By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Jan 27 2025

New recommendations address advances in immunosuppressive therapies and highlight antiviral prophylaxis for high-risk patients.

Study: AGA Clinical Practice Guideline on the Prevention and Treatment of Hepatitis B Virus Reactivation in At-Risk Individuals. Image Credit: Josep Suria / Shutterstock.com

In a recent study published in Gastroenterology, researchers update clinical practice guidelines for how to prevent and monitor hepatitis B virus (HBV) reactivation.

What is HBV reactivation?

HBV reactivation (HBVr) occurs when HBV activity is no longer suppressed by the immune system in people who are either positive for the HBV surface antigen (HBsAg) or HBV core antibody (anti-HBc). The most common cause of HBVr is prolonged immunosuppression due to medications, particularly B-cell depleting agents like rituximab, or disease. HBsAg-positivity also confers a greater risk of HBVr than past resolved HBV infection.

A measurable baseline risk is defined as the rate of HBVr among individuals who are either HBsAg-positive or anti-HBc-positive/HBsAg-negative, who are subject to exposures known to lead to HBVr, and whose risk is not being modulated by antiviral prophylaxis.”

Need for updated guidelines

The first American Gastroenterology Association (AGA) guideline on HBVr prevention and management was published in 2014 and focused on immunosuppressed patients. Since then, many new immunosuppressive drugs and interventions have been approved for clinical use, some of which include immune checkpoint inhibitors (ICIs), anti-interleukin (IL) therapies, chimeric antigen receptor T-cell (CAR-T) therapies, and Janus kinase (JAK) inhibitors.

These recent advances have required clinicians to update current guidelines to provide evidence-based recommendations on the appropriate use of antivirals and monitoring strategies for HBVr. These guidelines are particularly important for frontline medical professionals who encounter HBV patients in their practice, patients who are exposed to HBVr risk factors, and policymakers.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was utilized to formulate these recommendations. Following a systematic review of existing evidence, these new recommendations were based on the effects/adverse effects balance, with considerations of patient values, costs, and equity in healthcare.  

Risk categories

Previous guidelines categorized patients as low-, moderate- and high-risk, with less than 1%, 1-10%, and over 10% risk, respectively. The greatest variability in decision making was in the moderate risk category.

To formulate the updated guidelines, patients were provided a survey to understand their treatment preferences and values, such as when they would choose a specific treatment option and the degree of risk that was acceptable to them. Data from randomized controlled trials (RCTs) that compared two alternative treatment approaches were also used to determine the relative risk of different outcomes.

An 82% lower risk of HBVr was associated with antiviral prophylaxis, whereas a 77% lower risk of a hepatitis flareup was attributed to HBVr. However, the baseline risk determines the size of the actual effect, which could ultimately influence the final decision on antiviral use.

Exposures were also considered and classified according to the risk of HBVr to the patient if used as a single medication. Low-dose corticosteroids in HBsAg-negative, anti-HBc-positive individuals are typically low-risk as compared to the high risk associated with moderate to high doses used for four or more weeks in HBsAg-positive individuals. Immune checkpoint inhibitors and anti-TNF therapy were also low-risk unless the individual is HBsAg-positive.

Strong vs. conditional recommendations

Strong recommendations were based upon the observation that most people wanted the recommended option. Comparatively, conditional recommendations implied that most would prefer the recommended course of action.

For clinicians, the strongly recommended course of action would be agreed upon by most patients without the need for extensive discussions, the opposite often being true with conditional recommendations that depend more on the patient’s values and risk averseness. For policymakers, strong recommendations would be appropriate for policies, whereas conditional recommendations require additional stakeholder involvement and performance measures.

Four recommendations

Antiviral prophylaxis is recommended unequivocally for those at high risk of HBVr. These drugs should be started prior to the onset of the risk-associated medication and continued for six months after it is stopped. For B-cell-depleting therapy, antivirals should be continued for 12 months.

As with those at high risk, the selected antivirals must not be vulnerable to developing resistance. Patients concerned about the use and cost of these drugs and those are less risk-averse may choose monitoring.

Patients at low risk for reactivation may be regularly monitored without prophylaxis under certain conditions. Monitoring is required at intervals of one to three months and should include HBV viral load assessment and alanine aminotransferase (ALT) levels. However, risk-averse patients and those who are not concerned about its cost or use may elect to use antivirals.

All individuals at risk for HBV should be tested, irrespective of their risk level. This recommendation is based on the screening advice of the United States Centers for Disease Control and Prevention (CDC) targeting all adults with tests for HBsAg, anti-HBsAg, and anti-HBc. If either HBsAg or anti-HBc is positive, the patient should be tested for the presence of viral DNA.  

Conclusions

The updated guidelines prescribe best practices for the management of HBVr based on the patient’s risk level. Nevertheless, cost-effectiveness analyses are needed for each risk category, as out-of-pocket costs may limit their use and exacerbate healthcare inequities.

In future, an online database of HBV serological results could provide important information that may impact the establishment of baseline risk. By obviating the need to depend on biological plausibility and expert consensus, this would allow more accurate risk categorization.