What is the recommended treatment for a patient with a history of Hepatitis B (HBV) who is about to start biological therapy?

Hepatitis B Treatment Before Starting Biological Therapy

All patients with chronic HBV infection (HBsAg-positive) starting biological therapy must receive prophylactic antiviral therapy with entecavir or tenofovir, initiated prior to the first dose of immunosuppression and continued through treatment plus at least 12 months after the last dose. 1

Mandatory Pre-Treatment Screening

• Screen all patients for HBV before initiating biological therapy by testing HBsAg, anti-HBc (total or IgG), and anti-HBs—biological therapy should not be delayed while awaiting results 1
• Obtain baseline HBV DNA level, ALT, complete metabolic profile, complete blood count, and prothrombin time in all HBsAg-positive patients 1
• Coordinate care with a hepatologist or infectious disease specialist experienced in HBV management before starting therapy 1

Treatment Protocol for HBsAg-Positive Patients (Chronic HBV)

Initiate antiviral prophylaxis immediately, ideally 1-2 weeks before starting biological therapy: 1, 2

• First-line agents: Entecavir 0.5 mg daily OR tenofovir (disoproxil fumarate 300 mg or alafenamide 25 mg) daily 1, 3
• Never use lamivudine due to high resistance rates (20% at 1 year, 30% at 2 years, up to 70% at 5 years) which increases risk of resistance-related hepatic flares 1, 3
• Entecavir and tenofovir have high barriers to resistance with no resistance detected after 8 years of use 3

Duration of prophylaxis: 1

• Continue antiviral therapy throughout the entire course of biological therapy
• Extend for minimum 12 months after the last dose of biological therapy
• For rituximab or anti-CD20 antibodies specifically, extend to 18-24 months post-treatment 2

Treatment Protocol for HBsAg-Negative/Anti-HBc-Positive Patients (Resolved HBV)

Risk stratification determines management approach: 1

High-Risk Biological Therapies (Prophylaxis Mandatory):

• Anti-CD20 monoclonal antibodies (rituximab, ofatumumab, obinutuzumab) 1
• Hematopoietic stem cell transplantation 1
• Other B-cell depleting agents (alemtuzumab, ibritumomab, ustekinumab, natalizumab) 1

For these high-risk therapies: 1

• Start entecavir or tenofovir prophylaxis at initiation of biological therapy
• Continue for minimum 12 months (up to 18-24 months for rituximab) after cessation
• Obtain baseline HBV DNA and monitor every 6 months during prophylaxis
• Patients with negative anti-HBs are at higher risk than those with positive anti-HBs 1

Moderate-Risk Biological Therapies (Two Management Options):

Option 1 - Prophylactic approach (preferred for reliability): 1, 4

• Start entecavir or tenofovir at initiation of biological therapy
• Continue for 6-12 months after cessation

Option 2 - Monitoring approach (only if adherence assured): 1

• Monitor HBsAg and HBV DNA every 3 months during therapy and for 12 months after
• If HBV DNA becomes detectable (≥1,000 IU/mL) or HBsAg appears, immediately start entecavir or tenofovir 1
• If HBV DNA is quantifiable but <1,000 IU/mL, repeat testing monthly 1
• This approach requires strict patient and provider adherence to frequent monitoring 1

Low-Risk Biological Therapies:

• Monitoring with HBsAg and ALT every 3 months is sufficient 1
• Start antiviral therapy immediately if reactivation occurs 1

Monitoring During Prophylaxis

For all patients on antiviral prophylaxis: 1, 2

• Check ALT and HBV DNA at baseline
• Monitor ALT and HBV DNA every 6 months during antiviral therapy 1
• After stopping antivirals, monitor ALT monthly for first 3 months, then every 3 months thereafter to detect withdrawal flares 1
• Hepatitis flares presenting as elevated ALT can occur after discontinuation and may be severe 1

Risk Stratification by Biological Agent Type

High-risk agents (≥10% reactivation rate in HBsAg-positive): 1

• B-cell depleting therapies (rituximab, ofatumumab, alemtuzumab)
• Anthracycline derivatives (doxorubicin, epirubicin)
• High-dose corticosteroids (>20 mg prednisone daily for >4 weeks)
• Stem cell or solid organ transplantation

Moderate-risk agents (1-10% reactivation rate): 1

• Moderate-dose corticosteroids (10-20 mg prednisone daily for >4 weeks)
• TNF-alpha inhibitors (infliximab, adalimumab, etanercept, certolizumab, golimumab)
• Immunophilin inhibitors (cyclosporine, tacrolimus)
• Anthracyclines in HBsAg-negative/anti-HBc-positive patients

Low-risk agents (<1% reactivation rate): 1

• Methotrexate, azathioprine, 6-mercaptopurine
• Low-dose corticosteroids (<10 mg prednisone daily)
• Intra-articular steroid injections

Critical Pitfalls to Avoid

• Never delay biological therapy for HBV screening results—screening should occur concurrently, but treatment decisions can be made retroactively 1
• Never use lamivudine as first-line prophylaxis due to resistance development, which can compromise future treatment options 1, 3
• Never assume resolved HBV (anti-HBc-positive/HBsAg-negative) is safe—these patients can still reactivate, especially with high-risk biologicals like rituximab 1, 5
• Never stop antivirals immediately after finishing biological therapy—the 12-month continuation period is critical as delayed reactivation can occur months to years later 1
• Never use entecavir in patients with any prior lamivudine exposure, even if brief, due to archived resistance mutations 3

Special Considerations

For patients with decompensated cirrhosis: 2

• Require urgent antiviral treatment with entecavir or tenofovir
• Simultaneous evaluation for liver transplantation is mandatory

For pregnant patients requiring biological therapy: 2

• Tenofovir disoproxil fumarate is the preferred agent during pregnancy
• Can be used safely throughout pregnancy and does not contraindicate breastfeeding

For immune checkpoint inhibitors (anti-PD-L1, anti-CTLA4): 1

• These agents activate rather than suppress immunity, so HBV reactivation is unlikely
• However, prophylaxis is still recommended for HBsAg-positive patients due to concern about severe hepatitis exacerbation from immune activation