Editor’s Note: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a primary treatment for malignant blood diseases, with its numbers increasing annually. China is a region with moderate prevalence of hepatitis B virus (HBV), with approximately 5% to 6% of the population carrying hepatitis B surface antigen (HBsAg), and an annual incidence rate of about 1%. Patients positive for HBsAg or with past HBV infection are at risk of HBV reactivation during immunosuppressive therapy, chemotherapy, or monoclonal antibody-targeted therapy, with a higher risk during allo-HSCT. However, there is currently a lack of standardized clinical consensus or guidelines for the prevention and treatment of HBV reactivation after allo-HSCT in China. To address this, the Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association formulated and released the “Chinese Expert Consensus on Prevention and Treatment of Hepatitis B Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation (2023 Edition).” At the recently concluded 13th National Congress of Hematopoietic Stem Cell Transplantation of the Chinese Medical Association, Professor Yi Luo from the , as the principal expert of the consensus, provided an interpretation of the consensus, aiming to provide clinical guidance for hematologists, hematopoietic stem cell transplantation sub-specialists, and related physicians.
I. Definitions and Epidemiological Data
Chronic HBV infection refers to HBsAg (or) HBV-DNA positive for more than 6 months. HBV reactivation refers to the reappearance of HBV replication in patients with chronic HBV infection or past HBV infection after allo-HSCT, with a significant increase in HBV-DNA levels or conversion from negative to positive for HBsAg. Patients with hematological diseases undergoing allo-HSCT face a higher risk of HBV reactivation, which varies depending on the patient’s HBV serological status. HBsAg-positive patients are at particularly high risk, with a post-transplant HBV reactivation rate of up to 45% to 81% when prophylactic antiviral therapy is not administered. The reactivation rate in patients with past HBV infection who did not receive treatment ranges from 4.3% to 40.8%. Additionally, HBsAg-positive donors may transmit HBV to recipients, leading to a high incidence of HBV-related hepatitis after transplantation. Investigations have found that 15.3% of HBsAg-negative donors have occult HBV infection, with 73.7% of them also testing positive for HBsAb. Although there are no reports of the incidence of HBV-related hepatitis in recipients of allo-HSCT from donors with occult HBV infection (OBI), it has been confirmed that OBI patients are at risk of HBV reactivation during immunosuppressive therapy.
II. Mechanisms of HBV Reactivation
HBV enters the human body through mother-to-child transmission, blood, and sexual contact. HBV nucleic acid enters the nuclei of liver cells and transforms into covalently closed circular DNA (cccDNA). HBV cccDNA stably persists in the nuclei of liver cells. When the body is in an immunosuppressed state, the cytotoxic effect of HBV-specific T cells decreases, and the production of HBsAb by B cells decreases, allowing HBV-DNA to replicate again in the body. When the body’s immune function recovers, virus-induced immune responses lead to liver cell damage and inflammatory necrosis.
Diagnosis and Clinical Evaluation of HBV Reactivation
(A) Diagnostic Criteria Patients Positive for HBsAg: ① HBV-DNA elevation of ≥ 2 log compared to baseline; ② HBV-DNA undetectable before transplantation, and HBV-DNA ≥ 2 log (100) IU/ml after transplantation; ③ If the baseline HBV-DNA level before transplantation is unknown, HBV-DNA ≥ 4 log (10,000) IU/ml after transplantation. Patients with Past HBV Infection (HBsAg negative, HBcAb positive): ① HBsAg negative before transplantation, and HBsAg becomes positive after transplantation; ② HBV-DNA undetectable before transplantation, and HBV-DNA detected after transplantation. Hepatitis flare is defined as alanine aminotransferase (ALT) levels ≥3 times the baseline and >100 U/L. HBV-related hepatitis is defined as the simultaneous occurrence of HBV reactivation and hepatitis flare.
(B) Clinical Assessment HBV reactivation may manifest as asymptomatic hepatitis or severe liver dysfunction, impacting planned immunosuppressive therapy and posing a threat to the patient’s life. Assessing its severity should consider changes in HBV-DNA viral load, liver enzymes, international normalized ratio of prothrombin time, hepatitis-related mortality, and the impact on reducing immunosuppressants (or discontinuation) under a consistent definition of HBV reactivation. Due to the complexity of HBV reactivation issues, it is recommended to involve multidisciplinary experts from hepatology, gastroenterology, pathology, and other fields in making joint decisions.
(C) Differential Diagnosis Liver Graft-versus-Host Disease (GVHD): Acute and chronic types. Acute GVHD mostly occurs early after transplantation, accompanied by symptoms such as rash and greenish diarrhea; chronic GVHD occurs later, accompanied by symptoms such as dry eyes and oral ulcers. Liver biopsy shows infiltration of large numbers of allogeneic T lymphocytes. Drug-induced Liver Injury: Other causes need to be ruled out, and the causality between drugs and liver damage needs to be assessed. Liver damage may recover after discontinuation or clearance of the drug. Special attention should be paid to drugs such as calcineurin inhibitors and triazole antifungals that may cause liver injury. Sinusoidal Obstruction Syndrome (SOS)/Veno-occlusive Disease (VOD) of the Liver: Mostly occurs within 21 days after transplantation due to pre-transplantation-related hepatotoxicity. Manifestations include painful hepatomegaly, jaundice, etc., and diagnosis relies on clinical manifestations and imaging examinations. Transplant-associated Thrombotic Microangiopathy (TA-TMA): A severe complication after HSCT, mainly manifested as microangiopathic hemolytic anemia, thrombocytopenia, etc. Diagnosis can be made based on evidence such as elevated lactate dehydrogenase (LDH) and proteinuria. Additionally, differential diagnosis should be made with bacterial or fungal infections, viral hepatitis, non-hepatotropic viral infections, and capillary leak syndrome.
IV. Strategies for Prevention and Treatment of HBV Reactivation after Hematopoietic Stem Cell Transplantation
It is recommended to screen all patients and donors for HBV serological markers (HBsAg, HBsAb, HBcAb) and HBV-DNA before transplantation.
(A) Recommendations for Hematopoietic Stem Cell Transplant Recipients
01 Patients with Chronic HBV Infection
Commence prophylactic nucleos(t)ide analog (NA) therapy at least 1 week before transplantation, choosing potent and low-resistance drugs such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF). Antiviral therapy should be continued for at least 18 months after discontinuation of immunosuppressive agents. For patients in whom HBsAg clears after transplantation and HBsAb remains positive, consideration may be given to discontinuing antiviral therapy (recommended for consultation with hepatology specialists). Monitoring of HBV serological markers and HBV-DNA: ① every 3 months during antiviral therapy; ② monthly for the first 3 months after discontinuation of antiviral therapy, then every 3 months thereafter; ③ whenever liver function damage occurs (refer to Figure 2). Preferential selection of HBsAb-positive donors.
02. Management Protocol for Preventing Hepatitis B Virus Reactivation in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
- Patients with Previous HBV Infection
After transplantation, monitor HBV serological markers and HBV-DNA every 3 months. In case of HBV reactivation, promptly initiate nucleos(t)ide analog (NA) therapy or administer routine prophylactic NA therapy before transplantation. NAs such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) are recommended. Antiviral therapy should be continued for at least 18 months after discontinuation of immunosuppressive agents. For patients who achieve HBsAg clearance after transplantation with sustained HBsAb positivity, discontinuation of antiviral therapy may be considered (advisable to consult hepatology specialists). Monitoring of HBV serological markers and HBV-DNA: ① every 3 months during antiviral therapy; ② monthly for the first 3 months after discontinuation of antiviral therapy, then every 3 months thereafter; ③ whenever liver function damage occurs (see Figure 2). The necessity of prophylactic antiviral therapy for patients with previous HBV infection undergoing allo-HSCT remains controversial.
- Occult HBV Infection (OBI)
Preventive measures are the same as those for HBsAg-positive individuals. When OBI recipients receive treatment including anti-CD20 monoclonal antibodies, the incidence of HBV reactivation is higher (>10%). Considering the possibility of OBI in donors, the use of OBI donor grafts may lead to HBV reactivation after allo-HSCT in recipients. Therefore, all allo-HSCT donors should be screened for HBV-DNA before transplantation. If HBV-DNA is positive, management should follow that for HBsAg-positive donors.
- Recipients Negative for HBsAg and HBV-DNA, Donors Positive for HBsAg and/or HBV-DNA
Two comprehensive treatment strategies can be adopted: ① Initiating prophylactic NA therapy for recipients 1 week before transplantation; HBsAb-negative recipients may receive 1-3 doses of hepatitis B vaccine before transplantation, while HBsAb-positive (≥10 IU/L) recipients may receive 1 dose of hepatitis B vaccine before transplantation. ② Providing passive immunity to recipients using hepatitis B immune globulin (HBIG) (on the day of transplantation, 1 month after transplantation, 2 months after transplantation), followed by vaccination with 3 doses of hepatitis B vaccine at 0, 1, and 6 months after transplantation (see Figure 3).
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03. Management Protocol for Preventing Hepatitis B Virus Reactivation in Donors of Allogeneic Hematopoietic Stem Cell Transplantation
Recipients Negative for HBsAg and HBV-DNA, Donors Negative for HBsAg and Positive for HBcAb
Recipients may receive hepatitis B vaccination before transplantation, and HBV indicators should be closely monitored after transplantation.
(B) Recommendations for Donors of Hematopoietic Stem Cell Transplantation
HBV-Positive Donors: Administer NA therapy until HBV-DNA becomes negative before hematopoietic stem cell collection.
Donors Positive for HBsAg and Negative for HBV-DNA: Hematopoietic stem cells can be collected directly without antiviral therapy.
(C) Recommendations for Hepatitis B Vaccination
Both pre-transplantation donors and recipients are negative for HBV serological markers: Recipients may receive 3 doses of hepatitis B vaccine at 0, 1, and 6 months after transplantation.
Recipients previously vaccinated before transplantation with subsequent loss of HBsAb: Patients who lose protective antibodies after transplantation may receive 3 doses of hepatitis B vaccine at 0, 1, and 6 months after transplantation.
Recipients with HBsAb remaining negative or low-titer positive after transplantation: Patients with previous HBV infection should be regularly monitored for HBsAb titers after transplantation, and hepatitis B vaccination may be administered when the titers are below the protective level. If HBsAb titers remain <10 mIU/ml after 3 doses of hepatitis B vaccine, an additional dose may be administered 1-2 months later.
Hepatitis B vaccination in recipients after transplantation plays a protective role in preventing HBV infection, preventing transmission of HBV from HBcAb-positive grafts, and reducing the risk of HBV reactivation in patients with previous infections. However, most recipients lose the protective effect of the vaccine after transplantation. HBsAg-negative recipients should receive at least 3 doses of hepatitis B vaccine after transplantation to maintain protection. For recipients with previous HBV infection, hepatitis B vaccination after transplantation can also reduce the risk of reactivation. Therefore, it is recommended that all HBsAg-negative recipients undergo HBsAb titer testing 6 months after transplantation and receive hepatitis B vaccination as needed.
V. Other Issues to Consider
The management of recipients with chronic HBV infection or previous infection receiving CAR-T therapy can refer to the “Chinese Expert Consensus on Prevention and Treatment of Hepatitis B Virus Reactivation in CAR-T Cell Therapy Targeting B Cells and Plasma Cells.” In the future, the use of new drugs/treatment regimens after allo-HSCT will become more common. When using new drugs/therapies after allo-HSCT in patients with previous HBV infection or chronic HBV infection, attention should be paid to the possible occurrence of HBV reactivation.
Expert Profile
Professor Yi Luo
Doctor of Medicine, Professor, Chief Physician, Doctoral Supervisor
Deputy Director, Bone Marrow Transplantation Center, First Affiliated Hospital, Zhejiang University School of Medicine
High-level Innovative Talent in Zhejiang Province for Health
Deputy Leader, Hematopoietic Stem Cell Transplantation Group, Hematology Branch, Chinese Medical Association
Standing Committee Member, Hematology Branch, Zhejiang Medical Association
Member, Hematologic Oncology Professional Committee, Zhejiang Anti-Cancer Association
Member, Hematopoietic Stem Cell and Cell Therapy Group, Hematologic Oncology Professional Committee, Chinese Anti-Cancer Association
Member, Academic Committee on Transplantation Infections, Geriatric Society of China
Deputy Director, First Youth Committee, Hematologic Oncology Professional Committee, Chinese Anti-Cancer Association
Engaged in clinical and basic research on hematopoietic stem cell transplantation for a long time, leading multiple national natural science funds; published multiple SCI papers as first or corresponding author in journals such as Blood, Leukemia, AJH, BJH, BMT, and BBMT
As the second principal participant, won the second prize of National Science and Technology Progress Award in 2015, the first prize of Ministry of Education Science and Technology Progress Award in 2013, and the first prize of Zhejiang Provincial Science and Technology Progress Award in 2011.
