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

January 14, 2022 updated by: Mak Wing Yan, Chinese University of Hong Kong

Risk of Hepatitis Flare in Patients With Previous Hepatitis B Virus Exposure Amongst Patients on Immunosuppressive and Biological Modifier Therapies Exposure

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

Study Overview

Status

Terminated

Conditions

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 Type

Observational

Enrollment (Actual)

68

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • The Chinese University of Hong Kong

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

All patients with previous HBV exposure who are already on biological modifier therapies and who will be newly started on biological modifier therapies in the Department of Medicine and Therapeutics, Prince of Wales Hospital and Department of Medicine, University Malaya Medical Centre will be recruited.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of hepatitis flare
Time Frame: 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.
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of severe hepatitis flare
Time Frame: 24 months
Severe hepatitis flare, defined as ALT > 5xULN or > 10xULN, as defined by the APASL definition, while on biological modifier therapy
24 months
Rate of icteric flare
Time Frame: 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
24 months
Rate of HBsAg seroreversion
Time Frame: 24 months
HBsAg seroreversion, defined as reappearance of HBsAg
24 months
Risk factors associated with development of hepatitis flare
Time Frame: 24 months
Risk factors associated with development of hepatitis flare, Including concomitant use of steroid and immunosuppressants
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chinese University of Hong Kong

Collaborators

University of Malaya

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2020

Primary Completion (Actual)

January 12, 2022

Study Completion (Actual)

January 12, 2022

Study Registration Dates

First Submitted

April 19, 2020

First Submitted That Met QC Criteria

April 19, 2020

First Posted (Actual)

April 22, 2020

Study Record Updates

Last Update Posted (Actual)

January 28, 2022

Last Update Submitted That Met QC Criteria

January 14, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HEP-FLARE_Protocol_20210604_V5

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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