Diagnostic Workup for Positive Anti-HBc, Negative HBsAg
Order HBV DNA testing immediately to determine if this represents occult hepatitis B infection or resolved infection. 1
Initial Laboratory Assessment
The serologic pattern you describe (positive hepatitis B core antibody, negative hepatitis B surface antigen) indicates either past resolved HBV infection or occult HBV infection, and requires additional testing to distinguish between these states and guide management. 1
Essential Next Tests
HBV DNA (quantitative PCR): This is the critical test to differentiate occult infection (detectable HBV DNA) from resolved infection (undetectable HBV DNA). 1, 2
Anti-HBs (hepatitis B surface antibody): If positive, this confirms resolved infection with protective immunity; if negative, this represents isolated anti-HBc positivity which carries higher reactivation risk. 3, 1
Liver function tests: AST, ALT, alkaline phosphatase, GGT, bilirubin, albumin, and prothrombin time to assess for any hepatic inflammation or dysfunction. 1, 2
Complete blood count and creatinine: To establish baseline organ function. 1, 2
Additional Recommended Testing
Coinfection screening: Anti-HCV, anti-HDV, and anti-HIV testing, as coinfections significantly impact management and prognosis. 1, 2
Hepatitis A immunity: Check anti-HAV status and vaccinate if non-immune. 1, 2
Clinical Context Matters
If Patient Is or Will Be on Immunosuppressive Therapy
The management diverges significantly based on immunosuppression status:
For rituximab or stem cell transplantation: Prophylactic antiviral therapy is strongly recommended regardless of HBsAg status when anti-HBc is positive. Start entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide before therapy and continue for at least 12 months after completion. 3
For other biologics/immunosuppressants with HBsAg-negative, anti-HBc-positive status: The 2025 AGA guidelines recommend monitoring alone (HBV DNA and ALT every 1-3 months) over routine prophylaxis for moderate-risk therapies, though prophylaxis is conditionally recommended if the patient values avoiding even small reactivation risk. 3 However, the 2021 ACR guidelines suggest frequent monitoring is conditionally recommended over prophylaxis for non-rituximab biologics. 3
For high-risk immunosuppression (anti-CD20 therapy, CAR-T, anthracyclines, high-dose corticosteroids ≥4 weeks): Antiviral prophylaxis is strongly recommended even when HBsAg-negative. 3
If No Immunosuppression Planned
If HBV DNA is undetectable and anti-HBs is positive: This represents resolved infection with immunity. No specific HBV-directed treatment or monitoring is needed. 1
If HBV DNA is detectable (occult HBV): Measure HBV DNA level and ALT every 3-6 months. Consider antiviral therapy if HBV DNA >2,000 IU/mL with elevated ALT. 1
If isolated anti-HBc positive (anti-HBs negative, HBV DNA undetectable): Monitor HBV DNA and ALT every 6-12 months, as reactivation risk exists even without immunosuppression, though it is low. 1
Common Pitfalls to Avoid
Do not assume resolved infection without checking HBV DNA: Up to 14% of HBsAg-negative, anti-HBc-positive patients can have detectable HBV DNA (occult infection). 4, 5
Do not delay cancer or immunosuppressive therapy while obtaining results: Start prophylaxis empirically if high-risk therapy is urgent. 3
Do not use lamivudine for prophylaxis: Use only high-barrier agents (entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide) due to resistance concerns. 3
Do not stop monitoring after initial negative HBV DNA: Reactivation can occur months into immunosuppressive therapy, particularly with B-cell depleting agents. 3, 4
Monitoring Strategy If Prophylaxis Not Given
For patients on immunosuppression without prophylaxis (moderate-risk scenarios where monitoring is chosen):
Check HBsAg, HBV DNA, and ALT every 1-3 months during therapy and for 6-12 months after completion. 3
Immediately start antiviral therapy if HBsAg becomes positive or HBV DNA becomes detectable. 3
This strategy requires strict adherence and reliable follow-up; if either is uncertain, prophylaxis is safer. 3