What is the initial approach for a patient who is Hepatitis B surface antigen (HBsAg) positive, according to the European Association for the Study of the Liver (EASL) guidelines?

EASL Guidelines on HBsAg Positive Patient Approach

Initial Diagnostic Evaluation

All HBsAg-positive patients require immediate comprehensive serological, virological, and biochemical assessment to determine disease phase and treatment eligibility. 1

Mandatory Initial Laboratory Tests

• Measure HBeAg and anti-HBe to classify the phase of chronic HBV infection, as this distinction is essential for treatment decisions 1
• Quantify HBV DNA by PCR as this is essential for diagnosis, establishing infection phase, and determining treatment need 1
• Check ALT and AST levels along with a complete metabolic panel including bilirubin, albumin, gamma globulins, alkaline phosphatase, GGT, full blood count, and prothrombin time to assess liver disease severity 1
• Obtain quantitative HBsAg levels, which can be particularly useful in HBeAg-negative chronic infection and for patients being considered for interferon-alfa therapy 1
• Screen for coinfections including anti-HCV, anti-HDV (especially in high-risk groups), and anti-HIV, as these significantly impact management 1

Liver Disease Severity Assessment

• Perform abdominal ultrasound in all HBsAg-positive patients to evaluate liver parenchyma and establish baseline for surveillance 1
• Assess fibrosis using transient elastography (FibroScan) as the preferred non-invasive method when biochemical and HBV markers yield inconclusive results, though diagnostic accuracy is better at excluding than confirming advanced fibrosis 1
• Consider liver biopsy when non-invasive methods are inconclusive or when results would change management, particularly in patients with borderline ALT elevations and age >30 years 1

Important caveat: Transient elastography results may be confounded by severe inflammation with high ALT levels, so interpret cautiously in this context 1

Treatment Indications by Disease Phase

Immediate Treatment Required (No Observation Period)

• All patients with compensated cirrhosis and any detectable HBV DNA must start treatment immediately regardless of ALT level 1, 2
• All patients with decompensated cirrhosis and detectable HBV DNA require urgent antiviral therapy with entecavir or tenofovir AND simultaneous liver transplant evaluation 1
• HBV DNA ≥20,000 IU/mL with ALT ≥2× ULN warrants immediate treatment without liver biopsy 1, 2
• HBV DNA ≥2,000 IU/mL with moderate-to-severe fibrosis (liver stiffness ≥9 kPa with normal ALT or ≥12 kPa with ALT <5× ULN) should receive treatment even with normal ALT 1, 2

Age-Based Treatment Considerations

• HBeAg-positive patients >30 years old with persistently normal ALT and high HBV DNA may be treated regardless of histological severity, as delayed HBeAg seroconversion beyond age 30 is itself a treatment indication 1
• Patients >40 years old in apparent immune tolerance should be strongly considered for treatment given increased HCC risk from persistently high HBV DNA levels 1

Observation with Close Monitoring

• Immune tolerance phase (HBeAg-positive, high HBV DNA >20,000 IU/mL, normal ALT, age <30) can be monitored without treatment, but requires ALT testing every 3-6 months to detect transition to immune-active phase 1
• Inactive carrier state (HBeAg-negative, HBV DNA <2,000 IU/mL, persistently normal ALT) confirmed by 3 or more evaluations does not require treatment 1

First-Line Treatment Options

Entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) are the only recommended first-line agents due to their high genetic barrier to resistance. 1, 2

• Avoid lamivudine due to unacceptably high resistance rates reaching 70% at 5 years 3
• Pegylated interferon-alfa remains an option for finite-duration therapy (48 weeks) in selected non-cirrhotic patients desiring time-limited treatment, but is absolutely contraindicated in decompensated cirrhosis 1, 2
• Treatment is typically long-term or indefinite with nucleos(t)ide analogues until HBsAg loss (functional cure), which is rarely achieved 1, 2

Monitoring Protocol

For Untreated Patients

• ALT determinations every 3 months during the first year, then every 6-12 months after stabilization 2
• HBV DNA every 6-12 months to detect viral reactivation 2
• HBeAg/anti-HBe status every 6-12 months to monitor for spontaneous seroconversion 4
• Fibrosis assessment every 12 months using non-invasive methods 2

For Patients on Treatment

• HBV DNA every 3 months until undetectable, then every 6 months 1, 3
• ALT/AST every 3-6 months to monitor biochemical response 1, 3
• Annual quantitative HBsAg testing to assess for potential HBsAg loss 3
• Renal function monitoring if on tenofovir, with TAF preferred over TDF in patients with renal concerns 1, 2

Hepatocellular Carcinoma Surveillance

Ultrasound examination every 6 months is mandatory for all high-risk patients, even those with effective viral suppression on treatment. 1, 3

High-Risk Criteria Requiring HCC Surveillance

• All patients with cirrhosis regardless of treatment status 1, 3

• Asian men >40 years and Asian women >50 years 3, 4

• Any patient with family history of HCC 1, 4

• African patients >20 years 4

• Age >40 with persistent/intermittent ALT elevation and/or high HBV DNA 4

• Consider AFP measurement every 6 months in conjunction with ultrasound, though ultrasound is the primary surveillance modality 4

Special Populations and Circumstances

Immunosuppression and Chemotherapy

• All HBsAg-positive patients receiving cancer chemotherapy or immunosuppressive therapy require prophylactic antiviral therapy with entecavir, TDF, or TAF starting before immunosuppression 1
• Continue prophylaxis for at least 12 months (18 months for rituximab-based regimens) after cessation of immunosuppressive treatment 1
• HBsAg-negative, anti-HBc positive patients receiving high-risk immunosuppression (rituximab, stem cell transplant) also require prophylaxis, while those with moderate/low risk require pre-emptive monitoring with HBsAg and/or HBV DNA every 1-3 months 1

Renal Transplant Recipients

• All HBsAg-positive renal transplant recipients must receive entecavir or TAF as prophylaxis or treatment, with TDF avoided due to renal safety concerns 1
• Long-term NA therapy has been shown to reduce liver complications and improve survival in this population 1

Pregnancy

• Women of childbearing age should discuss pregnancy plans before initiating treatment, as this affects agent selection 1
• Tenofovir DF is the preferred agent during pregnancy for women with HBV DNA >200,000 IU/mL, with prophylactic use recommended beginning at 24-32 weeks to prevent mother-to-child transmission 2
• Pegylated interferon is contraindicated during pregnancy 2

Family and Contact Management

All first-degree relatives and sexual partners of HBsAg-positive patients must be tested for HBsAg, anti-HBs, and anti-HBc, and vaccinated if negative for all markers. 1

• Newborns of HBV-infected mothers must receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series 1
• Post-vaccination testing should be performed 1-2 months after completion of the vaccination series in high-risk individuals including healthcare workers, dialysis patients, and immunocompromised subjects 1

Additional Preventive Measures

• Hepatitis A vaccination is mandatory for all HBsAg-positive patients who are anti-HAV negative, as HAV coinfection increases mortality risk 5.6- to 29-fold 1, 3
• Strict alcohol abstinence is recommended for all patients with chronic HBV infection 1
• Smoking cessation should be strongly advised 1

HDV Screening

Anti-HDV antibody screening should be performed at least once in all HBsAg-positive individuals using a validated assay. 1

• Re-test for anti-HDV whenever clinically indicated (aminotransferase flares, acute decompensation) and consider yearly testing in those remaining at risk 1
• Universal anti-HDV screening is preferred over risk-based screening, as risk-based approaches miss a sizeable number of cases 1