What are the implications and management for a patient with a positive Anti-HBc (Antibody to Hepatitis B Core Antigen) and Alternate anti-HBc, negative HbsAg (Hepatitis B Surface Antigen) screening, and negative HBV NAT (Hepatitis B Virus Nucleic Acid Test)?

Hepatitis B Serologic Interpretation and Management

Your patient has resolved hepatitis B infection (past HBV infection) with either isolated anti-HBc positivity or resolved infection, and requires anti-HBs testing to complete the serologic profile and determine reactivation risk. 1, 2

Serologic Profile Interpretation

Your patient's results indicate:

• HBsAg negative = No active chronic infection 1
• Anti-HBc positive = Previous HBV exposure 1, 2
• HBV NAT (DNA) negative = No detectable viral replication 2

This pattern represents past HBV infection, not active disease. 1, 2 However, covalently closed circular DNA remains in the liver and can reactivate with immunosuppression. 1

Critical Next Step: Anti-HBs Testing

You must immediately order anti-HBs (hepatitis B surface antibody) testing to distinguish between: 1, 2

• Anti-HBs positive = Resolved infection with protective immunity (14% reactivation risk with high-risk immunosuppression) 1
• Anti-HBs negative = Isolated anti-HBc positivity (5% reactivation risk with high-risk immunosuppression) 1

The presence and titer of anti-HBs is protective against HBV reactivation, with negative anti-HBs conferring 3.51-fold higher reactivation risk (HR 3.51,95% CI 1.37-8.98) in patients receiving high-risk immunosuppression. 1

Management Based on Clinical Context

If Patient is NOT Receiving Immunosuppression

No treatment or prophylaxis is required. 2, 3

• Confirm resolved infection status with anti-HBs testing 2
• No routine monitoring needed 2
• Vaccinate against hepatitis A if non-immune 4, 3

If Patient is Receiving HIGH-RISK Immunosuppression

High-risk therapies include: anti-CD20 antibodies (rituximab), anti-CD52 antibodies, stem cell transplantation, CAR-T therapy, anthracyclines, or high-dose corticosteroids (>20-40 mg prednisolone equivalents). 1, 2, 5

Start antiviral prophylaxis immediately with: 1, 2, 3

• Entecavir 0.5 mg daily, OR
• Tenofovir disoproxil fumarate, OR
• Tenofovir alafenamide

These three agents have high potency and high resistance barriers. 1, 3

Duration of prophylaxis: 1

• Start before or at initiation of immunosuppressive therapy 1, 3
• Continue throughout therapy 1
• Continue for at least 12 months after completion of immunosuppressive therapy 1
• May need up to 24 months for highest-risk therapies 1

Test for HIV before starting antiviral therapy since these medications have anti-HIV activity and HIV monotherapy is contraindicated. 1

If Patient is Receiving MODERATE-RISK Immunosuppression

For moderate-risk therapies (standard solid tumor chemotherapy, moderate-dose corticosteroids), you have two options: 1, 2

Option 1: Close monitoring without prophylaxis (requires commitment to frequent testing) 1, 2

• Check HBsAg, HBV DNA, and ALT every 1-3 months during therapy 2, 3
• Continue monitoring for 6-12 months after therapy completion 2
• Start antiviral therapy immediately if HBsAg becomes positive or HBV DNA becomes detectable 2

Option 2: Prophylactic antiviral therapy 2

• Use same agents and duration as high-risk patients 2, 3
• Preferred if patient values avoiding even small reactivation risk 2

Baseline Assessment Required

Before any immunosuppression, obtain: 4, 2, 3

• Liver function tests: AST, ALT, alkaline phosphatase, GGT, bilirubin, albumin, prothrombin time 2, 3
• Complete blood count and creatinine 2, 3
• Coinfection screening: Anti-HCV, anti-HDV, anti-HIV 4, 2, 3
• Hepatitis A immunity (anti-HAV) - vaccinate if negative 4, 2, 3

Critical Pitfalls to Avoid

Do not delay cancer or immunosuppressive therapy for HBV test results - start prophylaxis empirically if needed. 3

False-positive anti-HBc can occur after intravenous immunoglobulin (IVIG) administration, with 15% passive transfer rate. 1, 3 If your patient recently received IVIG, interpret results cautiously and consider retesting. 1

Reactivation risk varies by anti-HBs status: The 25% reactivation rate in monitored patients receiving anti-CD20 therapy occurred without distinguishing anti-HBs status. 1 Patients with negative anti-HBs have significantly higher risk. 1

Corticosteroid dosing matters: Peak daily doses >20-40 mg prednisolone equivalents increase hepatitis flare risk (aHR 2.19-2.11), even for short durations <7 days. 5 Duration >7 days further increases risk (aHR 2.02-3.85). 5

Low-level viremia may exist: Despite negative HBV NAT, up to 32% of anti-HBc positive patients may have detectable HBV DNA <1000 copies/mL by highly sensitive PCR. 6 This represents low infectivity and likely low risk for progressive liver damage, but reactivation remains possible with immunosuppression. 6