In a groundbreaking multicenter study published in BMC Cancer, researchers have unveiled crucial insights into the impact of preoperative hepatitis B surface antigen (HBsAg) seroclearance on the long-term outcomes of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) undergoing liver resection. This extensive investigation spanning four leading Chinese hospitals offers a refined understanding of how the elimination of viral antigens prior to surgery may influence cancer prognosis and recurrence dynamics, shedding light on a pivotal factor in managing HBV-related HCC.
Hepatocellular carcinoma remains one of the deadliest malignancies worldwide, with chronic hepatitis B infection as a dominant etiological factor, particularly in East Asia. The presence of HBsAg, a marker of active HBV infection, has long been associated with ongoing viral replication and liver inflammation, both critical contributors to liver carcinogenesis. However, the clinical significance of patients achieving seroclearance — the disappearance of HBsAg from the serum — before surgical intervention has remained inadequately characterized, sparking debates about its effect on survival and cancer recurrence.
The current study controlled for various confounding factors by employing propensity score matching, facilitating a balanced comparison between patients retaining HBsAg positivity and those achieving seroclearance at the time of hepatectomy. This methodological rigor strengthens the validity of the associations uncovered between preoperative viral status and postoperative outcomes. The cohort analyzed included a substantial sample of 1008 patients, with 81 individuals (approximately 8%) achieving seroclearance, thus providing a statistically robust dataset.
One of the most striking findings lies in liver function preservation. Patients in the HBsAg-seroclearance group exhibited superior hepatic reserve before surgery, indicating less compromised liver health. This is particularly relevant given that liver functional reserve critically influences both surgical risk and overall patient prognosis. The fact that postoperative morbidity rates remained comparable between matched groups underscores that seroclearance does not compromise surgical safety, which has significant clinical implications for patient management.
Survival analysis revealed nuanced distinctions. While the initial entire-cohort data suggested better overall survival (OS) and extended time-to-recurrence (TTR) for the seroclearance group, these survival benefits diminished after stringent matching. This indicates that factors beyond HBsAg status—such as liver function, tumor characteristics, or patient demographics—may contribute substantially to survival differences observed in unmatched analyses, highlighting the complexity of prognostic determinants in HBV-related HCC.
Most revealingly, multivariable Cox regression and competing risk regression models identified preoperative HBsAg seroclearance as an independent predictor of reduced risk for tumor recurrence after hepatectomy. This finding accentuates a pivotal role of viral antigen clearance in modulating oncological outcomes, possibly by diminishing the oncogenic drive sustained by active viral replication and chronic liver inflammation. However, seroclearance did not independently translate into improved overall survival or cancer-specific survival (CCS), suggesting that recurrence control, while critical, may not be solely sufficient to enhance long-term survival owing to other factors like underlying liver disease or comorbidities.
This study provides a compelling argument for incorporating preoperative HBsAg status into the risk stratification and postoperative surveillance protocols for HBV-related HCC patients. Judicious monitoring of HBsAg dynamics could inform clinical decisions regarding adjuvant therapies and help identify patients who might benefit from intensified follow-up strategies targeting early tumor recurrence.
From a mechanistic perspective, seroclearance likely reflects effective immune control over HBV infection, leading to decreased hepatic inflammation and fibrosis progression. Such environmental shifts within the liver microenvironment may reduce carcinogenic stimulus, thereby attenuating the likelihood of new tumor nodules or metastatic spread. However, the persistence of risk factors despite seroclearance illustrates the multifactorial nature of HCC pathogenesis, where viral eradication represents one piece of a complex puzzle.
The findings prompt important inquiries about how antiviral therapies aiming to achieve HBsAg clearance preoperatively may be optimally deployed. Current antiviral regimens primarily focus on suppressing viral replication but rarely result in seroclearance, which remains a challenging endpoint. Nonetheless, emerging therapeutic approaches including novel immunomodulatory agents warrant exploration in the context of neoadjuvant strategies to potentiate seroclearance and improve oncologic outcomes.
Critically, the study underscores the necessity of large-scale, multi-institutional collaborations to elucidate the nuanced interplay between virology, tumor biology, and surgical oncology in HBV-related HCC. The Chinese multicenter design offers valuable generalizability for regions where HBV prevalence is high, but further validation in diverse populations will be essential to refine guidelines that are globally applicable.
In terms of clinical practice, surgeons and hepatologists should be aware that while preoperative HBsAg seroclearance is indicative of a favorable tumor recurrence profile, it should not be viewed in isolation as a predictor of enhanced overall survival. A comprehensive assessment that integrates viral status, liver function, tumor staging, and patient comorbidities remains vital to optimizing therapeutic outcomes.
Moreover, this study highlights the importance of routine serological monitoring of HBsAg in HBV-related HCC patients prior to surgery. Such data can help in tailoring personalized treatment pathways and identifying candidates for adjunctive antiviral or immune therapies aimed at consolidating viral control and minimizing oncogenic risk.
In summary, this pioneering analysis enriches our understanding of the prognostic landscape in HBV-related hepatocellular carcinoma, revealing that preoperative clearance of HBsAg is a significant determinant in reducing tumor recurrence risk after curative hepatectomy. While it may not independently improve overall survival, this biomarker holds promise for refining patient stratification and informing targeted interventions that could enhance long-term cancer control.
The quest to improve outcomes for HBV-related HCC patients is ongoing, with viral dynamics occupying a central role in therapeutic strategy formulation. This study opens new avenues for translational research aimed at harnessing viral antigen clearance to disrupt the vicious cycle of inflammation, fibrosis, and carcinogenesis that characterizes chronic hepatitis B infection.
As hepatology and oncology continue to converge in the era of precision medicine, integrating virological parameters such as HBsAg seroclearance into clinical algorithms represents a critical step forward. Future investigations involving randomized clinical trials will be key to validating intervention strategies that leverage seroclearance, ultimately improving survival and quality of life for patients burdened by this formidable disease.
Subject of Research: The impact of preoperative HBsAg seroclearance on long-term outcomes of hepatitis B virus-related hepatocellular carcinoma after liver resection.
Article Title: Preoperative HBsAg seroclearance affects long-term outcomes for hepatitis B virus-related hepatocellular carcinoma after liver resection: a multicenter analysis.
Article References:
Liu, SY., Zhu, L., Lu, WF. et al. Preoperative HBsAg seroclearance affects long-term outcomes for hepatitis B virus-related hepatocellular carcinoma after liver resection: a multicenter analysis. BMC Cancer 25, 1467 (2025). https://doi.org/10.1186/s12885-025-14869-4
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