoassays for hepatitis B surface and core-related antigens in patients with or without development of hepatocellular carcinoma after hepatitis B surface antigen seroclearance.

AIMS Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B virus (HBV) infection (CHB). However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core-related antigen (HBcrAg), measured by the ultra-highly sensitive assays, in cases with HCC development after HBsAg seroclearance. METHODS We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (5 HCC patients and 12 non-HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra-highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology. RESULTS All 5 patients who developed HCC were positive for HBsAg or HBcrAg by iTACT-HBsAg or iTACT-HBcrAg at all follow-up points. HBcrAg levels in the HCC group, using iTACT-HBcrAg, were significantly higher than those in the non-HCC group at HBsAg seroclearance (3.6 LogU/mL (2.8-4.2) vs. 2.6 (<2.1-3.8), p=0.020). The best cutoff value of iTACT-HBcrAg for predicting HCC development was 2.7 LogU/mL by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non-HCC group (100% (5/5) vs. 33% (4/12), p=0.029). CONCLUSIONS Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients. (239 words).