What is the recommended treatment approach for a patient with hepatitis B who requires rituxan (rituximab) therapy?

Management of Hepatitis B in Patients Requiring Rituximab

All patients with chronic hepatitis B (HBsAg-positive) requiring rituximab must receive prophylactic antiviral therapy with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide starting before rituximab and continuing for at least 12 months (preferably 18-24 months) after the last dose. 1

Pre-Treatment Screening (Mandatory)

Universal HBV screening is required before any rituximab administration because rituximab carries the highest reactivation risk among all immunosuppressive agents, with reactivation rates of 24-67% in HBsAg-positive patients without prophylaxis and mortality rates of 5-41% if hepatic failure occurs. 1, 2

Required Laboratory Tests:

• HBsAg (hepatitis B surface antigen) 3, 2
• Anti-HBc (hepatitis B core antibody) 3, 2
• Baseline quantitative HBV DNA by PCR in all patients testing positive for HBsAg or anti-HBc 3
• Complete hepatitis panel including anti-HBs, HBeAg, and anti-HBe 1
• Baseline ALT/AST 1

A negative baseline HBV DNA does not eliminate reactivation risk. 3

Management Based on HBV Status

HBsAg-Positive Patients (Chronic HBV)

Prophylactic antiviral therapy is mandatory regardless of HBV DNA level. 3

First-Line Antiviral Agents:

• Entecavir 0.5 mg daily 1
• Tenofovir disoproxil fumarate 300 mg daily 1
• Tenofovir alafenamide 25 mg daily 1

Never use lamivudine monotherapy due to resistance rates up to 70% at 5 years and breakthrough reactivation in 20-39% of patients even during prophylaxis. 3, 1

Timing:

• Start antiviral therapy 2-4 weeks before the first rituximab dose (or at the start of immunosuppressive therapy if timing does not permit earlier initiation) 3, 1

Duration:

• Continue for at least 12 months after the last rituximab dose 3, 1, 2
• Strong consideration for extending to 18-24 months after the last rituximab dose, as HBV reactivation has been documented up to 24 months post-rituximab 3, 1, 2
• If HBV DNA was elevated (≥2,000 IU/mL) before treatment, follow standard chronic hepatitis B treatment guidelines for discontinuation criteria 3

HBsAg-Negative but Anti-HBc-Positive Patients (Resolved HBV)

Prophylactic antiviral therapy is strongly preferred over monitoring alone because rituximab carries ≥10% reactivation risk even in resolved HBV, and HBsAg seroreversion consistently associates with severe hepatitis flares. 3, 1, 4

Exception for Monitoring Strategy:

If anti-HBs titer is high (>100 IU/mL), meticulous follow-up with ALT and HBV DNA monitoring every 1-3 months during and after therapy with prompt antiviral therapy upon reactivation is an acceptable alternative strategy. 3

However, prophylactic antiviral therapy remains the preferred approach for all anti-HBc-positive patients receiving rituximab due to the high-risk classification. 3, 1, 4

Monitoring During Treatment

For Patients on Prophylaxis:

• Monthly HBV DNA monitoring during treatment 3
• HBV DNA monitoring every 3 months after treatment completion 3
• Continue monitoring for at least 12 months after stopping antiviral prophylaxis 3

For Patients Being Monitored Without Prophylaxis (anti-HBc-positive only):

• HBsAg and HBV DNA every 1-3 months during and after chemotherapy 3
• Initiate antiviral therapy immediately upon detection of HBV reactivation 3

Management of HBV Reactivation

HBV reactivation is defined as abrupt HBV DNA increase or HBsAg seroreversion with ALT elevation. 2

If reactivation occurs:

1. Immediately discontinue rituximab and any concomitant chemotherapy 2
2. Initiate or intensify antiviral therapy immediately with entecavir or tenofovir regardless of ALT levels 1
3. Consult gastroenterology/hepatology 3
4. Insufficient data exist regarding safety of resuming rituximab after reactivation resolves; this decision requires hepatology expertise 2

Critical Pitfalls to Avoid

• Do not use lamivudine for prophylaxis due to high resistance rates and documented breakthrough reactivation 3, 1
• Do not stop antiviral prophylaxis at 6 months as with other immunosuppressants; rituximab requires at least 12 months post-treatment 3, 1, 4
• Do not rely on monitoring alone for HBsAg-positive patients; prophylaxis is mandatory 3
• Do not assume negative baseline HBV DNA eliminates risk; reactivation can still occur 3
• Do not skip screening in patients without traditional HBV risk factors; 57% of patients requiring prophylaxis in one cohort lacked recognized risk factors 5

Additional Considerations

Gastroenterology consultation is recommended for all patients testing positive for HBsAg or anti-HBc to determine optimal antiviral strategy and monitoring plan. 3

The risk of rituximab-induced HBV reactivation is substantially higher than with other immunosuppressive agents, with reactivation rates of 10-67% in various studies, making it the highest-risk agent for HBV reactivation. 3, 1, 6