Hepatitis B Testing Requirements Before Rituximab
Before administering rituximab, you must test for both hepatitis B surface antigen (HBsAg) AND hepatitis B core antibody (anti-HBc), not just anti-HBc IgM—a negative anti-HBc IgM alone is insufficient and dangerous. 1, 2
Required Screening Panel
You need a complete hepatitis B panel before any rituximab administration:
- Hepatitis B surface antigen (HBsAg) 1, 2
- Hepatitis B core antibody (anti-HBc total) - this detects both IgM and IgG 1, 2
- Baseline quantitative HBV DNA (PCR) if either HBsAg or anti-HBc is positive 1, 3
- Hepatitis B surface antibody (anti-HBs) - helpful for risk stratification but does NOT eliminate reactivation risk 1, 4
Why Anti-HBc IgM Alone Is Inadequate
Anti-HBc IgM only detects acute infection and misses the vast majority of patients at risk for reactivation. 1 The critical marker is total anti-HBc (which includes IgG), as this identifies patients with resolved hepatitis B infection who harbor occult HBV in hepatocytes as covalently closed circular DNA (cccDNA). 1
- Patients who are HBsAg-negative but anti-HBc-positive (resolved infection) have a 3-45% risk of HBV reactivation with rituximab, even if anti-HBs is present 4, 5
- Reactivation rates in anti-HBc-positive patients receiving rituximab reach 6.3% for clinical reactivation (ALT >3× normal with HBV DNA increase or HBsAg seroreversion) 6
- Reactivation can occur up to 24-33 months after the last rituximab dose, making this a prolonged risk 2, 7
Management Algorithm Based on Serologic Status
If HBsAg-Positive (Regardless of Anti-HBc Status)
Prophylactic antiviral therapy is STRONGLY RECOMMENDED and mandatory before rituximab. 1, 3
- Start entecavir 0.5 mg daily, tenofovir DF 300 mg daily, or tenofovir alafenamide 25 mg daily 2-4 weeks before first rituximab dose 3
- Never use lamivudine due to 70% resistance rates at 5 years and 20-39% breakthrough reactivation 1, 3
- Continue prophylaxis for at least 12 months, preferably 18-24 months after last rituximab dose 3, 2
- Without prophylaxis, reactivation risk is 24-67% with mortality rates of 5-41% if hepatic failure develops 3
If HBsAg-Negative but Anti-HBc-Positive (Resolved Infection)
Prophylactic antiviral therapy is STRONGLY RECOMMENDED for rituximab specifically, regardless of anti-HBs status. 1, 3
- The 2021 American College of Rheumatology guidelines state: "Prophylactic antiviral therapy is strongly recommended over frequent monitoring of viral load and liver enzymes alone for patients initiating rituximab who are hepatitis B core antibody positive (regardless of hepatitis B surface antigen status)" 1
- Even patients with anti-HBs >100 IU/mL can experience reactivation with rituximab 1
- Recent data shows 55-59% reactivation rates in anti-HBc-positive patients receiving rituximab without prophylaxis 5
- Use the same antiviral regimen and duration as HBsAg-positive patients 3, 4
If Both HBsAg and Anti-HBc Are Negative
Rituximab can be given without HBV prophylaxis, as the patient has never been exposed to hepatitis B. 1
Critical Pitfalls to Avoid
Do not rely on anti-HBs levels to determine safety. While some studies suggest anti-HBs >100 IU/mL may reduce risk, reactivation still occurs, and current guidelines do not use anti-HBs thresholds to guide prophylaxis decisions for rituximab. 1, 4
Do not use "monitoring alone" strategies for rituximab patients who are anti-HBc-positive. This approach is only conditionally recommended for other biologics (non-rituximab) in HBsAg-negative/anti-HBc-positive patients, but rituximab carries uniquely high reactivation risk requiring prophylaxis. 1
Do not stop monitoring after rituximab completion. HBV reactivation has been documented as late as 33 months post-rituximab, requiring extended surveillance. 7
Co-Management Requirements
Consult hepatology or gastroenterology for all patients with positive HBsAg or anti-HBc before initiating rituximab. 1, 3 Monitor HBV DNA quantitatively monthly during treatment and every 3 months for at least 12-24 months after completion. 1, 3