What is the workup for a patient with a reactive Hepatitis B surface antigen (HBsAg) test?

Workup for HBsAg Reactive Patient

All patients with a reactive HBsAg test require confirmatory testing with a neutralizing assay, followed by comprehensive serologic and virologic evaluation to determine infection phase, disease activity, and need for treatment. 1

Initial Confirmatory Testing

• Confirm HBsAg positivity using an FDA-licensed neutralizing confirmatory test, as initially reactive specimens must be verified to establish true infection 1
• A confirmed HBsAg-positive result indicates active HBV infection (either acute or chronic) 1
• All HBsAg-positive persons should be considered infectious 1

Distinguish Acute vs. Chronic Infection

• Test for IgM anti-HBc to differentiate acute from chronic infection 1, 2
  • Positive IgM anti-HBc indicates acute hepatitis B 1, 2
  • Chronic infection is confirmed by HBsAg persistence for ≥6 months OR absence of IgM anti-HBc 1
• If initial presentation, repeat HBsAg testing at 6 months to confirm chronicity if IgM anti-HBc is negative or unavailable 1

Complete Serologic Panel

Obtain the following markers to fully characterize infection status 1, 3:

• HBeAg and anti-HBe to assess replication status 1, 3
  • HBeAg-positive generally indicates high viral replication 1
  • Anti-HBe-positive suggests lower replication but does not exclude active disease 1
• Anti-HBc (total) - should be positive in all chronic infections 1, 2
• Anti-HBs - should be negative in chronic infection (positive indicates resolved infection or vaccination) 2

Virologic and Biochemical Assessment

• Quantitative HBV DNA level is essential for determining disease activity and treatment eligibility 1, 3
  • Levels >2000 IU/mL typically indicate active viral replication requiring closer monitoring 1
• ALT and AST levels to assess hepatocellular injury and disease activity 1, 3
• Complete liver function tests including bilirubin, albumin, and prothrombin time/INR 3
• Complete blood count and platelet count to screen for cytopenias suggesting cirrhosis 1

Screen for Coinfections and Immunity

• Anti-HAV (total IgG) to determine need for hepatitis A vaccination 1, 2
  • Vaccinate if negative, as HAV coinfection increases mortality 5.6- to 29-fold in HBV carriers 1
• Anti-HCV to exclude hepatitis C coinfection 1
• Anti-HDV (hepatitis D antibody) in high-risk populations or those with severe/fluctuating disease 3
• HIV testing given high prevalence of coinfection and increased HBV-related morbidity 1

Assess for Cirrhosis and HCC Risk

• Abdominal ultrasound to evaluate liver parenchyma, assess for cirrhosis, and exclude focal lesions 3
• Non-invasive fibrosis assessment (FibroScan, APRI, FIB-4) may be useful, particularly if HBV DNA >2000 IU/mL 1
• Consider liver biopsy in patients with elevated ALT, HBV DNA >2000 IU/mL, and unclear disease stage to determine urgency of treatment 1, 3
• Alpha-fetoprotein (AFP) as baseline for HCC surveillance if indicated 1

Determine Infection Phase

The workup should categorize patients into one of the following phases 1:

• Immune tolerant phase: HBeAg-positive, very high HBV DNA (>10^7 IU/mL), normal ALT 1
• Immune active phase: HBeAg-positive, elevated ALT, moderate-to-high HBV DNA 1
• Inactive carrier state: HBeAg-negative, anti-HBe-positive, HBV DNA <2000 IU/mL, persistently normal ALT 1
• HBeAg-negative chronic hepatitis B: HBeAg-negative, anti-HBe-positive, fluctuating HBV DNA and ALT levels 1

Establish Monitoring Plan

• Inactive carriers require ALT monitoring every 3-4 months and HBV DNA testing for at least 1 year to confirm stability, then every 6 months thereafter 1
• Active disease (elevated ALT, HBV DNA >2000 IU/mL) requires more frequent monitoring and treatment consideration 1
• Patients with HBV DNA >2000 IU/mL at baseline warrant closer follow-up even if ALT is normal 1

Special Considerations

• Quantitative HBsAg levels may provide additional prognostic information, with levels <1000 IU/mL suggesting inactive carrier state, though overlap exists 1
• Family screening is essential - test household contacts and sexual partners 1
• Vaccination of susceptible contacts should be initiated immediately 1
• Counsel on transmission prevention including safe sex practices and avoiding blood/body fluid exposure 1

Common Pitfalls

• Failing to confirm initially reactive HBsAg with neutralization assay leads to false-positive diagnoses 1, 4
• Distinguishing inactive carriers from HBeAg-negative chronic hepatitis B requires longitudinal monitoring (minimum 1 year with quarterly testing), not a single assessment 1
• A single normal ALT does not exclude active disease - HBeAg-negative CHB shows fluctuating patterns 1
• Patients may require immunosuppressive therapy in the future - document baseline status for reactivation risk stratification 1