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• In a pooled analysis of 2,674 non‑cirrhotic, HBeAg‑negative patients with inactive chronic hepatitis B (CHB) from two Asian cohorts, baseline HBsAg <100 IU/mL identified a subgroup with an annual HCC incidence of 0.08% (95% CI 0.05–0.13%), below commonly used surveillance thresholds (~0.2%/year).
• The HBsAg <100 IU/mL group had a markedly lower adjusted hazard for HCC (adjusted HR 0.35; 95% CI 0.21–0.61) compared with those with HBsAg ≥100 IU/mL, even after accounting for age and other covariates.
• Combining HBsAg <100 IU/mL with normal ALT enabled identification of low‑risk patients without requiring HBV DNA testing; findings were externally validated in an independent hospital cohort (NTUH‑iMD).
Background
Chronic hepatitis B virus (HBV) infection remains a leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Risk stratification guides surveillance intensity: lifelong ultrasound ± alpha‑fetoprotein is recommended for higher‑risk groups because HCC surveillance is resource‑intensive and carries potential harms from overdiagnosis and false positives. Identifying biologically defined, reliably low‑risk subgroups would allow more targeted surveillance and inform operational definitions of partial HBV cure.
HBsAg quantification has emerged as a practical biomarker that reflects composite viral activity from both cccDNA and integrated HBV DNA. Lower serum HBsAg levels correlate with reduced intrahepatic viral transcriptional activity and have been proposed as markers of inactive carrier state and as predictors of favourable clinical trajectories.
Study design
This analysis (Tseng et al., Gut 2025) pooled data from two long‑term Asian population cohorts—ERADICATE‑B and REVEAL‑HBV—comprising 2,674 patients meeting strict inactive CHB criteria: non‑cirrhotic, HBeAg‑negative, persistently normal alanine transaminase (ALT), and HBV DNA <2,000 IU/mL at baseline. The primary endpoint was incident HCC during follow‑up. Baseline serum HBsAg levels were measured and used to stratify risk; the prespecified clinical aim was to identify a subgroup with annual HCC risk below 0.2% (a commonly cited surveillance threshold used in cost‑effectiveness and guideline discussions).
Key features of the study population included a long median follow‑up (26.3 years), allowing robust estimation of long‑term event rates, and external validation using an independent hospital registry cohort (NTUH‑iMD).
Key findings
Patient numbers and outcomes
Of 2,674 inactive CHB patients included, 76 developed HCC over a median follow‑up of 26.3 years. When stratified by baseline HBsAg, 989 patients had HBsAg <100 IU/mL.
Absolute and relative HCC risk
The annual HCC incidence among patients with HBsAg <100 IU/mL was 0.08% (95% CI 0.05–0.13%), substantially lower than in those with HBsAg ≥100 IU/mL. After multivariable adjustment (including age, sex, and other clinical covariates), HBsAg <100 IU/mL was associated with a 65% lower hazard of HCC compared with higher HBsAg levels (adjusted HR 0.35; 95% CI 0.21–0.61).
Comparison to surveillance thresholds
The observed annual incidence in the HBsAg <100 IU/mL group was well below the frequently referenced surveillance threshold of ~0.2% per year, and approached estimated background HCC risk in general population cohorts—supporting the argument that this subgroup may not derive net benefit from routine surveillance programs targeted at higher‑risk CHB patients.
Subgroup and age considerations
Importantly, even among older patients (groups conventionally considered for surveillance), those with baseline HBsAg <100 IU/mL retained an annual HCC risk below the surveillance threshold. This suggests that HBsAg level may refine age‑based decisions in clinical practice.
Validation and simplified algorithms
The investigators validated the primary observations in the external NTUH‑iMD cohort. They further tested a simplified, pragmatic approach: using HBsAg <100 IU/mL together with normal ALT to identify low‑risk inactive carriers without contemporaneous HBV DNA measurement. This combination performed well in the validation cohort, offering a resource‑sparing strategy in low‑resource settings where HBV DNA testing is costly or unavailable.
Safety and secondary outcomes
No safety signals are applicable to an observational prognostic study. The practical implication is surveillance de‑escalation in low‑risk groups; the authors emphasise that clinical decisions must still account for evolving liver disease, fibrosis assessments, alcohol use, metabolic risk factors, and new symptoms that could change risk status.
Effect sizes of clinical relevance
• Annual HCC incidence with HBsAg <100 IU/mL: 0.08% (95% CI 0.05–0.13%).
• Adjusted hazard ratio for HCC for HBsAg <100 IU/mL vs ≥100 IU/mL: 0.35 (95% CI 0.21–0.61).
• Findings robust on external validation in the NTUH‑iMD cohort.
Expert commentary and interpretation
Clinical interpretation
These results build on existing knowledge that low HBsAg levels identify an inactive carrier phenotype with very low oncogenic potential. The strengths of the analysis include large sample size, very long follow‑up, and external validation. If replicated across diverse populations and incorporated into prospective decision rules, HBsAg quantification could help avoid unnecessary lifelong surveillance in clearly low‑risk patients, reduce healthcare costs, and lessen patient anxiety and false positive workups.
Biological plausibility
HBsAg derives from transcriptionally active cccDNA and integrated HBV sequences; persistently low HBsAg suggests minimal ongoing intrahepatic viral expression and low inflammatory drive—mechanisms plausibly linked to reduced hepatocarcinogenesis.
Limitations and cautions
Key limitations include the study population’s Asian origin, with likely predominance of HBV genotypes B and C; risk thresholds and biomarker dynamics may differ in other genotypes or ethnic groups. The cohorts predate widespread antiviral use for most subjects; antiviral therapy can alter HBsAg trajectories and HCC risk. HBsAg assays vary by platform—standardisation and cross‑platform validation are required before universal clinical adoption of a fixed 100 IU/mL cutoff. Finally, the observational design cannot fully account for all confounders; prospective interventional studies or decision‑analytic modelling would strengthen recommendations.
Guideline context
Current international guidelines (EASL, AASLD) recommend HCC surveillance for patients with cirrhosis and selected high‑risk noncirrhotic subgroups, typically guided by age, sex, family history, and viral activity indicators. This study provides evidence that a measurable biomarker (HBsAg) can add prognostic precision and may inform guideline revisions pending external confirmation.
Clinical implications and practical recommendations
Potential practice implications
• Consider measuring quantitative HBsAg in patients with presumed inactive CHB to refine HCC surveillance decisions—patients with HBsAg <100 IU/mL and persistently normal ALT may be counselled that their HCC risk is very low and similar to background population risk.
• Where HBV DNA testing is limited, a pragmatic algorithm combining HBsAg <100 IU/mL and normal ALT could be used to identify low‑risk patients, while ensuring mechanisms are in place for periodic reassessment (e.g., annual ALT, fibrosis assessment) and re‑entry into surveillance if clinical status changes.
• Do not discontinue surveillance in patients with additional risk factors (advanced fibrosis/cirrhosis, family history of HCC, persistent high HBV DNA, metabolic risk factors) regardless of HBsAg level.
Research gaps and future directions
Important next steps include prospective validation in non‑Asian cohorts and in settings with different HBV genotypes, assessment of HBsAg dynamics over time (not just baseline values), integration with fibrosis measures (transient elastography, serum fibrosis biomarkers) in multivariable risk scores, and cost‑effectiveness analyses of surveillance de‑escalation strategies guided by HBsAg. Studies evaluating how antiviral therapy modifies the predictive value of HBsAg are also needed.
Conclusion
The study by Tseng and colleagues offers compelling evidence that baseline HBsAg <100 IU/mL identifies a substantial subgroup of inactive chronic HBV patients with a negligible annual risk of HCC (≈0.08%/year). This biomarker threshold—especially when combined with normal ALT—could be used to rationalise surveillance strategies and informs operational discussions about partial HBV cure endpoints. Nevertheless, before widespread guideline change, additional validation across diverse populations, assay harmonisation, and prospective assessments of clinical outcomes with altered surveillance are required.
Funding and clinicaltrials.gov
See original publication for detailed funding and trial registry information: Tseng TC et al. Gut. 2025. DOI: 10.1136/gutjnl-2025-334911.
References
1. Tseng TC, Huang SC, Pan MH, Liu CJ, Chen CJ, Yang WT, Tsai CH, Su TH, Yang HC, Liu CH, Chen PJ, Yang HI, Kao JH. Hepatitis B surface antigen level identifies patients with inactive chronic hepatitis B from Asia with HCC risk below surveillance threshold. Gut. 2025 Oct 8;74(11):1896-1904. doi:10.1136/gutjnl-2025-334911.
2. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–398.
3. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, and the AASLD 2018 Hepatitis B Guidance Panel. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 Hepatitis B Guidance. Hepatology. 2018;67(4):1560–1599.
4. Chen CJ, Yang HI; REVEAL‑HBV Study Group. Hepatitis B virus DNA levels and risk of hepatocellular carcinoma. N Engl J Med. 2006;355:200-209. (REVEAL‑HBV cohort seminal work on HBV DNA and HCC risk.)
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A photorealistic clinical vignette: middle‑aged Asian patient seated in a hepatology clinic reviewing a blood test printout with a hepatologist; the lab sheet has a highlighted box reading “HBsAg <100 IU/mL"; subtle background elements include an ultrasound machine displaying a liver image and icons for ALT and HBV DNA; warm clinical lighting, calm reassuring atmosphere, high detail.
