Key concepts

Patients with evidence of current ((+)HBsAg) or past HBV exposure (HBsAg -negative/HBcAb positive) are at risk of HBV reactivation during and after treatments with immunosuppressive or biologic therapies. These agents are used widely for cancer chemotherapy as well as some hematologic, dermatologic and autoimmune conditions such as rheumatoid arthritis.

Abbreviations

• Ab: Antibody
• HBcAb: Hepatitis B core antibody
• HBsAg: Hepatitis B surface antigen
• HBsAb: Hepatitis B surface antibody
• HBV: Hepatitis B virus

Definitions

• Chronic HBV = HBsAg (+), quantifiable HBV DNA and ALT ranging from normal-elevated
• Chronic inactive HBV = HBsAg (+), undetectable or low level HBV DNA and normal ALT
• Previous HBV = HBsAg (-) HBsAb (-) HBcAb (+), undetectable HBV DNA and normal ALT

Hepatitis B Reactivation

HBV reactivation can range from a subclinical state with no symptoms to fulminant or even fatal hepatitis. Increase in ALT/AST elevations often accompany reactivation.

Reactivation can be defined by any one of the following (see Reactivation of Hepatitis B Virus: A review of Clinical Guidelines for society guidelines definitions):

• Newly detected HBV DNA (in someone who was previously undetected)
• A 1-2 log or greater increase in HBV DNA from baseline
• Sero-reversion of a prior negative HBsAg to positive status

HBV Reactivation is a potential complication of immunosuppressive therapy:

• can occur at any time during or months after immunosuppressive treatment
• can be prevented with HBV antivirals

HBV testing (HBsAg, HBcAb and HBsAb) is required for all patients who are initiating immunosuppressive:

• Within 6 months of immunosuppressive treatment
• A prior positive HBsAb does not indicate the patient is immune to reactivation
• Many patients are not aware of their HBV status

Hepatitis B antiviral prophylaxis:

• Use of HBV antivirals during immunosuppressive therapy and for 6-12 months post-therapy is required or recommended in many situations
• Recommendations depend on multiple factors:
  • The HBV status of the patient
  • The indication for immunosuppression
  • The risk of reactivation with a particular immunosuppressive agent
  • The presence/extent of underlying liver disease

High or moderate risk immunosuppressive treatments

*Incidence of HBV reactivation: High risk > 10%, moderate risk 1-10%

• The medications listed below are examples and may not be all inclusive.
• B-cell depleting agents (rituximab, ofatumumab, obinutuzumab, and ocrelizumab)
• Note: The risk of reactivation can increase from low or moderate risk to a higher risk when combinations of immunosuppressive treatments are utilized. For example: adding prednisone >20mg/day for more than 4 weeks to a biologic agent such as TNF alpha inhibitors used for rheumatoid arthritis. (Example: Adalimumab, ustekinumab, infliximab).
• Anthracycline derivatives (doxorubicin, epirubicin) — including trans arterial chemoembolization (TACE) for hepatocellular carcinoma.
• High risk if HBSAg+, moderate risk if HBSAg/HBcAb

Recommendations

• In all cases, before initiating immunosuppressive treatment → test for hepatitis B with HBsAg, HBsAb, HBcAb (total Ab)
• If HBsAg POSITIVE, additionally check HIV and HBV DNA and ALT and consider consulting GI ⁄ hepatology or ID.
• Consider consultation or referral to GI ⁄ hepatology or ID to follow patients during and following their HBV antiviral treatment
• Consider patients may be at higher risk of reactivation if certain immunosuppressive therapies are combined.

Resources

• Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update | Journal of Clinical Oncology (ascopubs.org)
  
• AGA Institute Guidelines on Hepatitis B Reactivation (HBVr): Clinical Decision Support Tool - Gastroenterology (gastrojournal.org)
  
• Reactivation of Hepatitis B Virus: A Review of Clinical Guidelines - PMC (nih.gov)
  
• Risk of HBV reactivation during therapies for HCC: A systematic review - Papatheodoridi - 2022 - Hepatology - Wiley Online Library