Highlights
Among nucleos(t)ide analogue-treated chronic hepatitis B patients with cirrhosis and complete viral suppression, HBsAg seroclearance was associated with a substantially lower risk of hepatocellular carcinoma.
The adjusted subdistribution hazard ratio for hepatocellular carcinoma was 0.37 (95% CI 0.15-0.91), suggesting that functional cure confers benefit beyond virologic suppression alone.
By contrast, HBsAg seroclearance did not reduce the risk of first or further hepatic decompensation, with an adjusted subdistribution hazard ratio of 1.01 (95% CI 0.52-1.95).
The study supports continued hepatocellular carcinoma surveillance even after HBsAg loss in cirrhosis, while also highlighting that removal of viral antigen does not fully reverse established portal hypertensive or structural liver risk.
Background and Clinical Context
Chronic hepatitis B remains a major global cause of cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). Long-term treatment with high-potency nucleos(t)ide analogues (NAs), particularly entecavir and tenofovir, reliably suppresses HBV replication and has transformed the prognosis of chronic hepatitis B. Even so, patients with established cirrhosis remain at ongoing risk for liver-related events despite durable viral suppression.
In this setting, hepatitis B surface antigen (HBsAg) seroclearance is widely considered the closest currently achievable endpoint to a functional cure. Clinically, HBsAg loss reflects deeper immune control and reduced transcriptional activity from covalently closed circular DNA and integrated viral sequences, although it does not equate to complete viral eradication. Observational studies have suggested that HBsAg seroclearance is associated with improved long-term outcomes, but whether it adds clinically meaningful benefit over and above complete viral suppression in patients who already have cirrhosis has been uncertain.
This is an important unresolved issue. For clinicians managing cirrhosis, the key practical questions are not simply whether HBsAg loss is biologically desirable, but whether it changes hard outcomes such as HCC and hepatic decompensation. These outcomes reflect distinct pathophysiologic pathways. HCC risk may remain driven by cumulative oncogenic injury, HBV DNA integration, inflammation, and fibrosis-related field effects. Hepatic decompensation, on the other hand, is often the downstream consequence of established portal hypertension and architectural distortion that may not be readily reversed even after excellent viral control. The study by Hui and colleagues directly addresses this gap.
Study Design and Methods
Study objective
The investigators aimed to compare the risks of HCC and hepatic decompensation between two clinically relevant groups of chronic hepatitis B patients with cirrhosis treated with entecavir or tenofovir: those with complete viral suppression alone and those who additionally achieved HBsAg seroclearance.
Population and setting
All adult patients with chronic hepatitis B and cirrhosis receiving entecavir or tenofovir from January 2005 through September 2020 were identified. The cohort represents a real-world, long-term treated cirrhotic population, precisely the group in whom residual risk remains a major management problem.
Key exclusions
To reduce bias and isolate the effect of HBsAg seroclearance beyond viral suppression, the investigators excluded patients with HCC before baseline or within the first 6 months of baseline, other cancers or liver transplantation before baseline, liver transplantation before HBsAg loss, and patients without complete viral suppression. This is a key design strength because it avoids conflating persistent viremia with the incremental impact of HBsAg loss.
Landmark analysis
The study used one-year landmark analyses, excluding patients who had clinical outcomes or follow-up shorter than one year. A similar two-year landmark analysis was also performed. Landmark methods are useful here because HBsAg loss is a time-dependent event; without appropriate handling, immortal time bias could make seroclearance appear more protective than it truly is. By anchoring the comparison at a fixed time point and including only patients who remained event-free to that landmark, the authors improved the validity of the comparison.
Endpoints
The primary outcomes were HCC and hepatic events, the latter reflecting first or further hepatic decompensation. The abstract reports adjusted subdistribution hazard ratios, indicating that competing-risk methods were used, an appropriate approach in liver disease cohorts where death and transplantation can preclude the event of interest.
Key Results
Cohort characteristics
In the one-year landmark analysis, 5,149 patients were included. Mean age was 60.1 ± 12.6 years and 66.3% were male. This demographic profile is consistent with an at-risk cirrhotic HBV population in which HCC incidence is clinically meaningful.
HBsAg seroclearance and HCC risk
At a median follow-up of 4.1 years (interquartile range 2.5-5.0), HCC developed in 456 of 4,988 patients (9.1%) with complete viral suppression alone compared with 5 of 161 patients (3.1%) who achieved HBsAg seroclearance. After adjustment, HBsAg seroclearance was associated with a significantly lower risk of HCC, with an adjusted subdistribution hazard ratio of 0.37 (95% CI 0.15-0.91; p=0.030).
From a clinical perspective, this effect size is notable. A 63% relative reduction in HCC risk suggests that HBsAg loss is not merely a biochemical milestone but a meaningful prognostic event, even in a population already benefiting from potent antiviral therapy. The effect was directionally consistent in the two-year landmark analysis as well, with an adjusted subdistribution hazard ratio of 0.37 (95% CI 0.14-1.04). Although this latter confidence interval crossed 1.0, the point estimate strongly resembled the one-year landmark result, supporting biological consistency despite reduced precision.
HBsAg seroclearance and hepatic decompensation
The picture was different for hepatic events. Hepatic decompensation occurred in 334 of 4,777 patients (7.0%) with complete viral suppression and 10 of 153 patients (6.5%) with HBsAg loss. The adjusted subdistribution hazard ratio was 1.01 (95% CI 0.52-1.95), indicating no detectable difference between groups.
This null result is clinically important. It suggests that while HBsAg seroclearance may reduce carcinogenic risk, it does not necessarily reverse the consequences of advanced cirrhotic remodeling sufficiently to lower decompensation risk over the follow-up period studied. In other words, functional cure may be oncologically beneficial but structurally incomplete once cirrhosis is established.
Clinical interpretation of the divergence between endpoints
The divergence between HCC and decompensation is one of the most interesting findings of the study. HCC risk likely reflects a combination of active viral biology, long-standing injury, and host factors. Achieving HBsAg loss may reduce ongoing low-grade viral transcription, immune-mediated hepatocyte turnover, and other pro-oncogenic influences. By contrast, hepatic decompensation is more closely tied to portal hypertension, synthetic failure, and the mechanical consequences of fibrosis and nodular transformation. These may persist despite antigen clearance, especially in older patients with established cirrhosis.
Why the Findings Make Biological Sense
HBsAg seroclearance probably represents deeper disease control than undetectable serum HBV DNA alone. Patients with complete viral suppression can still have residual transcriptional activity from covalently closed circular DNA or integrated HBV sequences. HBsAg loss may indicate lower viral protein expression, reduced immune stimulation, and less ongoing hepatocellular injury. That could plausibly diminish carcinogenic pressure.
At the same time, cirrhosis is not just a virologic state; it is an anatomic and hemodynamic condition. Once portal hypertension is clinically significant, the risk of ascites, variceal bleeding, encephalopathy, and jaundice may persist because the underlying hepatic architecture has already been permanently altered. Some fibrosis regression is possible during long-term antiviral therapy, but regression may be incomplete, slow, and insufficient to normalize portal pressure in many patients. This pathobiology offers a coherent explanation for why HBsAg seroclearance lowers HCC risk without clearly changing decompensation rates.
Strengths of the Study
The study has several notable strengths. First, it focuses on a clinically high-risk population with cirrhosis rather than mixed-fibrosis cohorts, making the findings directly relevant to surveillance and prognostic counseling. Second, the comparison is specifically between patients with complete viral suppression alone and those with additional HBsAg seroclearance, which sharpens the clinical question. Third, the use of one-year and two-year landmark analyses improves causal interpretation by limiting immortal time bias. Fourth, the use of competing-risk regression is methodologically appropriate for liver disease outcomes.
The sample size was also substantial overall, with more than 5,000 patients in the one-year landmark cohort. Even though the HBsAg seroclearance subgroup was relatively small, the broader underlying cohort strengthens the real-world relevance of the observations.
Limitations and Cautions
Several limitations should temper interpretation. The study appears observational, so residual confounding remains possible despite adjustment. Patients who achieve HBsAg seroclearance may differ systematically from those who do not in ways that are difficult to fully measure, including duration of infection, host immune phenotype, baseline fibrosis burden within the cirrhosis spectrum, metabolic comorbidities, alcohol exposure, platelet count, or portal hypertensive severity.
The number of HCC events in the HBsAg loss group was small, only 5 events in the one-year landmark analysis, which limits precision. This is reflected in the width of the confidence interval. The two-year landmark result, though similar in point estimate, narrowly missed conventional statistical significance, underscoring that the direction of effect is robust but exact magnitude remains uncertain.
The abstract does not provide granular data on cirrhosis definition, compensated versus decompensated status at baseline, HBeAg status, HBV genotype, quantitative HBsAg kinetics, fibrosis regression markers, or cause-specific decompensation events. These details would help clinicians judge applicability and mechanism. In addition, follow-up of roughly four years is meaningful but may still be too short to capture the full impact of antigen loss on long-term portal hypertensive outcomes.
Implications for Clinical Practice
HBsAg loss remains a meaningful therapeutic target
These data support the view that HBsAg seroclearance is more than a symbolic endpoint. In cirrhotic patients already doing well virologically on entecavir or tenofovir, HBsAg loss appears to confer additional protection against HCC. This strengthens the rationale for therapeutic strategies and future curative regimens that aim beyond viral suppression.
HCC surveillance should continue after HBsAg seroclearance in cirrhosis
Importantly, the finding is a reduction in risk, not elimination of risk. Five patients with HBsAg seroclearance still developed HCC. Current major society guidance has long emphasized that patients with cirrhosis require ongoing HCC surveillance even after viral control and even after HBsAg loss. This study reinforces that principle. Functional cure lowers residual risk but does not erase the carcinogenic legacy of cirrhosis.
Do not assume decompensation risk has resolved
Clinicians should also avoid overinterpreting HBsAg loss as proof that portal hypertensive or synthetic risk has normalized. Standard management of cirrhosis should continue, including endoscopic and noninvasive assessment of portal hypertension where appropriate, variceal prophylaxis when indicated, management of ascites risk, vaccination and lifestyle counseling, and ongoing monitoring for liver function deterioration.
Expert Commentary in the Context of Existing Evidence
Current international hepatitis B guidance recognizes HBsAg loss as the preferred endpoint of therapy because it is associated with the best long-term outcomes available short of sterilizing cure. At the same time, guidelines from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the World Health Organization all acknowledge that cirrhosis remains a high-risk state requiring continued surveillance and longitudinal care.
The present study refines that framework. It suggests that among patients who already achieved complete HBV DNA suppression, HBsAg seroclearance confers an additional anti-HCC signal, yet does not appear to substantially alter decompensation risk during medium-term follow-up. This endpoint-specific distinction is clinically useful because it clarifies what functional cure may and may not accomplish in established cirrhosis.
Research Priorities
Future work should determine whether the HCC benefit associated with HBsAg loss varies according to age, sex, diabetes, alcohol exposure, baseline portal hypertensive burden, quantitative HBsAg decline, or fibrosis regression. It would also be useful to know whether the absence of decompensation benefit persists with longer follow-up or in patients who achieve HBsAg seroclearance earlier in the disease course before severe portal hypertension becomes fixed.
Prospective studies incorporating liver stiffness, platelet trends, spleen size, hepatic venous pressure gradient where available, and biomarkers of immune control could help disentangle mechanisms. As finite-duration and curative HBV therapies move through development, studies like this will be essential for defining which clinical outcomes should be expected from functional cure in different disease stages.
Funding and Trial Registration
No ClinicalTrials.gov registration number is provided in the abstract. Funding information is not reported in the abstract provided and should be verified in the full published article.
Conclusion
In NA-treated chronic hepatitis B patients with cirrhosis who have already achieved complete viral suppression, HBsAg seroclearance is associated with a further reduction in HCC risk but not with a reduction in hepatic decompensation. The message for practice is straightforward: functional cure matters, especially for cancer risk, but it does not fully neutralize the structural consequences of cirrhosis. Patients with cirrhosis who lose HBsAg should still remain in long-term HCC surveillance and cirrhosis management pathways.
References
1. Hui VW, Tang JC, Wong VW, Liang LY, Tse YK, Chan HL, Wong GL, Lai JC, Yip TC. HBsAg seroclearance further reduces hepatocellular carcinoma but not hepatic decompensation in patients with cirrhosis and complete viral suppression. Hepatology (Baltimore, Md.). 2026-06-08. PMID: 42263224.
2. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599. PMID: 29405329.
3. 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. PMID: 28427875.
4. World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. Geneva: World Health Organization; 2024 update. Public guidance document; verify local implementation details in current regional recommendations.
5. Yip TC, Wong GL, Chan HL, Tse YK, Lui GC, Lam KL, Wong VW. HBsAg seroclearance further reduces the risk of hepatocellular carcinoma after complete viral suppression with nucleos(t)ide analogues. J Hepatol. 2019;70(3):361-370. PMID: 30445054.
