Diana Swift
March 07, 2025
The American Gastroenterological Association (AGA) has released an updated clinical practice guideline on the prevention of hepatitis B virus reactivation (HBVr) in at-risk persons. The document was published in Gastroenterology and replaces a previous guideline on prophylaxis for immunosuppressed patients issued in 2014.
Since then, many novel classes of immunosuppressives have been approved for various conditions, and potentially immunosuppressive therapies such as transcatheter arterial chemoembolization have been recognized as relevant to potential HBVr.
With reactivation a risk after immune-modulating exposures, such as to multiple drug classes and disease states, the update provides frontline clinicians with evidence-based advice for the management of HBVr in vulnerable individuals. And while antiviral prophylaxis is recommended for many, in select cases careful clinical monitoring may suffice for risk management.
“The risk of HBV reactivation depends on patient, drug, and disease-specific factors — and so it can range from very rare to more frequent,” said guideline Co-author Tracey G. Simon, MD, MPH, a hepatologist in the Division of Gastroenterology at Massachusetts General Hospital and an instructor at Harvard Medical School, both in Boston. “Not every at-risk individual needs pharmacologic treatment, but some certainly do, and this guideline was designed to try to better identify who needs treatment, based on those important drug- and virus-specific factors.”
Simon stressed the importance of creating this guideline to include many new therapies that carry varying degrees of reactivation risk. As to the strength of the evidence, she added, “For some of the questions, the panel was satisfied with the level of certainty. However, for other questions, the data are still very sparse, and so we have tried to ensure that these areas of uncertainty are highlighted clearly for providers and patients.”
Main Recommendations
The AGA based its clinical recommendations on balancing desirable and undesirable effects, patient values and preferences, costs, and health equity considerations. It also provided a clinical decision support tool for making pharmacologic management decisions.
The panelists reviewed data on multiple immunosuppressive therapies from older agents such as anthracycline derivatives, corticosteroids, and antitumor necrosis factor (anti-TNF) drugs to chimeric antigen receptor T cells and recent biologics and inhibitors.
1. For individuals at high risk for HBVr, the AGA recommended antiviral prophylaxis over monitoring alone. Strong recommendation, moderate-certainty evidence.
Implementation considerations. Use antivirals with a high barrier to resistance. Prophylaxis should be started before initiating medications that carry a risk for HBVr and should be continued for at least 6 months after discontinuation of risk-imposing therapy (at least 12 months for B-cell–depleting agents).
2. For individuals at moderate risk for HBVr, antiviral prophylaxis was recommended over monitoring alone. Conditional recommendation, moderate-certainty evidence.
Implementation considerations. Use antivirals with a high barrier to resistance. Patients who place a higher value on avoiding long-term antiviral therapy and its associated cost and place a lower value on avoiding the small risk of reactivation (particularly those who are hepatitis B surface antigen [HBsAg]–negative) may reasonably select active monitoring over antiviral prophylaxis.
Careful consideration should be given to the feasibility and likelihood of adherence to long-term monitoring performed at 1- to 3-month intervals and including assessment of hepatitis B viral load and alanine aminotransferase.
3. For low-risk individuals, the AGA said monitoring alone may be used. Conditional recommendation, moderate-certainty evidence.
Implementation considerations. This recommendation assumes regular and sufficient follow-up with continued monitoring. Patients who place a higher value on avoiding the small risk of reactivation (particularly those on more than one low-risk immunosuppressive) and a lower value on the burden and cost of antiviral therapy may reasonably select antiviral therapy.
4. For individuals at risk for HBVr, the guideline recommended testing for hepatitis B. Strong recommendation, moderate-certainty evidence.
Implementation considerations. Given the Centers for Disease Control and Prevention’s universal screening guidance on hepatitis B for everyone aged 18 years or older by testing for HBsAg, anti-HBs, and total anti-hepatitis B core (HBc), the guideline said that stratifying screening practices by magnitude of HBVr risk is no longer needed.
It is reasonable to test initially for serologic markers alone (at minimum for HBsAg or anti-HBc) followed by viral load testing (HBV-DNA) if HBsAg and/or anti-HBc is positive.
Hepatitis C Virus (HCV) Coinfection With Direct-Acting Antiviral (DAA) Treatment
The panel identified 11 studies that provided data for the computation of baseline risk for HBVr in the HCV coinfection cohort undergoing DAA therapy.
In patients who were HBsAg-positive, the pooled baseline risk for HBVr was 240 per 1000, categorizing them to be at high risk for HBVr. The panel stated it is therefore reasonable to extend antiviral prophylaxis beyond the 12-24 weeks of DAA therapy to 6-12 months after cessation of DAA therapy, tailored by clinician judgment and patient preference.
A ‘Useful Clinical Tool’
Commenting on the guideline but not involved in it, Saikiran Kilaru, MD, a hepatologist at NYU Langone Health in New York City, said the update is “absolutely a useful clinical tool. Since the prior guidance was published, there has been a deluge of new medications and medication classes. Prior to the guidance, I was making recommendations based on the limited data available for hepatitis B reactivation risk for these new medications, using the 1%-10% moderate-risk category as guidance.”
In addition, Kilaru said, this guidance is driven by a higher level of evidence certainty than the mostly retrospective evidence that was previously available.
She cautioned that few downgraded risk categories are likely to cause consternation among physicians who have been operating without the benefit of larger meta-analyses of HBVr in new medication categories. “For example, the prior guidance had put anti-TNF as of moderate risk for hepatitis B core–positive-only patients and is now downgraded to low risk.” And other medications such as immune checkpoint inhibitors, which seemed to pose at least moderate risk based on smaller, retrospective studies are now considered to be in the low-risk category.
“It may take some time for these recommendations to be adopted, especially for physicians in the community who have seen fatal or severe reactivations in the past few years,” Kilaru said.
Kilaru pointed out that the guidance update does not clearly cover some standard immunosuppressive therapies used in autoimmune, rheumatologic, and posttransplant regimens, such as mycophenolate, tacrolimus, and cyclosporine. Nor does it address HBVr risk in some liver cancer treatments such as yttrium-90, which have been associated with reports of HBV reactivation.
The Future
According to Simon, more data are needed to better estimate HBVr risk in several important settings, including treatment with the most recently approved immunosuppressive drugs for which data are still limited, as well as combination treatments.
Kilaru noted that guideline updates such as this become increasingly relevant as cancer diagnoses rise and hepatitis B exposure and detection increase as well.
The AGA panel acknowledged that uncertainty remains in some patient risk categorizations. “As the armamentarium of immunotherapeutics evolves, it will be crucial to search for, use, and maintain studies that provide baseline HBV serologies; include a clear definition of HBVr; and enroll a large, nonselective cohort that can guide categorization of risk of HBVr,” the panelists wrote.
The AGA provided all financial support for the development of this guideline. No funding from industry was offered or accepted to support the writing effort.
The authors reported no relevant competing interests, but Co-author Huang is an adviser for Gilead Sciences, and other authors disclosed various relationships with multiple private sector companies.
Kilaru had no competing interests to disclose.
Diana Swift is an independent medical journalist based in Toronto, Ontario, Canada.
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