Although effective antiviral therapies have substantially improved the management of chronic hepatitis B (CHB), achieving a functional cure remains a major clinical challenge worldwide. Current first-line antiviral therapies—including nucleos(t)ide analogues (NAs) and pegylated interferon-α (Peg-IFN-α)—effectively suppress viral replication but cannot completely eliminate covalently closed circular DNA (cccDNA), allowing hepatitis B virus (HBV) to persist.
Consequently, sustained hepatitis B surface antigen (HBsAg) loss, known as functional cure, has become the primary therapeutic goal. However, only a small proportion of patients achieve this outcome, highlighting the need for reliable viral biomarkers that can identify patients most likely to achieve functional cure before treatment begins and during therapy.
Biomarkers of infection
Addressing this challenge, a research team led by Professor Qishui Ou from the Department of Laboratory Medicine, Fujian Medical University, along with Professor Zhen Xun from the same institute, reviewed current evidence on HBV viral markers that predict functional cure. The review was recently published in the journal Portal Hypertension & Cirrhosis.
The researchers evaluated both classical and emerging biomarkers, assessed their predictive performance individually and in combination, and summarized clinical evidence supporting their application in patient stratification, treatment monitoring, treatment discontinuation, and post-treatment management.
The review highlights that among all currently available biomarkers, quantitative HBsAg (qHBsAg) remains the most clinically valuable single predictor of functional cure. Baseline HBsAg levels, together with early declines during Peg-IFN-α therapy, consistently predict the likelihood of sustained HBsAg clearance.
Combined models
Nevertheless, the authors found that in most large chronic hepatitis B cohorts receiving antiviral therapy, multi-viral marker combined models exhibit superior predictive discrimination compared to single viral markers, though single quantitative hepatitis B surface antigen remains the most cost-effective screening tool in primary care settings with limited testing resources.
Such multimarker models may better identify patients who are most likely to benefit from antiviral therapy while avoiding unnecessary treatment in those unlikely to achieve functional cure.
”Functional cure remains the most realistic treatment goal for chronic hepatitis B because complete elimination of the virus is not yet possible,” says Prof. Ou. ”Our review demonstrates that integrating multiple viral markers offers a more accurate and practical approach for predicting which patients are most likely to achieve sustained HBsAg loss, allowing clinicians to make more informed treatment decisions.”
Clinical frameworks
Beyond summarizing individual biomarkers, the review proposes an evidence-based clinical framework for personalized CHB management. The framework incorporates viral markers for pretreatment patient stratification, monitoring treatment response, determining appropriate timing for NA discontinuation, and guiding consolidation therapy after HBsAg loss.
The authors also emphasize that viral markers should be interpreted alongside host characteristics such as immune status, sex, age, and previous treatment history to maximize predictive performance. They further highlight the future potential of artificial intelligence, high-sensitivity diagnostic assays, and multidimensional predictive models to improve individualized care.
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“As standardized assays and multimarker prediction models become more widely available, clinicians will be better equipped to personalize treatment strategies and identify patients most likely to achieve functional cure,” explains Prof. Xun. “These advances have the potential to increase functional cure rates while reducing unnecessary treatment costs and supporting global hepatitis B elimination efforts.”
Overall, the review demonstrates that prediction of functional cure in chronic hepatitis B is evolving from reliance on single biomarkers toward integrated, multidimensional models combining classical viral markers, novel biomarkers, and host factors. As these approaches are validated in large prospective studies and incorporated into routine clinical practice, they could enable more personalized treatment strategies, improve long-term patient outcomes, and contribute to achieving the World Health Organization’s goal of eliminating viral hepatitis as a public health threat.
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