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Future HBV Management
The Future of HBV Management: Earlier Treatment and Biomarker Use

Released: October 18, 2023

Paul Y. Kwo
Paul Y. Kwo, MD
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Key Takeaways
  • A streamlined approach is essential to increase the number of diagnosed and treated chronic hepatitis B cases, reducing morbidity and mortality.
  • Hepatitis B surface antigen levels can have the same predictive ability as hepatitis B virus (HBV) DNA with regards to HBV-related outcomes.
  • The development of new biomarkers may further enhance our treatment strategies.

On Saturday, November 11, 2023, I will be part of a symposium at The Liver Meeting in Boston, Massachusetts, focusing on early hepatitis B virus (HBV) treatment and advancements in hepatitis B surface antigen (HBsAg) monitoring in people living with chronic hepatitis B (CHB). I invite you to read more about this topic below and then register to hear more at the live interactive symposium, either in person or virtually.

Early HBV Treatment and Cure
We currently lack curative treatments for HBV, but we have excellent suppressive therapies. The large undiagnosed and untreated proportion of people living with HBV results in substantial morbidity and mortality related to CHB. That’s why, even as we research curative therapies for HBV, it is crucial to identify infected individuals, link them to care, and initiate suppressive treatment for CHB earlier.

Current therapies—pegylated interferon and nucleos(t)ide analogs—dramatically reduce the risk of hepatocellular carcinoma (HCC), cirrhosis, and liver-related mortality. They are proven and can be initiated while we work toward developing curative therapies.

Recent data show that a naked oligonucleotide (an antisense oligonucleotide with no extra delivery vehicle) can lead to HBsAg clearance when given for 6 months, signaling a promising road towards higher functional cure rates beyond our existing therapies.

HBV Treatment Guidelines
Our societal guidance is comprehensive yet complex, requiring healthcare professionals to interpret multiple test results over a person’s lifetime to determine whether individuals with CHB need treatment.

Hepatitis specialists are used to doing this type of longitudinal testing, but most people worldwide aren't under the care of hepatitis specialists. Therefore, a large pool of individuals with CHB don't get treated because they aren’t being monitored or followed. These untreated individuals who go on to develop outcomes like progressive liver disease and HCC contribute to the ongoing substantial morbidity and mortality associated with HBV.

Simplifying guidelines toward a streamlined “screened, diagnosed, and treated” approach is crucial to facilitate more CHB treatment and address the prevalent treatment gap.

Simplified Guidance for HBV Treatment
Thankfully, simplified guidelines are emerging. One recent guidance suggested that we treat people with CHB aged 30 years or older with an HBV DNA level ≥2000 IU, regardless of ALT level. Recent modeling studies in China show that treating all people with CHB who are HBsAg positive significantly reduces morbidity and mortality. Another model in Korea showed that, even in the immune tolerant phase, treating CHB with nucleos(t)ide analogs was cost-effective for preventing HCC. To me, this suggests that we need to lower treatment thresholds to reduce HBV-related morbidity and mortality.

As promising data emerge, suggesting higher functional cure rates, it is imperative to ensure early and proper diagnosis so that treatment can be initiated and ongoing monitoring can occur.

HBsAg as a Monitoring Tool
HBsAg is a well-studied biomarker, and originates from 2 sources: (1) the HBV DNA residing in the host cell’s nucleus in the form of covalently closed circular DNA (cccDNA), which is the predominant source in people who are hepatitis B e antigen (HBeAg) positive, and (2) the HBV DNA integrated into the host genome, which is the predominant source in people who are HBeAg negative. Even if a person achieves undetectable HBV DNA levels and the cccDNA is eliminated from the liver cell, they may still be HBsAg positive because of HBV DNA integrated into the host genome. Knowing the source of HBsAg may also be important for measuring the efficacy of new treatments for HBV, but no current assays can distinguish between the 2 sources of HBsAg, which is currently a limitation of the use of HBsAg.

Regardless of the source, high HBsAg levels can predict the same outcomes as high HBV DNA levels, as we saw in the REVEAL-HBV study. Presence of a high HBsAg level also helps us identify people who we need to engage in care and for whom we can consider treatment. One use of quantitative HBsAg in practice is as a futility or stopping rule in patients treated with pegylated interferon. If HBsAg does not decrease by Week 24, it indicates that the treatment is likely not to be effective and can be stopped.

There are limited data in using quantitative HBsAg in those receiving nucleos(t)ide analog treatment. In HBeAg-positive individuals, a 1 log drop in HBsAg at Weeks 12-24 in a person receiving nucleos(t)ide analog treatment, there is a predicted higher rate of HBsAg clearance. There is also an emerging set of data looking at low HBsAg levels and discontinuation of nucleos(t)ide analog therapies and whether these people can go on to remain inactive carriers, achieve functional cure, or whether they are at higher risk for significant relapse, with preliminary data suggesting a level of <100 IU/mL may be a useful cutoff for deciding to stop therapy, but no definitive conclusions have been drawn.

Although quantitative changes in HBsAg are of limited help in monitoring our currently available HBV treatments, I think they will be more applicable to some of our novel therapies for treating CHB that are more robust at driving down HBsAg levels. 

The Future
Developing new biomarkers for monitoring people with CHB is an area of unmet need. A reliable assay to determine the source of HBsAg is a key unmet need. We hopefully will have a standardized HBV RNA assay that will help. In the future, use of new biomarkers for monitoring HBV treatment efficacy will allow us to bring together the right combination of antiviral agents and combine these with immunomodulators to improve our HBV functional cure rates.

To explore these critical discussions on HBV treatment and HBsAg monitoring, please register to join us at our symposium on November 11, 2023, either in person or virtually, at The Liver Meeting in Boston. 

Your Thoughts?
What is your approach to early treatment of HBV? How do you use HBsAg monitoring in your clinical practice? Join the discussion by posting a comment.