A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in Patients With Non Alcoholic Fatty Liver Disease (NAFLD) in Canada
Conditions: Non-Alcoholic Fatty Liver Disease, Hepatitis B, Vaccine Reaction
Sponsor: University of Calgary

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 1 of 18 
 
A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada 
 
Scientific Rationale  
The Global Burden of Hepatitis B and HBV Vaccination in Canada: 
 
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 1.  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 2.  
 
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 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
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Canadians (i.e., born before 1985) who missed childhood vaccination programs.  Although 
current guidelines recommend that certain high-risk populations receive hepatitis B 
immunization (Table 1), 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 3, 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 BBV exposure in patients with diabetes.  Further, our initial seroepidemiological survey of 
acute HBV outbreaks in Alberta revealed a decreasing prevalence in diabetic patients 
(unpublished data, see Table 2).  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.  In 1 Polish study 
on HBV vaccination in adults 4, good response to the HBV vaccine was observed in the patients 
with liver steatosis. As expected, patients with cirrhosis responded much less favorably to the 
hepatitis B vaccine than patients with liver steatosis. In addition, in an older study, obesity was 
also identified as a poor predictor of response to hepatitis B vaccination in pre-adolescents 5.  
Further studies are required in a North American adult (Canadian population). 
 
 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 3 of 18 
 
The Clinical Spectrum of Nonalcoholic Fatty Liver Disease (NAFLD) / and Non Alcoholic 
Steatohepatitis (NASH): 
 
NAFLD refers to the spectrum of disease and liver damage associated with hepatic 
steatosis. Patients can have simple steatosis, inflammation and fibrosis, or even cirrhosis. NASH, 
or non-alcoholic steatohepatitis, refers to the presence of inflammation and/or fibrosis in the 
presence of steatosis.  The prevalence of NAFLD varies widely, but in North America, it is 
estimated to be anywhere from 10-46%, with the prevalence of NASH ranging from 3-5% in the 
average population 6,7. NAFLD, and NASH, are most commonly seen in patients who are obese, 
diabetic, or have other features of the metabolic syndrome (defined as the presence of 3 of the 
following: abdominal obesity, hypertriglyceridemia, low HDL, insulin resistance/diabetes, and 
hypertension). 
 
Obesity is a growing epidemic in North America, with rates of obesity in the adult 
population increasing from a national average of 13% in 1962 to 34.9% in 2012 8. Since diabetes 
is closely related to obesity, rates of diabetes have also risen accordingly, with 9.3% of the US 
population, or 29.1 million people, having diabetes, although an estimated 27.8% of people are 
undiagnosed (CDC National Diabetes Statistics Report 2014).  
 
The pathophysiology of NASH is thought to be due to a multi-hit model, although it has 
not been fully explained. The initial hit, or insult, is thought to be secondary to steatosis. 
Steatosis, which arises from triglyceride accumulation, can be due to abnormal free fatty acid 
metabolism (either increased import into the liver, decreased export out of the liver, or abnormal 
beta-oxidation) 9.  Increased delivery is often seen in settings such as obesity, excess 
carbohydrate and fat consumption, or rapid weight loss. Defective secretion of triglycerides is 
often seen in patients with gene mutations resulting in abnormal cholesterol metabolism 10. The 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 4 of 18 
 
second insult is thought to result in inflammation and eventually fibrosis.  Some of the main 
mechanisms behind steatohepatitis are abnormal fatty acid β- oxidation and oxidative injury. 
Insulin resistance plays a role in both the development of hepatic steatosis and steatohepatitis, 
even in non-obese patients 11.  In the obese patient, as visceral adipose tissue increases, 
peripheral and hepatic insulin resistance develop and worsen, resulting in hepatic steatosis and 
inflammation 11,12. Obese patients have more visceral fat, which in turn is associated with higher 
levels of inflammation and pro-inflammatory cytokines 13.  Obesity, older age, Hispanic origin, 
diabetes, and the presence of inflammation and/or fibrosis on biopsy are predictors of 
progression to cirrhosis 14-17.  As with other hepatic diseases, the presence of multiple hepatic 
processes resulting in inflammation hastens the development of fibrosis. Therefore, in patients 
with NAFLD, the development of acute or chronic hepatitis B infection can result in an increased 
risk of development of cirrhosis. Studies have shown that in pediatric patients with NAFLD, 
rates of non-immunity to hepatitis B are alarmingly high, approaching nearly 50% 18. Although 
there have been many studies examining the prevalence of serological immunity to hepatitis B in 
patients with alcoholic liver disease, and the effect of concomitant infection in addition to the 
liver disease, no such similar studies exist examining the prevalence of hepatitis B antibodies in 
the adult population with NAFLD.  
 
In summary, there is a paucity of recent studies on HBV serology and HBV vaccine 
responses in adults, especially in the context of obesity and NAFLD.  We 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.  
 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 5 of 18 
 
Hypotheses/Aims: 
(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.  
3.0: Study Design and Methods  
Study Population:   
Study Population, Clinical Assessment, Inclusion/Exclusion Criteria: 
 
Patients will be recruited from large tertiary liver clinics in Canada (Dr. C. Coffin, 
University of Calgary, Dr. Mang Ma University of Alberta, Dr. Curtis Cooper, University of 
Ottawa, Dr. Edward Tam, LAIR Centre Vancouver, and Dr. Alnoor Ramji, St. Paul’s Hospital, 
BC) and following signed informed consent will be prospectively enrolled under an approved 
ethics protocol according to the declaration of Helsinki. Multi-site data will be collected using a 
web-based electronic report form in a secure computing environment custom developed by the 
PI and funded by a Canadian Foundation for Innovation infrastructure grant.  Baseline data 
collected will include: (i) epidemiological information such as, age, sex, alcohol use, smoking; 
(ii) anthropometric data (body mass index, BMI, and waist circumference), (iii) liver disease lab 
tests such as, complete blood count, transaminases and other liver function tests, liver imaging, 
and non-invasive assessment of liver fibrosis via transient elastography (i.e., TE, FibroScan®), 
liver biopsies, and inflammatory markers associated with disease progression (ferritin, 
hemoglobin A1C, HbAIC, lipid profile), (iv) HBV serology including HBsAg, anti-HBs titres 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 6 of 18 
 
and total HBV core antibody (anti-HBc) by conventional assays  (iv) tests for exclusion of other 
liver diseases (i.e., HCV, autoimmune hepatitis, alpha 1 antitrypsin deficiency, hemochromatosis 
etc.) and, pregnancy.  The investigators have access to large patient cohorts and are ideally 
positioned to perform this study. The Calgary Liver Unit services a catchment area of two 
million individuals and receives approximately 40 to 60 new NAFLD referrals a month, or 
approximately 20% of all new hepatology referrals.  Inclusion criteria: Subjects 18-60 years of 
age, who provide signed informed consent, with a diagnosis of NAFLD/NASH according to 
expert assessment (by imaging, TE, abnormal lab tests and/or liver biopsy) and no evidence of 
prior infection or immunity to hepatitis B (negative HBsAg, anti-HBs, anti-HBc). Exclusion 
criteria: Subjects < 18 years of age, 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. 
The results of a recent pooled analysis of GSK clinical trial data (N=2620, total vaccinated 
cohort) showed a statistically significant decrease with age in sero-protection rates, and a 
predictive model that showed the anti-HBs sero-protection rate remains ≥90% up to 49 y of age 
and ≥80% up to 60 y of age 19. 
Study Design and Outcomes  
Following initial clinical investigations (i.e., labwork and transient elastography as described 
above), patients are triaged as low, moderate, or high risk based on expert clinical consensus 
opinion and current clinical trial protocols in NAFLD/NASH.  Low risk patients are those who 
do not have any risk factors for fibrosis progression, liver decompensation or HCC, or 
development of NAFLD complications, based on presence of dyslipidemia, diabetes, and HbAIC 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 7 of 18 
 
levels (Table 3).  These patients then attend a 3-hour teaching session with a dedicated NAFLD 
nurse clinician, a dietician, an exercise counselor, and also a social worker. Patients who have 
risk factors for progression to fibrosis, or who already have fibrosis are seen in clinic by a 
hepatologist. Finally, patients with metabolic syndrome, poorly controlled diabetes or 
hyperlipidemia that is difficult to treat are seen in a multidisciplinary clinic by a hepatologist and 
dedicated general internist with an interest in vascular risk modification. Thus, the highest risk 
patients are seen by multiple specialists in order to maximize care of all their medical issues, 
especially as they relate to NAFLD and NASH. Currently, no other clinics of this kind (either the 
low risk or multidisciplinary clinics) exist of their kind in Canada. 
 
Baseline HBV Serology Testing and HBV Vaccination in Patients with NAFLD/NASH:  
 
All subjects enrolled will be assessed for HBV serology by conventional immunoassays 
(i.e., HBsAg, anti-HBs, anti-HBc) to determine the prevalence of protective HBV immunity, 
either from natural exposure or immunization.  At-risk individuals will be prospectively 
immunized for hepatitis B with standard dose of vaccine as per standard of care, at 0, 1 and 6 
months (20 microgram intramuscular).  Patients will be subsequently tested at 7 months (~1 
month after completion of the vaccine series) for anti-HBs titres by conventional enzyme 
immunoassay (EIA, Abbott Architect).   If titres are low, subjects will be given a second round 
of a series of 3 vaccinations, as per guidelines and re-tested for anti-HBs titres.  Additionally, 
PBMC will be isolated from ~ 40 - 60 ml of peripheral blood according to standard protocol on 
Ficoll density gradient centrifugation at 2 time-points: (1) prior to first vaccine dose and (2) 
following the 3rd vaccine dose, at the time of serological testing for anti-HBs titres.  All PBMC 
samples will be cyropreserved in liquid nitrogen until use, under conditions optimized in our lab 

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Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
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for storage and recovery of PBMC for functional studies.  To assess HBV specific T and B cell 
responses, cyropreserved PBMCs will be thawed, re-suspended in RPMI/fetal calf serum and 
stimulated in quadruplicates of 3 x 105 cells/well with a 5 μg/ml recombinant HBsAg (American 
Research Products, Waltham, MA), a negative control HCV peptide pool (kindly provided by Dr. 
T.I. Michalak), and 1 µg/ml of phytohemagglutinin (PHA; Invitrogen, Carlsbad, CA) or DMSO.  
HBV memory B-cell responses will be determined by an HBsAg-IgG B cell enzyme linked 
immunospot (ELISpot assay).   IFN-gamma-secretion by HBV specific T cells will also be 
enumerated by ELISpot 19.  The number of specific spots (i.e., the number of spots in the 
presence of antigen minus the number in the absences of antigen) will be determined and a 
positive HBsAg specific T cell responses defined as >3-fold than the negative control (DMSO) 
background response and compared to the baseline (i.e., prior to vaccination) PBMC sample 20. 
The PBMC cell supernatant released from unstimulated and stimulated cells will also be 
collected at 72 hours and cytokine secretion 21,22  (i.e., IL-2, IL-4, IL-10, TNF-alpha, IL-6, and 
IFN-gamma etc.) quantified using commercially available ELISA kits according to 
manufacturers protocol.  All laboratory investigations are considered standard of care except for 
the extra blood draw for PBMC isolation and further testing as noted.  All subjects will be 
monitored after each vaccine dose for possible adverse events (A/Es), as per standard clinical 
care.  Most A/Es expected are mild (i.e., injection site redness). 
 
 
4.1.3. Sample Size Calculation and Data Analysis Plan:  
 
The primary objective of the study is to determine how NAFLD-associated metabolic risk 
factors and liver inflammation / fibrosis affects vaccine response.  The primary outcome is anti-

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 9 of 18 
 
HBs titres (mIU/ml), and HBsAg specific T and B cell response (i.e., IFN-gamma producing T 
cells and B cells by ELISpot assay, cytokine response after ex-vivo stimulation of PBMC), 
measured at 1 month after completion of the vaccine series (i.e., the recommended time for 
assessment of vaccine responses according to the Public Health Agency of Canada).  We expect 
that protective immunity to the HBV vaccine will correlate with obesity risk assessment (i.e., 
lean-low = BMI < 34.9, medium-high = BMI >35).  Subjects with anti-HBs titres 10 mIU/ml 
will be considered as responding to the vaccine while patients with anti-HBs <10 will be 
considered as vaccine non-responders. The literature has shown that in vaccination of 427 pre-
adolescents, obesity was a significant predictor of poor immune response (P = 0.015) 23.  In 
another study of 239 adult health care workers, older age (> 50 y) and diabetes was a predictor of 
non-response 24.   A study in cirrhotic patients (N=52) showed that cirrhosis, especially alcoholic 
chronic liver disease, was associated with lower antibody responses compared to the general 
population 25.  There is limited data in adult obese patients with NAFLD and/or related fibrosis, 
thus a convenience pilot sample of 70 subjects stratified by lean-low and medium-high risk 
obseity groups, adjusting for potential confounding variables affecting vaccine response (i.e., 
age, sex, BMI, co-morbidities. Based on preliminary results as well as supporting animal model 
data (Joshi S et al., abstract presentation 2019, EASL) this sample size will be sufficient to detect 
a difference with Power 80% and 5% Type I error.   
It is the current standard of care in our clinic to evaluate all new patients referred for hepatitis B, 
and to recommend HBV vaccination if non-immune. Thus, based on the number of new referrals 
seen (40 - 50 NAFLD patients/per month at the University of Calgary and similar numbers in 
other Canadian sites), we expect there will be sufficient patients recruited. Analyses will be 
performed using SAS 9.3 (SAS Institute, Cary NC).  Summary statistics will be presented as 

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Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 10 of 18 
 
mean ± standard deviation for continuous data while for categorical data it will be presented as 
proportions. The chi-square and Fisher exact tests will be used to look at the association between 
immunological responses with the categorical variables. Comparisons of mean anti-HBs titres for 
patients with and without protective antibodies, ELISpot data and cytokine responses, within and 
between groups will be made using Student's t-test and analysis of variance (ANOVA) if the 
distribution is normal, while the Mann-Whitney U test and Kruskall-Wallis tests will be used if 
normality assumption is violated. The association between obesity as well as NAFLD and 
vaccine response will be analyzed using a logistic regression model adjusting for known factors 
impacting vaccine responses (i.e., age, co-morbidities).  
4.1.4. Potential Limitations of HBV Vaccination Studies in NAFLD/NASH Patients:  Some 
subjects may be lost to follow-up or refuse participation (i.e., due to religious or cultural 
objections to vaccination). Additionally some patients may decline to undergo a liver biopsy, 
which is important to confirm a histological diagnosis of NAFLD/NASH.  However, it is 
standard practice for the PI to perform liver biopsy on all patients in which TE cannot be 
accurately performed (i.e., due to obesity) or if there is elevated liver stiffness suggesting at least 
moderate fibrosis.  Additionally, the non-invasive markers (i.e., TE, ferratin, transaminases) and 
presence of metabolic risk factors are accepted surrogates in clinical practice and often used to 
base decisions on the need for a liver biopsy and eligibility for NASH/NAFLD clinical trials.  
Regardless, any data obtained will generate novel data on the severity of liver histology and 
HBV vaccine responses.  Previously, the referring physician (i.e., family Dr.) was asked to 
immunize the patients, which may have affected compliance and follow-up. We plan to 
vaccinate patients in the specialist hepatology / infectious disease clinic. A clinical research 
study coordinator will be responsible for contacting the patients in follow up and to provide 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 11 of 18 
 
reminders for vaccine appointments and blood work (within 1 month due to natural anti-HBs 
decline after vaccination).  People may be more willing to be vaccinated if prescribed by a 
specialist since the cost is covered by health care plan.  The investigators have access to large 
cohorts and are ideally positioned to perform this study. The Calgary Liver Unit services a 
catchment area of two million individuals and receives approximately 40 - 60 new NAFLD 
referrals a month, or ~20% of all new hepatology referrals to our group, and similar numbers are 
seen in other sites.  This study does not include a healthy adult control arm, due to the nature of 
our patient population referred who usually has underlying liver disease.  However, the results 
can be compared to data available from multiple large vaccine efficacy clinical trials in healthy 
adult individuals conducted by our industry partner (GlaxoSmithKline, GSK) 19. 
 
Expertise and Support:   
Dr. Coffin (MD, MSc, Assistant Professor of Medicine) is a hepatologist with a dedicated 
clinical and research interest in hepatitis B. Dr. Coffin holds a CIHR New Investigator Award 
and is appointed to the World Health Organization Expert Advisory Panel for Essential 
Medicines.  She co-authored the Canadian Association for the Liver Disease (CASL) guidelines 
on Management of Chronic Hepatitis B.  She has published extensively in both HBV molecular 
and clinical studies and has the wet-laboratory and clinic infrastructure (i.e., clinical database, 
bio-banking) to support her research.  Dr. Jenne (PhD, Assistant Professor of Medicine).  Dr. 
Jenne holds a Tier 1 Canada Research Chair on Intravital Imaging in Infections. He has expertise 
in the role of innate immunity in viral infections.  Dr. Jenne has collaborations with Dr. Matteo 
Iannocone for HBV transgenic mice model (see letter of support).  The Canadian HBV Network:  
(Drs. C. Cooper, MD; S. Fung, MD; M. Ma, MD; A. Ramji, MD, C. Osiowy, PhD; E. Tam, MD; 

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Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
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E. Yoshida MD).  The Canadian HBV network is a group of clinicians and scientists dedicated to 
research and improved care of hepatitis B (www.CanadianHBVNetwork.ca).  Our members are 
on the governing board of the CASL and are involved in public education on hepatitis B and 
NAFLD.  Thus, we are well positioned to assist in these laboratory and clinical studies, and in 
collaboration with our industry partner facilitate Knowledge Translation to inform public health 
policy and promote excellence in clinical care. 
 
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Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
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Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
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Roni DA, Pathapati RM, Kumar AS, et al. Safety and efficacy of hepatitis B vaccination 
in cirrhosis of liver. Adv Virol 2013;2013:196704. 
 
 
 
 
 
 
 
 
 
 
 
 
 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 16 of 18 
 
Table 1.  Canadian Association for the Study of the Liver Recommendations for HBV 
Vaccination  
 
Infants of HBV+ mothers (plus HBV immune globin) 
Intravenous Drug Users 
Multiple sexual partners 
Health care workers, including laboratory personnel 
Institutionalized persons 
Recipients of pooled blood products (hemophiliac) 
All sexual and household contacts of HBV+ persons 
Travelers to endemic countries 
Dialysis 
Diabetics 
Chronic Liver Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 17 of 18 
 
 
Table 2: Proportion of Hepatitis B (Acute & Chronic) cases with Diabetes in Alberta 2000-
2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Alberta Health and Wellness tracks all cases with Hepatitis B diagnosed included 
those with acute and chronic infection. The cases identified were merged using their provincial 
health care number with a provincial diabetes registry. The Diabetes registry was created using 
a validated National Surveillance Case definition. The diabetes and hepatitis B diagnoses were 
matched regardless of date, thus it is not possible to determine whether the diagnosis of diabetes 
was before or after the diagnosis of hepatitis B infection. 
 
Year 
Alberta 
Proportion  
2000 
5.6% 
2001 
4.1% 
2002 
3.2% 
2003 
4.3% 
2004 
3.4% 
2005 
2.6% 
2006 
3.0% 
2007 
1.5% 
2008 
4.7% 
2009 
3.9% 
2010 
4.6% 
2011 
2.5% 
2012 
3.0% 
2013 
2.3% 
2014 
1.3% 

A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in 
Patients with Non Alcoholic Fatty Liver Disease (NAFLD) in Canada. Protocol, Version 3, 13-
June-2019. Dr. Carla Coffin Page 18 of 18 
 
 
https://clinicaltrials.gov/ct2/show/NCT02466516?term=nonalcoholic+fatty+liver+disease+AND
+Gilead&rank=1