Can patients with a history of resolved Hepatitis B (HBV) infection, previously positive for antibodies to Hepatitis B surface antigen (anti-HBs), experience recurrence of the infection?

Can Patients with Resolved Hepatitis B Infection (Anti-HBs Positive) Experience HBV Recurrence?

Yes, patients with resolved hepatitis B infection who are anti-HBs positive can experience HBV reactivation, particularly when receiving immunosuppressive therapy, though the risk is substantially lower than in patients without anti-HBs antibodies. 1

Understanding the Mechanism of Reactivation

Even after apparent resolution of HBV infection with development of anti-HBs antibodies, the virus persists as covalently closed circular DNA (cccDNA) in hepatocytes and other tissues. 1 This dormant viral reservoir can reactivate when the immune system is suppressed, allowing viral replication to resume despite the presence of protective antibodies. 1

Risk Stratification Based on Anti-HBs Status

The presence of anti-HBs provides partial but not complete protection against reactivation:

• Patients who are anti-HBs negative prior to immunosuppression have a significantly higher 2-year cumulative incidence of HBV reactivation (68.3%) compared to those who are anti-HBs positive (34.4%). 1

• Anti-HBs titers >100 IU/mL are associated with 0% reactivation risk in some studies, while lower titers carry reactivation rates of 8.3% at 6 months and 17.3% at 24 months post-chemotherapy. 1

• However, current guidelines state that anti-HBs presence or titer cannot be used to definitively assess reactivation risk or guide decisions on antiviral prophylaxis. 1

Clinical Scenarios Where Reactivation Occurs

High-risk immunosuppression scenarios include:

• Anti-CD20 monoclonal antibodies (rituximab, ofatumumab) - reactivation risk 3-45% even in anti-HBs positive patients 1
• Hematopoietic stem cell transplantation 1
• High-dose corticosteroids (>40 mg prednisolone equivalents) 2
• Anti-CD52 monoclonal antibodies 1
• Tyrosine kinase inhibitors 1

Reactivation can occur up to 12 months after cessation of immunosuppression with agents like rituximab due to prolonged immune reconstitution. 1

Spontaneous Reactivation Without Immunosuppression

While rare, spontaneous HBV reactivation can occur in elderly patients with resolved infection without any immunosuppressive trigger, particularly in the context of surgical stress, aging, or comorbid conditions like diabetes mellitus, cancer, or arteriosclerosis. 3 However, this represents an uncommon scenario compared to immunosuppression-related reactivation.

Management Algorithm for Anti-HBs Positive Patients

For patients receiving high-risk immunosuppression (anti-CD20 therapy, stem cell transplant):

• Initiate antiviral prophylaxis with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide before starting immunosuppression 1
• Continue prophylaxis for at least 12 months after completing immunosuppressive therapy, and up to 24 months for rituximab-based regimens 1
• Check baseline HBV DNA prior to therapy 1
• Monitor HBV DNA and ALT every 6 months during antiviral therapy 1

For patients receiving moderate-risk immunosuppression:

• Consider either prophylactic antiviral therapy or close monitoring approach 1
• If monitoring without prophylaxis: check HBsAg and ALT every 3 months during therapy 4
• If HBV DNA becomes detectable or ALT elevates, initiate antiviral therapy immediately 1

For patients NOT receiving immunosuppression:

• No routine HBV DNA testing or antiviral prophylaxis is necessary 4
• Standard clinical monitoring is sufficient 4

Consequences of Reactivation

HBV reactivation can range from asymptomatic biochemical hepatitis to fulminant liver failure and death. 1 Reactivation may necessitate interruption of chemotherapy (occurring in 71% of breast cancer patients who reactivate), potentially compromising treatment of the underlying malignancy and increasing morbidity and mortality. 1

Critical Pitfalls to Avoid

• Do not assume anti-HBs positivity provides complete protection - reactivation can still occur with potent immunosuppression even when anti-HBs is present. 1

• Do not use anti-HBs titer alone to guide prophylaxis decisions - current guidelines recommend prophylaxis based on the type and intensity of immunosuppression, not antibody levels. 1

• Do not stop monitoring too early - reactivation can occur up to 12 months (or even 24 months with rituximab) after completing immunosuppression. 1

• Do not overlook corticosteroid doses - even short courses of high-dose corticosteroids (>40 mg prednisolone equivalents) increase hepatitis flare risk. 2