What is the clinical significance of a patient with negative Hepatitis B surface antigen (HBsAg) and positive Hepatitis B core antibody (anti-HBc)?

Clinical Significance of Negative HBsAg and Positive Anti-HBc

A patient with negative hepatitis B surface antigen (HBsAg) and positive hepatitis B core antibody (anti-HBc) represents a case of resolved past HBV infection or occult HBV infection with risk of viral reactivation during immunosuppressive therapy. This serological pattern requires careful interpretation and management based on clinical context.

Interpretation of Serological Pattern

The serological pattern of negative HBsAg and positive anti-HBc can indicate several clinical scenarios:

1. Resolved past HBV infection - Most common interpretation, especially if anti-HBs is also positive 1

   • Indicates natural immunity from previous infection
   • Generally low risk of complications if no cirrhosis developed before HBsAg clearance

2. Occult HBV infection - HBsAg negative but HBV DNA may be detectable in liver and sometimes at low levels (<200 IU/ml) in serum 1

   • May have normal ALT values
   • HBV DNA may persist in liver tissue despite serological clearance

3. False negative HBsAg - Rare situation where HBsAg assay sensitivity is insufficient 1

4. Window period - Transitional phase during acute HBV infection when HBsAg has disappeared but anti-HBs has not yet appeared 2, 3

   • Anti-HBc IgM would be positive in this scenario

Clinical Implications

Risk of HBV Reactivation

The most significant clinical concern for these patients is the risk of HBV reactivation during immunosuppressive therapy:

• High risk with immunosuppressive therapy - Patients receiving anti-CD20 monoclonal antibodies (e.g., rituximab) have 3-45% risk of reactivation 1, 4
• Fatal outcomes possible - Reactivation can lead to liver failure and death if not properly managed 5
• Prophylactic approach needed - Antiviral prophylaxis is recommended for patients undergoing immunosuppressive therapy 1, 4

Management Algorithm

1. Determine anti-HBs status:

   • If anti-HBs positive: Likely resolved infection with natural immunity
   • If anti-HBs negative: Consider occult infection or window period

2. Test for HBV DNA if clinically indicated:

   • Positive HBV DNA confirms occult infection
   • Negative HBV DNA suggests resolved infection but doesn't rule out occult infection

3. Assess liver function:

   • Check ALT/AST to evaluate liver damage
   • Consider non-invasive fibrosis assessment or liver biopsy in selected cases

4. Evaluate need for prophylaxis:

   • Required for immunosuppressive therapy: Especially with anti-CD20 agents, stem cell transplantation, or high-dose corticosteroids 1, 4
   • Entecavir or tenofovir preferred for prophylaxis

5. Monitor for reactivation:

   • During immunosuppression: Regular monitoring of ALT and HBV DNA
   • Continue prophylaxis for at least 12 months after completing immunosuppressive therapy

Special Considerations

Differential Diagnosis

When encountering this serological pattern, consider:

• Testing for anti-HBc IgM to rule out acute or recent HBV infection 2, 3, 6
• Evaluating for other viral hepatitis (HCV, HDV) 4
• Assessing for other causes of liver disease

HBV Reactivation Prevention

For patients requiring immunosuppressive therapy:

• High-risk regimens (anti-CD20 agents): Prophylactic antiviral therapy mandatory 1
• Moderate-risk regimens (TNF inhibitors, cytotoxic chemotherapy): Consider prophylaxis or close monitoring 4
• Low-risk regimens: Regular monitoring may be sufficient 4

Long-term Follow-up

• If no immunosuppression planned: Routine follow-up not typically required
• If cirrhosis developed before HBsAg clearance: Continue HCC surveillance 1
• Patient education about potential reactivation risk with future immunosuppressive therapy

Common Pitfalls

1. Misinterpreting as immunity from vaccination - Vaccination produces anti-HBs without anti-HBc
2. Failing to recognize reactivation risk - Critical before immunosuppressive therapy
3. Inadequate monitoring - Patients on immunosuppression need regular liver function tests and viral markers
4. Overlooking occult infection - HBV DNA testing may be needed despite negative HBsAg
5. Missing window period - Consider anti-HBc IgM testing to identify recent infection

This serological pattern requires careful interpretation in clinical context, with particular attention to immunosuppression risk and appropriate prophylactic management to prevent potentially fatal HBV reactivation.