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    Home > Active Ingredient News > Digestive System Information > Interpretation of the main points of the 2021 APASL immunosuppressive therapy-related HBV reactivation guidelines

    Interpretation of the main points of the 2021 APASL immunosuppressive therapy-related HBV reactivation guidelines

    • Last Update: 2021-09-30
    • Source: Internet
    • Author: User
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    It is only for medical professionals to read for reference.
    Screen before starting immunosuppressive treatment, and start preventive antiviral treatment as soon as possible
    .

    Chronic hepatitis B (CHB) is a global health problem
    .

    In recent years, with the widespread application of immunosuppressive therapy (IST) in cancer chemotherapy, rheumatic diseases, inflammatory bowel disease, solid organ transplantation and other diseases, patients with hepatitis B virus (HBV) appear after receiving IST The reactivation of HBV is an important cause of acute and chronic liver failure and even death, which is also a major health problem in the Asia-Pacific region
    .

    In order to better help clinicians to effectively prevent and manage IST-related HBV reactivation and reduce its incidence and mortality, the Asia-Pacific Association for Liver Research (APASL) steering committee invited multiple fields from 21 countries/administrative regions in the Asia-Pacific region ( Experts including liver disease, tumor, rheumatism, transplantation, kidney disease and intervention, etc.
    , jointly formulated the IST-related HBV reactivation clinical practice guidelines (hereinafter referred to as the guidelines)
    .

    The guide has been published in Hepatology International in August 2021 [1]
    .

    Screenshot of the paper homepage.
    Recommendations for IST-related HBV reactivation guidelines Unfold
    .

    The following are the recommended points of the guide, let's take a sneak peek
    .

    1.
    Definition of HBV reactivation 1.
    Exacerbation of chronic HBV infection (HBsAg positive)
    .

    ① HBV DNA increased by ≥2 log from baseline
    .

    [Level of Evidence—II-2 Level of Recommendation-1] ②Patients with undetectable baseline HBV DNA have HBV DNA>100 IU/mL
    .

    [Level of Evidence—II-2 Level of Recommendation-1] 2.
    After IST treatment, patients with previous HBV infection (HBsAg negative, anti-HBc positive) developed HBV reactivation
    .

    ① Serological reversal of HBsAg occurred, from HBsAg negative to HBsAg positive
    .

    [Level of Evidence—II-2 Level of Recommendation-1] ②When HBsAg remains negative, undetectable HBV DNA becomes measurable
    .

    [Level of Evidence—II-2 Level of Recommendation-1] 2.
    Key Screening Populations All patients who plan to receive IST should be screened
    .

    [Level of Evidence—II-1 Level of Recommendation-1] III.
    Screening items 1.
    HBsAg, anti-HBs, and anti-HBc should be screened
    .

    [Level of Evidence—II-2 Recommendation Level-1] 2.
    For patients with HBsAg positive, it is necessary to consider adding HBsAg and HBV DNA quantitative testing [Level of Evidence—II-2 Recommendation Level-1] 3.
    All HBsAg positive and HBsAg negative, anti-HBsAg -Patients with positive HBc should be evaluated by a liver disease expert for the degree of liver fibrosis
    .

    [Level of Evidence—III Recommendation Level-2] IV.
    Disease Management 1.
    It is necessary for the following patients to take preventive nucleoside (acid) analog (NA) treatment.
    Targeting the middle-risk and high-risk groups can save the lives of patients
    .

    (See below for risk stratification) ① High-risk group, all patients who are HBsAg positive or HBsAg negative but anti-HBc positive
    .

    [Level of Evidence—I Recommendation Level-1] ②In the medium-risk group, all HBsAg-positive and anti-HBc-positive patients with advanced liver fibrosis/cirrhosis
    .

    [Level of Evidence—II-2 Level of Recommendation-1] ③Low-risk group, all HBsAg-positive or HBsAg-negative but anti-HBc-positive patients with advanced liver fibrosis/cirrhosis
    .

    [Level of Evidence—II-2 Level of Recommendation-1] 2.
    NA is preferably entecavir (ETV), tenofovir disoproxil fumarate (TDF) and propofol tenofovir fumarate (TAF)
    .

    [Level of Evidence—I Recommendation Level-1] 3.
    6 months after the end of IST, NA drug withdrawal should be considered
    .

    ①Applicable to HBsAg-positive patients without advanced liver fibrosis/cirrhosis
    .

    [Level of Evidence—II-2 Level of Recommendation-1] ②Applicable to HBsAg-positive patients with low HBV DNA load (<2000 IU/mL) before NA treatment
    .

    [Level of Evidence—II-2 Level of Recommendation-1] ③Applicable to patients who maintain HBsAg negative but anti-HBc positive
    .

    [Level of Evidence—II-2 Recommendation Level-1] V.
    Liver function test 1.
    Liver function test should be performed for the following patients (check every 3 months, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin Protein, albumin, globulin, etc.
    )
    .

    ①In the middle risk group, patients with HBsAg negative but anti-HBc positive and no advanced liver fibrosis/cirrhosis
    .

    [Level of Evidence—II-2 Level of Recommendation-1] ②Low-risk group, patients with HBsAg-positive or HBsAg-negative but anti-HBc-positive and without advanced liver fibrosis/cirrhosis
    .

    [Level of Evidence—II-2 Level of Recommendation-2] ③If ALT>2 times the baseline value, serum HBsAg and HBV DNA levels should be tested.
    If the patient's HBsAg has been reverted by serology and/or HBV DNA is detectable, NA should be performed immediately Treatment
    .

    [Level of Evidence—II-2 Level of Recommendation-1] The immune pathogenesis of HBV reactivation is currently believed to be related to the persistence of cccDNA in liver cells, but the specific mechanism has not been elucidated.

    .

    Part of the answer is given in this guide
    .

    IST-related HBV reactivation is mainly divided into two stages (see the figure below).
    The first stage is the immunosuppressive stage, which is usually related to the host's immune level.
    IST can indirectly increase HBV by weakening the host's immune response (especially cellular immunity).
    Duplication leads to reactivation of HBV
    .

    In addition, studies have shown that HBV reactivation may also occur in HBV/hepatitis C virus (HCV) sympathetic patients.
    Direct antiviral drug (DAA) treatment can quickly inhibit HCV replication, and the inhibitory effect of HCV on HBV weakens or disappears.
    This leads to the occurrence of HBV reactivation [2]
    .

    The second stage is the immune reconstitution period after the IST stops.
    At this time, the host's immune response is enhanced, and the HBV-infected cells are rapidly attacked.
    Liver failure and even death
    .

    The mechanism of IST-related HBV reactivation The incidence of IST-related HBV reactivation HBsAg-positive patients have a higher risk of HBV reactivation after receiving IST
    .

    For example, in patients who underwent hematopoietic stem cell transplantation (HSCT) without antiviral therapy, the risk of HBV reactivation is 45%-100% [3,4], in cancer patients treated with immune checkpoint inhibitors (ICIs) , The risk is 9.
    1%-17%[5,6], and among HBV-related hepatocellular carcinoma (HCC) patients, HBV-related HCC patients who have undergone transhepatic arterial chemoembolization (TACE) have the risk of HBV reactivation Up to 32% (30%–43%) [7,8]
    .

    There is also a risk of HBV reactivation in HBV/HCV sympathetic patients.
    Data shows that after DAA treatment, the risk of HBV reactivation in sympathetic patients is 41.
    1% (range 14%-100%) [1]
    .

    Similarly, in HBsAg-negative and anti-HBc-positive patients, there are also different proportions of HBV reactivation risk.
    For example, if HSCT is performed without antiviral therapy, the risk of HBV reactivation is 6%-29%[9- 11]; In patients with lymphoma treated with rituximab, the risk of HBV reactivation is 10% [12]
    .

    However, patients currently receiving tyrosine kinase inhibitors (TKIs) or ICIs have limited data on the risk of HBV reactivation, and further research is needed
    .

    As for HBV/HCV sympathetic patients, after receiving DAA treatment, the risk of HBV reactivation is between 0% and 2.
    6% [13]
    .

    The risk factors of HBV reactivation and its risk stratification The influencing factors related to HBV reactivation mainly include the following three points, which are virological factors, host factors, and the type and degree of IST
    .

    Among virological factors, high baseline HBV DNA levels, HBsAg positive, HBeAg positive, co-infection with HCV, hepatitis D virus (HDV) or human immunodeficiency virus (HIV) are all risk factors for HBV reactivation
    .

    Host factors mainly include gender, age, liver cirrhosis, and disease types that require immunosuppressive treatment (such as bone marrow transplantation or solid organ transplantation), among which males are the most relevant host factors for increased risk of HBV reactivation [14]
    .

    Finally, there are the factors of IST, including type and dose
    .

    Based on the above three factors, the risk of HBV reactivation can be divided into high risk (HBV reactivation rate ≥10%), medium risk (HBV reactivation rate 1%-10%), and low risk (HBV reactivation rate <1%) 3 levels (risk stratification as shown in the figure below)
    .

    ▲Swipe up HBV reactivation risk stratification.
    Prevention and management of HBV reactivation Based on the above introduction, we need to actively prevent the occurrence of HBV reactivation, conduct screening before starting IST, and start preventive antiviral treatment as soon as possible, which will help To reduce the incidence of liver failure and mortality caused by this
    .

    At present, the guidelines have revised the indicators for screening before starting IST, and specifically stated that all patients should be tested for serum HBsAg, anti-HBs and anti-HBc levels before IST treatment, so as to have a more comprehensive understanding of whether the patient has existed in the past HBV infection
    .

    In terms of antiviral therapy, HBsAg-positive patients are undoubtedly the most clear candidates, but for HBsAg-negative and anti-HBc-positive patients, whether antiviral therapy should be given or not, this guide also gives the corresponding management process
    .

    HBV reactivation management process.
    In short, the APASL 2021 HBV reactivation guidelines comprehensively cover the content of IST-related HBV reactivation, and provide clinicians with detailed HBV reactivation management guidance.
    These guidelines and suggestions may be expected to become Asia Pacific The regional daily IST-related HBV reactivates the new standard of clinical practice
    .

    References: [1]Lau G,Yu ML,Wong G,et al.
    APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy[J].
    Hepatology International,2021:1-18.
    [2]Calvaruso V,CraxìA.
    HBV recurrence after HCV clearance on DAAs:Sometimes they come back[J].
    Journal of hepatology,2017,67(5):898-901.
    [3]Nakamoto S,Kanda T,Nakaseko C,Sakaida E, Ohwada C, Takeuchi M, Takeda Y, Mimura N, Iseki T, Wu S, Arai M, Imazeki F, Saito K, Shirasawa H, Yokosuka O.
    Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficiency of nucleos (t)ide analogues for prevention and treatment.
    Int J Mol Sci.
    2014;15(11):21455–21467.
    [4]Lau GKK,He ML,Fong DYT,et al.
    Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation[J].
    Hepatology,2002,36(3):702-709.
    [5]Pu D,Yin L,Zhou Y,et al.
    Safety and efficacy of immune checkpoint inhibitors in patients with HBV/HCV infection and advanced-stage cancer: a systematic review[J].
    Medicine,2020,99(5).
    [6]Zhang X,Zhou Y,Chen C ,et al.
    Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition[J].
    Journal for immunotherapy of cancer,2019,7(1):1-10.
    [7]Jang JW,Choi JY,Bae SH,et al.
    A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo‐lipiodolization[J].
    Hepatology,2006,43(2):233-240.
    [8]Jang JW,Kwon JH,You CR ,et al.
    Risk of HBV reactivation according to viral status and treatment intensity in patients with hepatocellular carcinoma[J].
    Antiviral therapy,2011,16(7):969.
    [9]Seto WK,Chan TSY,Hwang YY,et al .
    Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation:a prospective study[J].
    Hepatology,2017,65(5):1451-1461.
    [10]Wu T,Wu N,Ma YX,et al.
    Role of hepatitis B antibody in predicting reactivation of resolved hepatitis B virus infection in leukemia patients[J].
    Antiviral research,2020,177:104765.
    [11]Nishikawa K,Kimura K,Kanda Y,et al.
    A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation[J].
    Bone marrow transplantation,2020,55(7):1388-1398.
    [12]Paul S,Dickstein A,Saxena A,et al.
    Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: a meta-analysis[J].
    Hepatology,2017,66(2):379-388.
    [13]Kawagishi N,Suda G,Onozawa M,et al.
    Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C[J].
    Journal of viral hepatitis,2017,24(12):1098-1106.
    [14]Hwang JP,Lok AS F.
    Management of patients with hepatitis B who require immunosuppressive therapy[J].
    Nature reviews Gastroenterology&hepatology,2014,11(4):209-219.
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