AASLD/IDSA 2025 Practice Guideline on Chronic Hepatitis B: Key Updates and Clinical Implications

Vol. 31, Special Issue 1 (July 2026)

Leandro Sierra, MD
Resident, Internal Medicine
Cleveland Clinic
Cleveland, Ohio, USA
 

Nikki Duong, MD
Assistant Professor of Medicine
Division of Gastroenterology & Hepatology
Stanford University Medical Center
Stanford, California, USA

 

I - Introduction

Chronic hepatitis B virus (CHB) infection remains a major global health challenge, affecting approximately 258 million individuals worldwide and accounting for an estimated 1.1 million deaths annually due to cirrhosis and hepatocellular carcinoma (HCC).¹ Despite the availability of safe and effective antiviral therapies and a highly efficacious vaccine, significant gaps persist in diagnosis, monitoring, and treatment, particularly in low- and middle-income countries.²

The American Association for the Study of Liver Diseases (AASLD), in collaboration with the Infectious Diseases Society of America (IDSA), recently published an updated practice guideline for CHB management.³ This update, the first since 2018,⁴ was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. It addresses six critical PICO questions covering prevention, HCC surveillance, and treatment across specific clinical scenarios that have evolved considerably since the prior guidance.³

This article provides a focused overview of the most clinically relevant updates, highlighting the areas in which the 2025 guideline diverges from or significantly expands upon prior recommendations.

II - Core Concepts

CHB is a dynamic disease characterized by five phases: immune-tolerant, HBeAg-positive immune active, HBeAg-negative immune active, inactive carrier, and HBsAg-negative immune clearance. The 2025 guideline reinforces the concept of “indeterminate phases,” also referred to as the “grey zone,” to describe patients whose ALT and/or HBV DNA levels fall outside the thresholds defining immune-tolerant, immune active, or inactive CHB. Notably, up to 40% of adults with CHB fall into this category.^{5, 6}

The preferred antivirals remain entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), selected based on availability, cost, renal and bone profile, pregnancy status, HIV coinfection, and prior treatment history.³ One of the goals of treatment is functional cure, defined as HBsAg loss with undetectable HBV DNA on at least 6 months off therapy. A new concept, “partial cure,” is introduced for patients who achieve HBsAg <100 IU/mL with undetectable HBV DNA sustained off therapy.⁷ The key updates across these six domains are summarized in Table 1.

Table 1. Key recommendation changes: AASLD 2018 vs. AASLD/IDSA 2025


Abbreviations: HBIG, hepatitis B immune globulin; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HDV, hepatitis D virus; HIV, human immunodeficiency virus; MTCT, mother-to-child transmission; NA, nucleos(t)ide analogue; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

III - Prevention: Mother-to-Child and Horizontal Transmission

Prevention of Mother-to-Child Transmission (MTCT)
The 2025 guideline issues a strong recommendation to initiate TDF or TAF at gestational week 28, continuing until delivery (if the sole indication is MTCT prevention), for all HBsAg-positive pregnant individuals with HBV DNA >200,000 IU/mL, regardless of HBeAg status.^8-10 This represents a refinement from the 2018 conditional recommendation, which suggested initiation between weeks 28 and 32 with continuation up to 3 months postpartum.⁴

A key practical addition addresses settings where hepatitis B immune globulin (HBIG) is unavailable for the infant: based on a recent randomized controlled trial, TDF may be initiated as early as gestational week 16, with the infant receiving the HBV vaccine series at birth as the sole neonatal prophylactic intervention in lieu of HBIG.¹¹ For individuals whose sole indication for antiviral therapy is MTCT prevention, discontinuation at delivery is now explicitly suggested, representing a meaningful change from prior practice. Post-cessation monitoring of HBV DNA and ALT every 1 to 3 months for up to 6 months is recommended, with reinitiation of treatment for significant withdrawal flares (ALT ≥5× ULN).^{4, 12} Breastfeeding on TDF or TAF is safe for both mother and infant.⁸

Antiviral Prophylaxis for Horizontal Transmission
For viremic HBsAg-positive individuals who do not meet standard treatment indications but are in high-risk scenarios for horizontal transmission (e.g., unprotected sex with multiple partners, injection drug use, healthcare workers performing SHEA Category III exposure-prone procedures), the guideline issues a conditional recommendation favoring a shared decision-making approach regarding antiviral therapy. Evidence for this recommendation is graded as very low, and non-pharmacologic measures such as vaccination of susceptible contacts, universal precautions, and harm reduction remain the cornerstone of prevention.¹³

IV - Treatment of the Immune-Tolerant Phase: A Paradigm Shift

Immune-Tolerant Phase
Perhaps the most impactful update involves the immune-tolerant phase (HBeAg-positive, HBV DNA ≥10⁷ IU/mL, persistently normal ALT). Prior guidance recommended observation for most patients in this phase⁴; the 2025 guideline now conditionally suggests antiviral therapy for patients over age 40 or with significant liver inflammation (grade ≥2) or fibrosis (F2 or greater) on non-invasive testing or liver biopsy.¹⁴ For individuals under 40 without these risk features, shared decision-making is recommended, weighing HCC risk reduction against the need for long-term therapy.¹⁵

This shift is driven by accumulating evidence linking persistently high HBV DNA levels with HCC risk even in the absence of elevated transaminases, as well as data showing that subclinical histologic disease (significant fibrosis or inflammation) can be present in up to one-third of immune-tolerant patients over age 40 despite normal ALT.¹⁴ Vibration-controlled transient elastography (VCTE) ≥8 kPa is suggested as the threshold for identifying F2 or higher fibrosis in this population.¹⁶ Monitoring every 6 months remains appropriate for patients in whom treatment is deferred, with the primary goal of detecting transition to the immune-active phase.¹³ An integrated management algorithm based on the updated 2025 recommendations is presented in Figure 1.

Figure 1. AASLD/IDSA 2025 recommended algorithm for management of chronic hepatitis B.

Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HDV, hepatitis D virus; HIV, human immunodeficiency virus; HBIG, hepatitis B immune globulin; NA, nucleos(t)ide analogue; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal.

V - The Indeterminate Phase: Moving Toward Individualized Therapy

HBeAg-Negative Indeterminate Phase
The HBeAg-negative indeterminate phase comprises patients who are HBsAg-positive, HBeAg-negative, without cirrhosis, and with HBV DNA and/or ALT levels that do not meet criteria for immune-active or inactive CHB. Previous guidance recommended observation for this group with initiation of treatment upon transition to immune-active disease.⁴

The 2025 guideline conditionally suggests considering antiviral therapy using a shared decision-making approach, with re-evaluation at each follow-up visit if treatment is deferred.³ Key factors favoring treatment include male sex, age >40 years, and platelet count <180,000/mm³ as surrogates for higher fibrosis risk.¹⁷ A systematic review supporting this recommendation demonstrated that antiviral therapy was associated with a significantly lower annual HCC incidence (adjusted incidence rate ratio 0.36, 95% CI 0.16 to 0.81) in this population.¹⁷ However, the certainty of evidence is very low, largely due to the observational nature of available studies and wide heterogeneity in outcomes.¹⁷

VI - Nucleos(t)ide Analogue Withdrawal: When (if ever) to Stop

Nucleos(t)ide Analogue Discontinuation
Among HBeAg-negative, non-cirrhotic patients with sustained undetectable HBV DNA on nucleos(t)ide analogue (NA) therapy, the 2025 guideline conditionally suggests against withdrawing NA therapy until HBsAg loss is achieved.¹⁸ This position differs notably from EASL 2025 and APASL guidance, which allow consideration of NA cessation in selected patients with prolonged viral suppression.¹⁹

The guideline acknowledges that NA discontinuation can lead to HBsAg loss in a subset of patients (approximately 10% over 2 years in RCTs), but weighs this benefit against the substantial risks of virologic relapse, ALT flares, and hepatic decompensation: risks that appear even higher in real-world cohort studies than in RCTs.¹⁸ For patients who strongly desire to stop therapy, eligibility requires HBsAg <100 IU/mL, undetectable HBV DNA for ≥2 years, no cirrhosis or prior decompensation, and no HIV or HDV co-infection, with post-cessation monitoring of HBV DNA and ALT every 1–3 months for the first 6 months and immediate retreatment if HBV DNA ≥10,000 IU/mL or ALT ≥5× ULN.⁷

VII - Hepatocellular Carcinoma Surveillance: Expanding the Net

Hepatocellular Carcinoma Surveillance After HBsAg Loss and in Co-infected Patients
Hepatocellular Carcinoma Surveillance in Special Populations The 2025 guideline provides refined and expanded HCC surveillance recommendations for several previously under addressed populations.³

For patients who have achieved HBsAg loss, surveillance is conditionally suggested for those with cirrhosis, a family history of HCC, men who experienced HBsAg clearance after age 40, and women after age 50.²⁰

For HBV-HDV co-infected adults, HCC surveillance is conditionally suggested independent of cirrhosis status, reflecting data showing that HDV co-infection significantly amplifies HCC risk, even in the absence of cirrhosis, with an incidence rate of 18.65 per 1,000 person-years compared to 4.84 for HBV monoinfection.²¹

For HBV-HIV co-infected individuals, HCC surveillance is suggested for men ≥18 years and women ≥40 years of age. For HBV-HCV co-infection, HCV treatment with direct-acting antivirals is strongly recommended, and HCC surveillance follows the same criteria as for HBV monoinfection after HCV cure.^{22, 23}

In all populations, surveillance with abdominal ultrasound and serum AFP at 6-month intervals remains the recommended approach.²⁴

VIII - Future Directions

Several important areas are anticipated to shape future guideline iterations. These include defining the role of novel biomarkers, quantitative HBsAg, HBV RNA, and hepatitis B core-related antigen (HBcrAg) as tools to guide treatment initiation and monitoring.²⁵ The potential benefit of antiviral therapy in inactive carriers with HBsAg levels >1,000 IU/mL, the role of peginterferon add-on or switch strategies to enhance functional cure rates, and the diagnostic performance of non-invasive tests as treatment decision guides remain unaddressed.^{13, 26} As new finite therapies targeting functional cure advance through clinical trials and reach regulatory approval, updated guidelines are anticipated, including those from the World Gastroenterology Organisation (WGO).²⁷

IX - Conclusion

The 2025 AASLD/IDSA practice guideline represents a meaningful evolution in the management of CHB, moving beyond the established framework of treating immune-active disease toward a more proactive, individualized approach for immune-tolerant and indeterminate phase patients. The expanded attention to MTCT prevention, HCC surveillance in co-infected and post-HBsAg-clearance populations, and the nuanced guidance on NA withdrawal reflect a maturation of the HBV field. Implementation of these recommendations, particularly in resource-limited settings, will require adaptation to local contexts and continued emphasis on equitable access to diagnosis and treatment.

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