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A Prospective Study of HBV Immunity and HBV Vaccination in Patients With NAFLD in Canada

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ClinicalTrials.gov Identifier: NCT02985450
Recruitment Status : Completed
First Posted : December 7, 2016
Results First Posted : November 3, 2021
Last Update Posted : November 3, 2021
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
University of Calgary

Brief Summary:
(1) Due to missed childhood vaccination programs, the majority of adult patients with NAFLD in Canada do not have immunity to hepatitis B. (2) Adults with NAFLD who receive the HBV vaccine have reduced immunogenic responses in the setting of obesity (i.e., protective anti-HBs titres). Aims: (1) To determine the sero-prevalence of immunity against hepatitis B in a cohort of prospectively evaluated adult NAFLD patients. (2) To prospectively determine HBV vaccine responses (anti-HBs titres) in adult NAFLD patients.

Condition or disease Intervention/treatment
Non-Alcoholic Fatty Liver Disease Hepatitis B Vaccine Reaction Biological: Engerix-B

Detailed Description:

The hepatitis B virus (HBV) is truly a global human pathogen that affects at least 2 billion people worldwide including ~240 million chronic hepatitis B (CHB) carriers that are at risk for end-stage liver disease. The diagnosis of CHB is confirmed by the persistence of the HBV surface antigen (HBsAg) in serum for >6 months. However, a latent form of HBV infection known as occult hepatitis B infection (OBI) characterized by low-level viremia (i.e., HBV DNA < 200 IU/ml) despite undetectable serum HBsAg has been described with unclear clinical consequences.

A safe and effective HBV vaccine has been available for ~3 decades and consists of recombinant HBsAg which contains the major viral antigenic epitopes and induces a protective neutralizing antibody to HBsAg (anti-HBs) response in >85% of children vaccinated. Canada is a low HBV-endemic region and in Alberta, and Ontario, public health uses maternal screening for HBsAg to identify babies at-risk for CHB. Thus, all infants born to HBsAg (+) mothers are given passive-active immunoprophylaxis with hepatitis B immune globulin (HBIG) and the HBV vaccine within 12 hours of birth, as well as 2 doses at ~2 and ~6 months of age. Testing of the infants for anti-HBs is recommended at 9 months to ensure immunity. In the late 1990's, a universal HBV childhood vaccination program was initiated in all Canadian provinces and jurisdictions. In Alberta and in Ontario, school-age children are scheduled to receive the 3-dose HBV vaccine series in grade 5. However there remain a significant proportion of adult Canadians (i.e., born before 1985) who missed childhood vaccination programs. Although current guidelines recommend that certain high-risk populations receive hepatitis B immunization, appropriate identification and compliance is generally much lower in adults compared to children.

According to the most recent Canadian Association for the Study of Liver Disease guidelines, all adults with diabetes, as well as all patients with chronic liver disease should receive the hepatitis B vaccine. The basis for these recommendations are two-fold, (1) diabetics may be at risk of blood-borne virus (BBV) exposure through contact with contaminated blood glucose monitoring devices and (2) diabetic patients are at increased risk of the metabolic syndrome and the development of non-alcoholic fatty liver disease (NAFLD). The improvement in blood glucose monitoring devices, and increased knowledge has reduced the risk of HBV exposure in patients with diabetes. Further, the investigators' initial seroepidemiological survey of acute HBV outbreaks in Alberta revealed a decreasing prevalence in diabetic patients. Therefore the main incentive for HBV vaccination in diabetics is due to the concomitant risk of the metabolic syndrome and advanced liver disease due to NAFLD. There is limited data on HBV vaccination in NAFLD patients. Further studies are required in a North American adult (Canadian population).

The investigators propose that adults with NAFLD should undergo comprehensive screening for hepatitis B immunogenicity, in addition to screening for infection, and catch up or booster vaccinations should be administered to non-immunized patients with confirmatory immunity testing thereafter.

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Study Type : Observational
Actual Enrollment : 82 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in Patients With Non Alcoholic Fatty Liver Disease (NAFLD) in Canada
Study Start Date : August 2016
Actual Primary Completion Date : January 2021
Actual Study Completion Date : January 2021

Intervention Details:
  • Biological: Engerix-B
    Hepatitis B Vaccine
    Other Name: Twinrix

Primary Outcome Measures :
  1. Anti-HBs Titres (IU/L) [ Time Frame: 1 month after completion of the vaccine series ]
    to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response

  2. Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells [ Time Frame: 1 month after completion of the vaccine series ]

    to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response. Fresh (or cryopreserved in 4 patients) PBMC (~106) were labeled with 1 μM carboxyfluorescein-diacetate-succinimidyl-ester. Labeled PBMC were stimulated with 5 μg HBsAg) in RPMI 1640 with 10% FBS and 2mmol/L glutamine. Anti-CD3 (1 μg/mL) and anti-CD28 (5 μg/mL) stimulated cells served as a positive control.

    Unstimulated DMSO-treated cells were used as negative controls. Cells were cultured in triplicates and plates incubated at 37 °C with 5% CO2 for ~8 days. Cell proliferation was assessed on day 8. SI was calculated as % CFSE low cells in stimulated cells / % CFSE low cells in the unstimulated control46. SI> 3 was considered positive for HBsAg-specific proliferation. Cells were stained using the memory T-cell panel and analyzed by flow-cytometry

Biospecimen Retention:   Samples With DNA
PBMCs will be cryopreserved to assess HBV specific T and B cell responses.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
NAFLD patients will be recruited from large tertiary liver clinics in Canada

Inclusion Criteria:

  • Subjects 18-60 years of age, who provide signed informed consent
  • Diagnosis of NAFLD/NASH according to expert assessment (by imaging, TE, abnormal lab tests and/or liver biopsy)
  • No evidence of prior infection or immunity to hepatitis B (negative HBsAg, anti-HBs, anti-HBc).

Exclusion Criteria:

  • Subjects < 18 years of age,
  • Subjects who refused vaccination
  • Have documented immunity / prior exposure to hepatitis B (i.e., positive for ant-HBs, anti-HBc, HBsAg)
  • Pregnancy
  • HIV-positive
  • Decompensated cirrhosis (i.e., Child-Pugh Class B or C) due to impact on immune response.
  • Subjects >60 y will be excluded, due to effect of age and reduced response to HBV vaccination.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02985450

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Canada, Alberta
University of Calgary
Calgary, Alberta, Canada, T2N 4Z6
Sponsors and Collaborators
University of Calgary
Canadian Institutes of Health Research (CIHR)
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Principal Investigator: Carla Coffin University of Calgary
  Study Documents (Full-Text)

Documents provided by University of Calgary:
Informed Consent Form  [PDF] June 14, 2019

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Responsible Party: University of Calgary
ClinicalTrials.gov Identifier: NCT02985450    
Other Study ID Numbers: REB16-0274
First Posted: December 7, 2016    Key Record Dates
Results First Posted: November 3, 2021
Last Update Posted: November 3, 2021
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Hepatitis B
Non-alcoholic Fatty Liver Disease
Hepatitis A
Liver Diseases
Fatty Liver
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Blood-Borne Infections
Communicable Diseases
Hepadnaviridae Infections
DNA Virus Infections