HBsAg glycan isomer: a potential circulating biomarker for monitoring cccDNA and predicting virologic response in chronic hepatitis B.

BACKGROUND: Previous research has identified that Hepatitis B surface antigen glycan isomer (HBsAgGi) specifically marks O-glycosylated M-HBsAg exclusively present on infectious Dane particles (unlike total HBsAg, which is dominated by non-infectious subviral particles), it offers a more specific association with infectious viral burden and cccDNA activity. Accordingly, the present study aims to assess the potential of HBsAgGi as a circulating biomarker to reflect intrahepatic covalently closed circular DNA (cccDNA) and transcriptional activity, and for monitoring antiviral response. METHODS: A total of 73 individuals diagnosed with chronic genotype C HBV infection were recruited for this study. Serum concentrations of HBsAgGi, HBsAg, HBeAg, HBV DNA, and HBV RNA were measured. Intrahepatic cccDNA and HBV RNA loads were determined in liver biopsy specimens obtained from 16 patients. Correlations between serum HBsAgGi and intrahepatic markers were analyzed. We measured serum Hepatitis B core-related antigen (HBcrAg) levels in 28 patients. 18 patients received nucleos(t)ide analogue therapy for 48 weeks and we evaluated levels of HBsAgGi after therapy. Additionally, receiver operating characteristic (ROC) curve analysis was conducted to assess the discriminative ability of the candidate biomarkers in predicting virological response (VR). RESULTS: Serum HBsAgGi demonstrated significant positive correlations with intrahepatic cccDNA (r = 0.7172, P < 0.01), HBV RNA (r = 0.7879, P < 0.01), and the RNA/cccDNA ratio (r = 0.5840, P < 0.05), showing stronger correlations than conventional serum markers (HBcrAg, HBV RNA, DNA, HBsAg). HBsAgGi also showed the strongest correlation with serum HBcrAg (r = 0.5361, P < 0.01) in 28 patients. During treatment, HBsAgGi levels declined and baseline HBsAgGi predicted VR with superior accuracy (AUC = 0.9538) versus other markers. CONCLUSION: Serum HBsAgGi represents an emerging, minimally invasive serum indicator for assessing intrahepatic cccDNA loads and viral transcriptional activity, demonstrating stronger correlations with intrahepatic markers compared to conventional serum markers in this cohort. It also shows promising utility for predicting treatment response.