A Prospective Study of HBV Immunity and HBV Vaccination in Patients With NAFLD in Canada
Study Details
Study Description
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 | Phase |
|---|---|---|
|
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.
Study Design
Outcome Measures
Primary Outcome Measures
- Anti-HBs Titres (IU/L) [1 month after completion of the vaccine series]
to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response
- Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells [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
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Calgary | Calgary | Alberta | Canada | T2N 4Z6 |
Sponsors and Collaborators
- University of Calgary
- Canadian Institutes of Health Research (CIHR)
- GlaxoSmithKline
Investigators
- Principal Investigator: Carla Coffin, University of Calgary
Study Documents (Full-Text)
More Information
Publications
None provided.- REB16-0274
Study Results
Participant Flow
| Recruitment Details | Patients with non-alcoholic fatty liver disease (NAFLD), without prior exposure to hepatitis B or hepatitis B vaccine. Recruitment period was August 2016-March 2020. |
|---|---|
| Pre-assignment Detail | No significant events were noted. 7 patients were lost to follow-up. |
| Arm/Group Title | HBV Vaccine Cohort |
|---|---|
| Arm/Group Description | Of 82 participants, all received the HBV vaccine. Vaccines were not blinded as patients were followed as standard of care. We followed the product monograph for TWINRIX and Engerix vaccines. |
| Period Title: Overall Study | |
| STARTED | 82 |
| COMPLETED | 75 |
| NOT COMPLETED | 7 |
Baseline Characteristics
| Arm/Group Title | HBV Vaccine Cohort |
|---|---|
| Arm/Group Description | Of 82 participants, all received the HBV vaccine. Vaccines were not blinded as patients were followed as standard of care. |
| Overall Participants | 82 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
82
100%
|
| >=65 years |
0
0%
|
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
82
100%
|
| >=65 years |
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
48.5
(8.7)
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
48.5
(8.7)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
40
48.8%
|
| Male |
42
51.2%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
1.2%
|
| Not Hispanic or Latino |
81
98.8%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| Canada |
82
100%
|
| BMI (body mass index) (kg/m^2) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kg/m^2] |
33.6
(6.1)
|
Outcome Measures
| Title | Anti-HBs Titres (IU/L) |
|---|---|
| Description | to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response |
| Time Frame | 1 month after completion of the vaccine series |
Outcome Measure Data
| Analysis Population Description |
|---|
| Anti-HBs levels were compared between two groups: low and high-risk obesity patients with NAFLD. |
| Arm/Group Title | BMI < 35 | BMI > 35 |
|---|---|---|
| Arm/Group Description | 40 patients with BMI < 35 | 28 patients with BMI > 35 |
| Measure Participants | 40 | 28 |
| Mean (Standard Deviation) [Anti-HBS IU/L] |
642
(68.2)
|
385
(79)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | BMI < 35, BMI > 35 |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.02 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 513.5 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 73.6 |
|
| Estimation Comments | Anti-HBs levels difference: high risk obesity group - low risk obesity group NAFLD patients | |
| Title | Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells |
|---|---|
| Description | 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 |
| Time Frame | 1 month after completion of the vaccine series |
Outcome Measure Data
| Analysis Population Description |
|---|
| 17 patients with BMI < 35 and 14 patients with BMI > 35 for PBMC analysis. |
| Arm/Group Title | BMI < 35 | BMI > 35 |
|---|---|---|
| Arm/Group Description | 17 patients with BMI < 35 and PBMCs collected for analysis. | 14 patients with BMI > 35 and PBMCs collected for analysis. |
| Measure Participants | 17 | 14 |
| Mean (Standard Deviation) [Stimulation index] |
5.1
(0.68)
|
3.1
(0.62)
|
Adverse Events
| Time Frame | Each patient was assessed with 18 months of their baseline visit. Antibodies titers were assessed within 3 months after their last hepatitis vaccine dose. | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | HBV Vaccine Cohort | |
| Arm/Group Description | Of 82 participants, all received the HBV vaccine. Vaccines were not blinded as patients were followed as standard of care. | |
All Cause Mortality |
||
| HBV Vaccine Cohort | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/82 (0%) | |
Serious Adverse Events |
||
| HBV Vaccine Cohort | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/82 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| HBV Vaccine Cohort | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/82 (0%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. |
|---|---|
| Organization | Carla Coffin |
| Phone | 403-220-7808 |
| cscoffin@ucalgary.ca |
- REB16-0274