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Risk of Hepatitis Flare in Patients With Previous Hepatitis B Virus Exposure Amongst Patients

Sponsor
Chinese University of Hong Kong (Other)
Overall Status
Terminated
CT.gov ID
NCT04356404
Collaborator
University of Malaya (Other)
68
Enrollment
1
Location
20.4
Actual Duration (Months)
3.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to study the risk of hepatitis flare in patients with previous hepatitis B virus exposure amongst patients on immunosuppressive and biological modifier therapies

Condition or Disease Intervention/Treatment Phase

    Detailed Description

    Chronic hepatitis B infection remains a global health threat despite vaccination program.[1] Nearly 3 billion population are infected with chronic hepatitis B infection globally. In China, the pooled prevalence of chronic hepatitis B infection was around 7% in year 2018, making an estimated 84 millions of population living with chronic hepatitis B infection. Hepatitis B virus infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, leading to significant morbidity and mortality. Patients with hepatitis B infection can present with a wide range of clinical presentation, ranging from inactive carrier to fulminant hepatitis, cirrhosis or development of hepatocellular carcinoma. Besides, a significant proportion of patients are suffering from occult hepatitis B infection (OBI), which is defined as a state of undetectable serum HBsAg yet detectable serum and/ or intrahepatic HBV DNA. Report from the European Association for the Study of the Liver (EASL) in 2008 has revealed that around one-third of the global population has serological evidence of past or present HBV infection. Disappearance of HBsAg, also known as HBsAg seroclearance, can occur either spontaneously or after anti-viral treatment. However, patients with past or resolved HBV infection are still at risk of development of hepatocellular carcinoma, liver cirrhosis and liver-related mortality.The reported prevalence of OBI amongst patients with non-alcoholic fatty liver disease in Hong Kong was 35% (submitted to American Journal of Gastroenterology, under review). It is well known that there is risk of HBV reactivation after chemotherapy or immunosuppressive therapy which can lead to fulminant liver failure or even death. Short course of high dose corticosteroid could increase the risk of hepatitis flare in patients with chronic hepatitis B infection. Even in patients with OBI, a high daily dose of corticosteroid (>40mg prednisolone equivalents) increased risks of hepatitis flare. It is thus important to know the hepatitis B virus status before start of chemotherapy, immunosuppressive therapy or corticosteroid.

    Biologics is one of the mainstay treatments for many autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), psoriasis etc. The incidence of IBD has increased rapidly in Hong Kong over the past 30 years. The age-adjusted incidence of IBD in Hong Kong has rose from 0.10 per 100,000 individuals in 1985 to 3.12 per 100,000 individuals in 2014. The reported prevalence of RA in Hong Kong was 0.35% while the reported prevalence of SLE in Hong Kong was 0.1% with annual incidence of 6.7 per 100,000 individuals. It is well known that treatment with biological agent like anti-CD20 monoclonal antibody (rituximab) in patients with OBI can lead to fulminant hepatitis B flare. Recently, anti-tumor necrosis factor alpha (TNF α) has been widely used in patients with inflammatory bowel disease and various rheumatological diseases. Risk of hepatitis B reactivation after anti-TNF α has been reported, but actual risk remains controversial. In a report from Japan including 135 rheumatoid arthritis patients with previous HBV infections, 17/135 (12.6%) had HBV reactivation after receiving immunosuppressants and patients who were treated with biologics were more frequent to develop HBV reactivation compared to those who were not on biologics. In another study, 9/168 (5%) anti-HBc positive patients developed HBV reactivation after receiving anti-TNF α and one patient died due to fulminant liver failure.However, another three studies revealed low rates of HBV reactivation (0-2%) amongst rheumatology patients with previous HBV infections receiving anti-TNF α. The European Crohn's and Colitis Organisation (ECCO) suggested routine antiviral prophylaxis for patients with previous HBV infection starting biologics is not recommended. Instead, regular monitoring of ALT/ AST, change in HBV serology and HBV DNA every 1 to 3 months should be performed. In 2015, the American Gastroenterology Association (AGA) has developed guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive therapy. It classifies patients receiving anti-TNF α as moderate risk of developing HBV reactivation and antiviral prophylaxis is preferred over monitoring alone, but it is a weak recommendation. Therefore, it is now still uncertain whether prophylactic anti-viral should be given for patients with previous HBV exposure before starting anti-TNF α.

    With the advancement of technology, there are now more biological agents and small molecules for the treatment of IBD and various rheumatological conditions. These include anti-integrin, cytokine inhibitors, and small molecules e.g. JAK inhibitors. Cytokine inhibitor, ustekinumab (anti-IL12/23), has been reported to be leading to hepatitis reactivation in a psoriasis patient who has past HBV infection.[26] Whether these agents can lead to hepatitis flare in patients with past HBV exposure remains largely unknown.

    Based on the compelling data, the investigators hypothesize that use of biologic modifier therapies in patients with occult hepatitis B infection will lead to hepatitis flare. The investigators aim to assess the rate of hepatitis flare while on biological modifier therapies in both retrospective population-based database and prospectively in patients who are on biological modifier therapies.

    Study Design

    Study Type:
    Observational
    Actual Enrollment :
    68 participants
    Observational Model:
    Cohort
    Time Perspective:
    Prospective
    Official Title:
    Risk of Hepatitis Flare in Patients With Previous Hepatitis B Virus Exposure Amongst Patients on Immunosuppressive and Biological Modifier Therapies Exposure
    Actual Study Start Date :
    May 1, 2020
    Actual Primary Completion Date :
    Jan 12, 2022
    Actual Study Completion Date :
    Jan 12, 2022

    Arms and Interventions

    Arm Intervention/Treatment
    Prospective group

    Patients will be followed up until development of hepatitis flare or at 2 years after study recruitment. We plan to recruit 150 patients for the prospective cohort.

    Outcome Measures

    Primary Outcome Measures

    1. Rate of hepatitis flare [24 months]

      Hepatitis flare, defined as ALT >2xULN IU/L, according to the Asia Pacific Association for the Study of the Liver (APASL) definition while on biological modifier therapy. The upper limit of normal (ULN) was defined as 40 IU/L by APASL.

    Secondary Outcome Measures

    1. Rate of severe hepatitis flare [24 months]

      Severe hepatitis flare, defined as ALT > 5xULN or > 10xULN, as defined by the APASL definition, while on biological modifier therapy

    2. Rate of icteric flare [24 months]

      Icteric flare, defined as ALT raised >3xULN together with serum total bilirubin >2xULN (i.e. >38 µmol/L), while on biological modifier therapy

    3. Rate of HBsAg seroreversion [24 months]

      HBsAg seroreversion, defined as reappearance of HBsAg

    4. Risk factors associated with development of hepatitis flare [24 months]

      Risk factors associated with development of hepatitis flare, Including concomitant use of steroid and immunosuppressants

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Age ≥ 18 years old at the time of starting biological modifier therapies or at the time of recruitment

    • Positive for anti-HBc OR

    • Positive for anti-HBs and born before year 1988

    Exclusion Criteria:

    • Known HBV carrier with HBsAg positive

    • Concomitant HCV and/ or HIV infection

    • Already on HBV anti-viral

    • Refuse to consent

    • Baseline ALT > 80 IU/ml

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 The Chinese University of Hong Kong Hong Kong Hong Kong

    Sponsors and Collaborators

    • Chinese University of Hong Kong
    • University of Malaya

    Investigators

    • Principal Investigator: WingYan Mak, MRCP, Chinese University of Hong Kong

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Mak Wing Yan, Assistant Professor, Chinese University of Hong Kong
    ClinicalTrials.gov Identifier:
    NCT04356404
    Other Study ID Numbers:
    • HEP-FLARE_Protocol_20210604_V5
    First Posted:
    Apr 22, 2020
    Last Update Posted:
    Jan 28, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Mak Wing Yan, Assistant Professor, Chinese University of Hong Kong
    Occult Hepatitis B infection
    Biologics
    Immunosuppressants
    Additional relevant MeSH terms:
    Hepatitis A
    Hepatitis B
    Hepatitis

    Study Results

    No Results Posted as of Jan 28, 2022