HBV Diagnostic Strategies in the Era of Novel Therapies

This is a verbatim transcript of an interview conducted with Prof Man-Fung Yuen in July 2026. The transcript has been lightly edited for clarity.

Introduction

I am Professor Man-Fung Yuen, Chair Professor of Gastroenterology and Hepatology at The University of Hong Kong. My academic and research focus is chronic hepatitis B, with particular emphasis on hepatitis B virus virology, the natural history of disease, biomarkers of disease monitoring and treatment response, as well as the development of novel therapeutic approaches for hepatitis B.

The pipeline for chronic hepatitis B therapies is highly diverse. How do you see these emerging hepatitis B treatments with novel mechanisms of action contributing to the goal of achieving a functional cure?

Over the past five to ten years, the hepatitis B treatment landscape has evolved substantially, with a broad range of novel agents being evaluated. The key objective of these therapies is to achieve functional cure, an endpoint associated with reduced risk of disease progression, complications, and mortality. Many of these direct-acting antiviral agents are designed to target different stages of the viral replication cycle, including RNA-targeting approaches such as antisense oligonucleotides and small interfering RNA therapies. In addition, more potent oral agents, including capsid assembly modulators, are being actively investigated for their ability to suppress both HBV DNA and viral antigen production beyond what is typically achieved by current nucleos(t)ide analogue therapy. While some RNA-targeting agents have shown encouraging activity as monotherapy, higher rates of functional cure are likely to require rational combination strategies that pair direct antiviral agents with immunomodulatory approaches.

We have traditionally relied on HBV DNA levels and HBsAg loss for treatment monitoring. With novel therapies, how should diagnostic and monitoring strategies evolve to support treatment monitoring as well as patient selection?

As novel agents increasingly aim to reduce viral antigen production, quantitative HBsAg measurement will become an essential component of patient assessment and treatment monitoring. Because HBsAg loss remains a central requirement for functional cure, routine quantitative HBsAg testing is likely to become an increasingly important standard in hepatitis B management. It will help guide patient selection, predict treatment response, inform the choice between monotherapy and combination therapy, and support decisions regarding treatment duration.
Additional biomarkers, including HBV RNA and hepatitis B core-related antigen, may provide valuable insight into intrahepatic cccDNA activity. These measurements can help confirm target engagement, compare the antiviral potency of different agents, and assess the likelihood of viral relapse after treatment discontinuation.
HBV DNA measurement will remain a foundational biomarker as we move towards functional cure. Durable suppression of HBV DNA to undetectable levels remains essential. As newer agents, such as capsid assembly modulators, may achieve deeper viral suppression, more sensitive HBV DNA assays with lower limits of detection will become increasingly important for treatment monitoring and endpoint assessment.

With increasing interest in quantitative HBsAg, how can clinicians best leverage its use in the management of patients with chronic hepatitis B?

Evidence consistently suggests that patients with lower baseline HBsAg levels, for example below 1,000 IU/mL, have a higher likelihood of achieving functional cure. These patients may therefore represent an appropriate population for novel therapeutic strategies. In addition, an early and substantial decline in HBsAg during the first 12 to 16 weeks of treatment appears to be an important indicator of subsequent response. Quantitative HBsAg measurement before treatment initiation and during the early treatment phase will therefore be critical for monitoring response and guiding timely clinical decisions, including whether to continue, stop, modify, or intensify therapy through combination approaches.

I have patients who joined previous novel therapy trials. And luckily they actually achieved a loss of surface antigen during therapy or immediately after the therapy.

And then I stopped the nucleos(t)ide analogue therapy and they are very happy to take off the therapy, which is supposed to be long term. And now they are free of any medications, and the viral status is actually at a very low level, and we can’t detect the surface antigen, we can’t detect HBV DNA in the blood. And I believe this kind of patients, they actually have lower risks of development of complications, including hepatocellular carcinoma.

We continue to measure the surface antigen and also HBV DNA for these patients who achieved functional cure, for example every six months or every one year. And they remain to be very stable particularly the negativity of both biomarkers over time, and this functional cure status can be maintained. But we still need to monitor these patients with biomarkers and also imaging, for example, to screen for the development of HCC (hepatocellular carcinoma (HCC).

And that already was put at a lowest rate for our patients. And these patients still have the virus inside the body. So we cannot just leave it and then say okay we say goodbye to the patients. We need to monitor the patients for life.

How can a clinician today begin to modernise their diagnostic approach to better position patients for emerging HBV therapies and improved long-term outcomes?

To prepare for the era of novel HBV therapies, clinicians should begin modernising their diagnostic approach now. This includes routine assessment of HBV DNA to evaluate viral activity, identify patients who may benefit from earlier intervention, and establish a clear baseline before future treatment. At the same time, clinicians should incorporate quantitative HBsAg testing into routine practice to better characterise their patient population, stratify suitability for emerging therapies, and support informed discussions with patients about future treatment options. These steps will help position patients appropriately for advanced therapeutic strategies aimed at achieving functional cure.

The views and opinions expressed by Prof Man-Fung Yuen are his own views and opinions. Roche disclaims all liability in relation to these views and opinions.