What does a negative Hepatitis B (HBV) surface antibody result indicate and what are the recommended next steps?

Hepatitis B Surface Antibody Negative: Interpretation and Management

What This Result Means

A negative hepatitis B surface antibody (anti-HBs) indicates lack of immunity to hepatitis B virus, meaning you are susceptible to HBV infection and require further evaluation to determine your complete HBV status and need for vaccination. 1

The interpretation depends critically on your other hepatitis B markers, which must be checked to determine your next steps.

Complete Serologic Testing Required

You need a full hepatitis B panel to interpret the negative anti-HBs result properly:

• HBsAg (Hepatitis B surface antigen) - determines if you have active infection 2
• Anti-HBc (Hepatitis B core antibody) - indicates past or current exposure 3, 2
• Anti-HBs (already negative) - confirms lack of immunity 1

Interpretation Based on Complete Panel

If HBsAg Negative + Anti-HBc Negative + Anti-HBs Negative

• You have never been infected with HBV and are susceptible to infection 2
• Immediate action: Hepatitis B vaccination series is indicated 1
• This is the most common scenario requiring vaccination 2

If HBsAg Positive + Anti-HBs Negative

• You have active hepatitis B infection (acute or chronic) 2
• Check anti-HBc IgM to distinguish acute from chronic infection 2
• If HBsAg persists beyond 6 months, this indicates chronic HBV infection requiring specialist referral 2
• You are infectious and can transmit HBV to others 2

If HBsAg Negative + Anti-HBc Positive + Anti-HBs Negative

• You have resolved past HBV infection but lack protective antibodies 3
• This pattern carries significant risk (3-45%) of HBV reactivation if you require immunosuppressive therapy 3
• Before any immunosuppression, you must have HBV DNA testing to assess reactivation risk 3
• Antiviral prophylaxis is required if you need immunosuppressive therapy, particularly with anti-CD20 antibodies (rituximab), anti-CD52 antibodies, or high-dose corticosteroids 4, 3
• The absence of anti-HBs in this setting increases reactivation risk compared to those with anti-HBs present 4

Critical Clinical Scenarios

If You Require Immunosuppressive Therapy

Patients who are anti-HBc positive but anti-HBs negative have the highest risk of HBV reactivation (up to 68.3% with rituximab-based chemotherapy) compared to those with anti-HBs present (34.4%) 4

Management algorithm:

• Obtain HBV DNA level before starting immunosuppression 3
• Initiate antiviral prophylaxis with nucleos(t)ide analogues regardless of HBV DNA level if receiving high-risk immunosuppression 3
• Continue prophylaxis during therapy and for 6-12 months after cessation (up to 12 months for rituximab due to prolonged immune reconstitution) 4
• Monitor liver function tests throughout treatment 3

If You Are Immunocompetent

• If HBsAg negative and anti-HBc negative: Proceed with hepatitis B vaccination series 1
• If HBsAg negative and anti-HBc positive: No immediate treatment needed, but document this status for future reference if immunosuppression becomes necessary 3

Important Caveats

Anti-HBs Titers and Protection

• Even if anti-HBs becomes positive later, titers >100 IU/mL are associated with 0% reactivation risk, while lower titers still carry 8.3-17.3% reactivation risk over 24 months 4
• Current evidence does not support using anti-HBs presence or titer alone to guide decisions about antiviral prophylaxis in the setting of immunosuppression 4

False Interpretations to Avoid

• Passively acquired anti-HBs from blood product transfusions can give false-positive results and does not indicate true immunity 5
• Low-level positive anti-HBs or anti-HBc results may be nonspecific and should be interpreted with caution, as they persist in less than half of cases at 1 year 6
• Transient HBsAg positivity can occur up to 18 days after vaccination (52 days in hemodialysis patients), which could confuse interpretation 2

Occult HBV Infection

• In rare cases, HBV DNA may be present in serum or liver despite negative HBsAg, particularly in immunocompromised patients with unexplained elevated liver enzymes 2
• Consider HBV DNA testing if you have unexplained hepatitis and are immunocompromised 2

Monitoring in Special Populations

• Healthcare workers and those with ongoing HBV exposure risk require periodic testing 1
• Dialysis patients may need annual anti-HBs screening even if previously immune 1
• Pregnant women with resolved HBV (anti-HBc positive) may experience postpartum flares 4