HBV Reactivation Risk With ICIs vs TKIs in Liver Cancer

Hepatitis B virus (HBV) reactivation is a recognized risk during systemic therapy for liver cancer, particularly in high-endemic regions where HBV is a leading cause of hepatocellular carcinoma (HCC). The comparison of HBV reactivation risk between immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) is a critical area of investigation.

### Key Findings on HBV Reactivation Risk:

1. **No Excess Risk With ICIs Compared to TKIs**:

• Studies indicate that the use of ICIs does not increase the risk of HBV reactivation compared to TKIs, which are widely used systemic therapies for advanced liver cancer. This suggests that ICIs are as safe as TKIs in terms of HBV reactivation risk when proper prophylactic measures are employed.

2. **Consistency Across ICI Regimens**:

• Different types of ICIs, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapies, show similar profiles regarding HBV reactivation risk. This consistency highlights the general safety of ICIs in HBV-endemic populations under routine antiviral prophylaxis.

3. **Low Overall Reactivation Risk**:

• Routine antiviral prophylaxis significantly reduces HBV reactivation risk across both ICIs and TKIs. However, while prophylaxis is protective, it does not completely eliminate the risk, necessitating ongoing surveillance.

4. **Mechanistic Considerations**:

• ICIs theoretically raise concerns for HBV reactivation due to their immunological effects, such as enhancing immune responses that could impact latent HBV reservoirs in liver cells. Despite this, real-world evidence does not show an increased reactivation risk compared to TKIs.

5. **Patients With Past HBV Infection**:

• Individuals with resolved HBV infection (negative HBV surface antigen but positive HBV core antibody) are more vulnerable to reactivation than those with active infection. This is due to the persistence of latent viral reservoirs in liver cells, which can be triggered under immunotherapy.

6. **Antiviral Prophylaxis**:

• Preventive antiviral therapy is essential for reducing HBV reactivation risk in patients receiving systemic therapy for liver cancer. However, antiviral prophylaxis is less consistently prescribed for patients with past HBV infection, leaving them at higher risk.

7. **Role of Surveillance**:

• Even with antiviral prophylaxis, ongoing monitoring of HBV DNA and liver function is necessary to detect reactivation early and manage potential complications.

8. **Impact of Prior Liver Procedures**:

• Patients who have undergone transarterial chemoembolization (TACE) or other invasive liver procedures may have increased susceptibility to HBV reactivation during systemic therapy, regardless of whether they are on ICIs or TKIs.

### Clinical Implications:

• Systematic HBV screening is critical before initiating ICIs or TKIs in patients with liver cancer, particularly in HBV-endemic regions.
• Proactive antiviral prophylaxis should be implemented for all patients at risk, including those with resolved HBV infection, to minimize reactivation risk.
• Regular surveillance of HBV DNA and liver enzymes is essential for detecting reactivation or immune-related liver toxicity during therapy.

### Conclusion:

Under routine antiviral prophylaxis, ICIs do not pose an excess risk of HBV reactivation compared to TKIs for liver cancer treatment. However, patients with past HBV infection and those with a history of liver procedures require heightened vigilance due to their increased susceptibility. Comprehensive screening, prophylaxis, and surveillance are key to safe and effective management of HBV reactivation risk during systemic therapy in HCC.