Authors: Zegui Fang, Longfeng Jiang, Jun Li
Affiliation: The First Affiliated Hospital of Nanjing Medical University
Editor's Note: In a study conducted by Metzler F et al. from 2005-2007, involving 258 patients who received one course of Rituximab treatment, 46% had received the hepatitis B vaccine, 11% were Anti-HBc/anti-HBs positive, and less than 1% were HBV DNA positive. The study found that the average Anti-HBs level in vaccinated individuals dropped significantly from 80 IU/mL to 38 IU/mL (P<0.05) after Rituximab treatment. Among three patients with inactive HBV infection, HBV DNA became detectable, and ALT levels increased post-treatment. With the increasing use of antitumor drugs in recent years, HBV reactivation and hepatitis B flare-ups have become significant clinical concerns. We have invited Professor Jun Li from the First Affiliated Hospital of Nanjing Medical University to discuss the comprehensive management of HBV reactivation related to antitumor treatment for the benefit of our peers.HBV Reactivation and Hepatitis B Flare-ups
China has approximately 75 million people with chronic HBV infection. The intrinsic and acquired immune escape mechanisms of HBV are crucial for its persistent infection. Recent studies on the tumor microenvironment have revealed similarities between the immune escape mechanisms of tumor cells and chronic HBV infection.
In HBV-infected individuals, antitumor treatment may disrupt the existing balance between liver immunity and HBV, leading to increased viral replication, characterized by HBV DNA reemergence or a significant rise in viral load compared to pre-treatment levels, known as HBV reactivation. Increased viral replication or immune response due to immune restoration can cause liver damage, clinically manifesting as significant ALT elevation, with or without jaundice, and potentially leading to liver failure, termed as hepatitis B flare-up. HBV reactivation often necessitates the interruption of antitumor treatment (e.g., chemotherapy), delaying the control of the primary disease and resulting in poor clinical outcomes.
Immunological Imbalance Leading to HBV Reactivation
Common drugs causing HBV reactivation include antimetabolites, immunosuppressants, corticosteroids, small molecule inhibitors, biological antibodies, and chemotherapeutic agents. Clinical features of HBV reactivation include:
- Increased serum HBV DNA levels during or after chemotherapy, followed by elevated ALT levels, and in severe cases, liver failure.
- HBV DNA levels may drop to undetectable levels when clinical manifestations of hepatitis appear.
- Patients with preexisting liver disease are more susceptible to potential disease worsening and drug-induced liver toxicity.
- Lymphoma patients with HBV reactivation are more likely to present with subacute or delayed liver failure.
Immunosuppressants, corticosteroids, and chemotherapeutic agents typically impair the body’s immune control over HBV, leading to enhanced viral replication and HBV reactivation. During the immunosuppressive phase, HBV DNA levels may rebound, and ALT levels may increase during the immune restoration phase. In contrast, immune checkpoint inhibitors or immune-activating treatments often cause liver damage due to immune cells attacking HBV-infected cells, characterized by low-level HBV DNA or slight rebounds, along with elevated ALT levels.
Comprehensive and Stratified Management to Prevent HBV Reactivation and Hepatitis B Flare-ups
The “Chinese Guidelines for the Diagnosis and Treatment of Drug-Induced Liver Injury (2023 Edition)” classify drugs into high, medium, low, and uncertain risk levels based on their potential to cause HBV reactivation.
Comprehensive Management for High-Risk Populations
High-risk individuals for HBV reactivation should undergo comprehensive management. Before starting antitumor treatment, patients should be routinely screened for HBsAg and Anti-HBc. If positive, HBV DNA should be further tested. Depending on the risk level of the drug and the patient’s HBV status, high and medium-risk individuals should receive prophylactic antiviral therapy before treatment. Low-risk individuals should be closely monitored for HBV DNA changes and given timely antiviral therapy. If HBV DNA monitoring is not feasible, prophylactic antiviral therapy should be considered to maximize the prevention of HBV reactivation.
HBV reactivation can occur during or after antitumor treatment. Antiviral therapy should continue for 6-12 months after completing antitumor treatment; for patients using B-cell monoclonal antibodies or undergoing hematopoietic stem cell transplantation, antiviral therapy should continue for at least 18 months. After stopping antiviral therapy, follow-up should continue for 12 months, with HBV DNA and ALT/AST monitored every 1-3 months.
For HBV reactivation associated with immune checkpoint inhibitors or immune-activating treatments, reducing HBV DNA and HBsAg levels through antiviral therapy can help prevent immune-mediated liver damage. If ALT levels significantly rise, antiviral therapy should continue, and treatment for immune checkpoint inhibitor liver toxicity should be considered.
Conclusion
In summary, antitumor treatment involves multidisciplinary participation and various treatment methods, with immunotherapy being a critical component. However, “immune imbalance” is a significant cause of HBV reactivation in patients with previous or current HBV infection. Preventing HBV reactivation during antitumor treatment should adhere to principles of comprehensive monitoring, stratified management, and timely intervention. Different mechanisms of HBV reactivation or hepatitis flare-ups require varied treatment strategies, necessitating continuous experience accumulation and exploration of new treatment protocols by clinicians.
