Phase-dependent interpretation of quantitative hepatitis B surface antigen and hepatocellular carcinoma risk in chronic hepatitis B infection

Table 1 Phase-dependent interpretation of quantitative hepatitis b surface antigen for hepatocellular carcinoma risk stratification

Disease phase	Typical qHBsAg	Primary HBsAg source	The qHBsAg-HCC association	Key evidence	Clinical action beyond guidelines	Ref.
HBeAg-positive chronic infection	> 10000 IU/mL	cccDNA (replication-driven)	Inverse or neutral; higher HBsAg associated with delayed HCC	ERADICATE-B/REVEAL-HBV (n = 6139; 21.7 years f/u): HBsAg ≥ 10000 associated with delayed HCC in HBeAg-positive	The qHBsAg not recommended; HBV DNA is dominant predictor	Kumada et al[1], Tseng et al[4], Yang et al[6]
HBeAg-negative, low viremia (DNA < 2000 IU/mL)	100 to > 1000 IU/mL	Integrated HBV DNA	Strongly positive; HR 13.7 (4.8-39.3) for ≥ 1000 vs < 1000	ERADICATE-B (n = 2688; 14.7 years); Shanghai OR 2.21 (1.10-4.43); meta-analysis OR 2.46 (2.15-2.83)	Measure qHBsAg; if ≥ 1000 sustained ≥ 1 year: Enhanced surveillance and consider treatment	Seto et al[2], Terrault et al[3], Tseng et al[4]
Indeterminate phase (“grey zone“)	Variable	Mixed	Positive; biomarkers stratify heterogeneous risk	HBcrAg stratified risk (HR = 4.47, 2.62-7.63); annual HCC 0.32%	The qHBsAg > 1000 may identify higher-risk subset	Tseng et al[4], Ghany et al[25]
Intermediate viremia (DNA 2000-20000 IU/mL)	Variable	Mixed	Attenuated; HBcrAg may be more informative	HBcrAg ≥ 10 KU/mL: HR = 6.29 (2.27-17.48)	Modest adjunctive value; HBcrAg preferred	Zhao et al[23]
High viremia (DNA > 20000 IU/mL)	> 10000 IU/mL	cccDNA	Neutral; HBV DNA dominates	REVEAL-HBV: HR of 10.7 for DNA ≥ 200000 vs undetectable	The qHBsAg not recommended; manage per guidelines	Yucuma et al[5], Grudda et al[9]
Cirrhosis/advanced fibrosis (F3-F4)	Variable	Variable	Neutral; fibrosis dominates	Annual HCC 3%-5%; AASLD recommends surveillance for all	Fibrosis supersedes viral biomarkers	Tseng et al[4], Mahajan et al[8]

Integration burden is inferred from persistently elevated quantitative hepatitis B surface antigen in low-viremic patients; it is not directly measurable in clinical practice. Hazard ratios represent estimates from individual cohort studies and meta-analyses; individual patient risk varies. Fibrosis stage remains the dominant predictor of hepatocellular carcinoma risk in patients with advanced fibrosis/cirrhosis and supersedes viral biomarkers in clinical decision-making. Quantitative hepatitis B surface antigen cutoffs (100 IU/mL, 1000 IU/mL) were derived from Asian cohorts with hepatitis B virus genotypes B and C and have not been validated in non-Asian populations. AASLD: American Association for the Study of Liver Diseases; cccDNA: Covalently closed circular DNA; HBcrAg: Hepatitis B core-related antigen; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HR: Hazard ratio; OR: Odds ratio; qHBsAg: Quantitative hepatitis B surface antigen.

Table 2 Implementation barriers and proposed solutions for quantitative hepatitis b surface antigen-guided risk stratification

Barrier	Details	Proposed solution
Cost	$50-$100 per test	Targeted testing in higher-risk subgroups (age > 50, family history of HCC, ≥ F2 fibrosis)
Insurance coverage	Not covered in some regions	Advocate for coverage in high-risk subgroups (HBeAg-negative, low viremia)
Accessibility	Not available in low-resource settings where HBV burden is highest	Point-of-care qHBsAg tests in development; advocate for technology transfer[40]
Assay standardization	Different absolute values across platforms (Abbott, Roche, Siemens)	Use same platform for serial monitoring; cross-platform calibration studies needed
Clinician training	Unfamiliarity with phase-dependent interpretation	Educational materials and clinical decision aids
Turnaround time	Results may take days	Not suitable for same-day decisions; plan testing at routine visits
Genotype applicability	Cutoffs validated only for genotypes B and C	Prospective validation in non-Asian populations required before broad adoption[3,40]

HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HBeAg: Hepatitis B e antigen; qHBsAg: Quantitative hepatitis B surface antigen.