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Canadian Journal of Gastroenterology logoLink to Canadian Journal of Gastroenterology
. 2013 Mar;27(3):137–147. doi: 10.1155/2013/924640

Disease burden of chronic hepatitis B among immigrants in Canada

William WL Wong 1,3,✉, Gloria Woo 1, E Jenny Heathcote 2,4, Murray Krahn 1,2,3,4
PMCID: PMC3732151  PMID: 23516678

Abstract

BACKGROUND:

The prevalence of chronic hepatitis B (CHB) infection among immigrants to North America ranges from 2% to 15%, 40% of whom develop advanced liver disease. Screening for hepatitis B surface antigen is not recommended for immigrants.

OBJECTIVE:

To estimate the disease burden of CHB among immigrants in Canada using Markov cohort models comparing a cohort of immigrants with CHB versus a control cohort of immigrants without CHB.

METHODS:

Markov cohort models were used to estimate life years, quality-adjusted life years and lifetime direct medical costs (adjusted to 2008 Canadian dollars) for a cohort of immigrants with CHB living in Canada in 2006, and an age-matched control cohort of immigrants without CHB living in Canada in 2006. Parameter values were derived from the published literature.

RESULTS:

At the baseline estimate, the model suggested that the cohort of immigrants with CHB lost an average of 4.6 life years (corresponding to 1.5 quality-adjusted life years), had an increased average of $24,249 for lifetime direct medical costs, and had a higher lifetime risk for decompensated cirrhosis (12%), hepatocellular carcinoma (16%) and need for liver transplant (5%) when compared with the control cohort.

DISCUSSION:

Results of the present study showed that the socio-economic burden of CHB among immigrants living in Canada is sub-stantial. Governments and health systems need to develop policies that promote early recognition of CHB and raise public awareness regarding hepatitis B to extend the lives of infected immigrants.

Keywords: Chronic hepatitis B, Disease burden, Immigrants

A large proportion of the chronic hepatitis B (CHB) population in Canada is comprised of individuals who were born abroad and are currently living in Canada (ie, immigrants). Canada accepted approximately four million immigrants between 1981 and 2006. More than 90% came from countries where hepatitis B virus (HBV) is either highly (>8%) or moderately (>2%) endemic, whereas the overall prevalence of HBV in Canada is <1% (1). Approximately 5% of immigrants in Canada have CHB, 40% of whom will silently progress to cirrhosis and, consequently, be at risk of dying prematurely from liver failure and/or liver cancer (2).

The objective of the present study was to estimate the health and economic burden associated with CHB among immigrants living in Canada and to determine the magnitude of disease burden.

METHODS

Two state-transition cohort models (3) were developed to project health outcomes and costs: one for a cohort of immigrants with CHB living in Canada in 2006, and one age-matched control cohort of immigrants without CHB living in Canada in 2006. The differences in life expectancy (life years [LYs]), quality-adjusted life expectancy (quality-adjusted LYs [QALYs]), and lifetime direct medical costs between the two cohorts were calculated to evaluate the health and economic burden associated with CHB in this population (4).

Cohort

The estimated number of immigrants with CHB residing in Canada in 2006 was 297,700 individuals (HBV prevalence of 4.81%) (Appendix 1). This number was estimated by multiplying the number of people who immigrated into Canada from each country by the prevalence in that country (5,6). The total number of immigrants, their age and country of origin were determined using data from the 2006 national census (1). The prevalence in various countries was obtained from review of the literature (5,7,8).

To estimate the distribution of disease states (see Appendix 2 for description of modelled health states) among immigrants with CHB, the medical records of immigrant patients with CHB who attended the tertiary referral liver clinic at the Toronto Western Hospital (Toronto, Ontario) were reviewed. The date of birth, country of origin, date of first visit, serological status (hepatitis B surface antigen [HBsAg], hepatitis B e antigen [HBeAg] and anti-HBeAg), alanine transaminase (ALT) level, and viral load (IU/mL) from the clinic database to estimate the distribution of disease progression states in patients stratified according to eight age groups (zero to 15, 16 to 25, 26 to 35, 36 to 45, 46 to 55, 56 to 65, 66 to 75, and 75 years of age and older) were extracted. A total of 774 medical records were retrieved.

Individuals born abroad and currently living in Canada may already have been tested and aware of their infection (9–11). According to a recent community-based immigrant survey conducted in Vancouver, British Columbia (10), between 19% and 89% of immigrants had been tested for HBV, depending their country of birth. In the present analysis, it was assumed that 30% (5% to 90% in sensitivity analysis) of the immigrants in Canada are aware of their infection with HBV, and for every year 0.5% (12) (0.1% to 2% in sensitivity analysis) of the unknown individuals will be diagnosed as having CHB infection.

The control cohort of immigrants without CHB in the present study was created with a similar sample size and age distribution as the cohort of immigrants with CHB living in Canada in 2006.

Decision model

In the present analysis, two state-transition cohort models were implemented using TreeAge Pro 2009 software (TreeAge Software, USA). The CHB model had 37 health states that included a combination of serological status (HBsAg and HBeAg), liver inflammation (ALT [normal/elevated]), viral load (high/low) and clinical states (cirrhosis, hepatocellular carcinoma [HCC], liver transplant). The formal definition of all 37 health states can be found in Appendix 2 (5).

In the simulation, cohort members with CHB moved between predefined health states in annual cycles until all members had died. Health states and allowed transitions among health states are shown in Appendix Figure 1 and Appendix Figure 2. In this model, CHB-infected individuals are initially assumed to have no cirrhosis but progress over time to different clinical states of CHB characterized by a combination of serology, ALT value and viral load, and/or development of cirrhosis. Those developing cirrhosis may develop decompensated liver disease and/or HCC and may die from the complications of liver disease or require a liver transplant.

Another Markov model with a one-year cycle length was constructed for each of the eight age groups in the control cohort of immigrants without CHB. It was assumed that this control cohort of immigrants without CHB were free of infection with HBV during their lifetime. Within each cycle, immigrants without CHB may die from all disease causes except CHB according to Canadian life tables.

Model probabilities

Probabilities representing the likelihood of HBV-related events were identified from literature reviews and expert sources (Table 1). Distribution of CHB health states at the start of the simulation is listed in Appendix 3.

TABLE 1.

Values for model variables

Variable Baseline Low High Source
Population
  Prevalence
    Immigrants with chronic HBV infection 4.81% 0.24% 14.08% Appendix 1
(5,7)
    Annual CHB diagnostic rate 0.5% 0.1% 2% (12)
    Known to be infected rate 30% 5% 90% (10,11)
Annual transition probabilities related to chronic infection
CHB: No treatment states
    Immune tolerant (HBsAg+; HBeAg+; viral load: high; ALT level: normal)
      HCC 0.00032 0.000028 0.00035 (35)
      Chronic HBeAg+ hepatitis B 0.1423 0.12 0.16 (36)
    Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Compensated cirrhosis 0.044 0.022 0.088 (37–39)
      HCC 0.008 0.004 0.016 (39–41)
      HBeAg seroconversion 0.1 0.07 0.13 (39,42–44)
    Inactive (HBsAg+; HBeAg−; viral load: low; ALT level: normal)
      Compensated cirrhosis 0.001 0.001 0.002 (2,39)
      HCC 0.003 0.0015 0.006 (2,39)
      Immune (HBsAg loss) 0.008 0.0005 0.02 (39,43)
      Reactivation (chronic HBeAg− hepatitis B) 0.0254 0.02 0.05 (2,45)
      Reversion (chronic HBeAg+ hepatitis B) 0.0048 0.004 0.018 (2,39,43)
    Chronic HBeAg− hepatitis B (HBsAg+; HBeAg−; viral load: high; ALT level: high)
      Compensated cirrhosis 0.029 0.015 0.058 (2,46,47)
      HCC 0.008 0.004 0.012 (2,41,47,48)
Compensated cirrhosis: No treatment states
    Chronic HBeAg+ hepatitis B with cirrhosis (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Decompensated cirrhosis 0.073 0.035 0.1 (49)
      HCC 0.034 0.01 0.12 (49,50)
      HBeAg seroconversion 0.1 0.07 0.13 *
    Inactive w/cirrhosis (HBsAg+; HBeAg−; viral load: low; ALT level: normal)
      Decompensated cirrhosis 0.008 0.004 0.016 (39,51)
      HCC 0.022 0.011 0.044 (39,51)
      Immune (HBsAg loss) 0.008 0.0005 0.02 (39,43)
      Reactivation (chronic HBeAg− hepatitis B) 0.0254 0.02 0.05 (2,45)
      Reversion (chronic HBeAg+ hepatitis B) 0.0048 0.008 0.018 (39,43)
    Chronic HBeAg− hepatitis B w/cirrhosis (HBsAg+; HBeAg−; viral load: high; ALT level: high)
      Decompensated cirrhosis 0.073 0.035 0.1 (49)
      HCC 0.037 0.01 0.12 (41,49,50)
    Decompensated cirrhosis
      HCC 0.06 0.01 0.113 (12,41,52)
      Liver transplant 0.05 0 0.4 (12,52)
      Death 0.173 0.058 0.221 (12,52)
    HCC
      Liver transplant 0.15 0.05 0.4 (12,52)
      Death 0.351 0.181 0.451 (12,52)
    Liver transplant
      Death 0.067 0.02 0.113 (12,52)
Treatment-related transition probabilities
Entecavir
    Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Resistance 0.003 0 0.01 (18,39,53–55)
      Withdrawal of treatment 0.0028 0 0.01 (18,39,53,55)
      Undetectable HBV DNA 0.61 0.39 0.80 (18,39,53,55)
      Normalization of ALT 0.69 0.45 0.86 (18,39,53,55)
      HBeAg seroconversion 0.21 0.14 0.23 (18,39,53,55)
      HBsAg loss 0.01 0 0.05 (18,39,53,55)
    Chronic HBeAg− hepatitis B (HBsAg+; HbeAg−; viral load: high; ALT level: high)
      Resistance 0.003 0 0.01 (18,47,56)
      Withdrawal of treatment 0.018 0 0.02 (18,47,56)
      Undetectable HBV DNA 0.86 0.51 0.98 (18,47,56)
      Normalization of ALT 0.76 0.63 0.82 (18,47,56)
  Tenofovir
    Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Resistance 0 0 0 (18,57)
      Withdrawal of treatment 0.028 0.01 0.05 (18,57)
      Undetectable HBV DNA 0.89 0.71 0.98 (18,57)
      Normalization of ALT 0.71 0.41 0.93 (18,57)
      HBeAg seroconversion 0.18 0.12 0.30 (18,57)
      HBsAg loss 0.05 0 0.54 (18,57)
    Chronic HBeAg− hepatitis B (HBsAg+; HBeAg−; viral load: high; ALT level: high)
      Resistance 0 0 0.01 (18,57)
      Withdrawal of treatment 0 0 0.03 (18,57)
      Undetectable HBV DNA 0.92 0.44 1 (18,57)
      Normalization of ALT 0.73 0.43 0.84 (18,57)
  Lamivudine
    Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Resistance 0.11 0.05 0.15 (18)
      Withdrawal of treatment 0.028 0.01 0.05 †
      Undetectable HBV DNA 0.31 0.17 0.49 (18)
      Normalization of ALT 0.60 0.46 0.72 (18)
      HbeAg seroconversion 0.18 0.15 0.21 (18)
      HbsAg loss 0.008 0 0.02 (18)
    Chronic HbeAg− hepatitis B (HBsAg+; HBeAg−; viral load: high; ALT level: high)
      Resistance 0.11 0.05 0.15 (18)
      Withdrawal of treatment 0 0 0.03 †
      Undetectable HBV DNA 0.73 0.65 0.80 (18)
      Normalization of ALT 0.75 0.54 0.89 (18)
  Pegylated interferon
    Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Withdrawal of treatment 0.03 0.01 0.05 (18,58)
      Undetectable HBV DNA 0.2 0.08 0.36 (18)
      Normalization of ALT 0.39 0.2 0.61 (18)
      HbeAg seroconversion 0.23 0.14 0.35 (18)
      HbsAg loss 0.01 0 0.07 (18)
    Chronic HbeAg− Hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high)
      Withdrawal of treatment 0.07 0.01 0.08 (18,59)
      Undetectable HBV DNA 0.67 0.41 0.89 (18)
      Normalization of ALT 0.60 0.09 0.89 (18)
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*

Assume same as chronic hepatitis B (CHB) positive;

†

Assume same as tenofovir/entecavir. − Negative; + Positive; ALT Alanine aminotransferase; HBeAg Hepatitis B e antigen; HBsAg Hepatitis B surface antigen; HBV Hepatitis B virus; HCC Hepatocellular carcinoma

Treatment for CHB

The baseline analysis assumed that patients offered antiviral therapy would be treated with either entecavir or tenofovir because they are the two most potent drugs with the highest genetic barrier to resistance. According to the Canadian guidelines (13), HBeAg-positive patients should be treated if both the HBV DNA concentration is >20,000 IU/mL and the ALT level is elevated (>1.5 × upper limit of normal [ULN]) for up to 12 months after HBeAg seroconversion. HBeAg-negative patients whose HBV DNA concentration is consistently >2000 IU/mL and have an elevated ALT level (>1.5×ULN) would be treated indefinitely. All patients with compensated cirrhosis with HBV DNA concentration >2000 IU/mL are treated indefinitely.

Patients on entecavir who develop resistance (1.5% at five years) (14) are switched to tenofovir. Presently, there is no evidence that patients receiving tenofovir develop resistance for up to four years after initialization of therapy (15). Thus, no resistance was assumed for patients who are treated with tenofovir.

Also performed were two additional analyses on lamivudine and pegylated interferon. Because the cost of lamivudine is relatively low, it is still frequently prescribed in North America (16,17) for CHB, despite the high rate of drug resistance. In the lamivudine analysis, patients on lamivudine who develop resistance are switched to tenofovir or entecavir. For the pegylated interferon analysis, HBeAg-positive patients were treated for 48 weeks while the HBeAg-negative patients were treated for one year (13) with pegylated interferon alpha-2a according to Canadian guidelines (13).

Estimates of treatment effectiveness were obtained from a systematic review and Bayesian meta-analysis (18) (Table 1). The probability of being treated was estimated using the medical records of immigrant patients with CHB who attended the liver clinic at Toronto Western Hospital (Appendix 4). This probability was changed accordingly as the disease progression state changed.

Direct medical costs and utilities

The health care costs included in the analysis include the direct costs of screening and the cost of treatment for the different CHB health states. These costs included diagnostic laboratory testing, procedures, outpatient visits, inpatient admission and medication, and were collected from published sources (Table 2). For the age-matched control cohort of immigrants without CHB living in Canada, the annual average health care costs reported by the Canadian Institute for Health Information (19) were used.

TABLE 2.

Costs and utilities used in the model

Costs and utilities Cost*
Reference(s)
Baseline Low High
Acute hepatitis B
  Symptomatic/hospitalized $17,537 $10,317 $19,092 12,60
  Symptomatic/not hospitalized $576 $370 $862 12,60
Chronic hepatitis B
  Diagnostic tests and laboratory tests $483 $442 $534 61
  Procedures (professional fees only) $20 $17 $24 61
  Outpatient visits $400 $340 $487 61
  Medications (entecavir) $8,000 $7,000 $9,000 39,47,62
  Medications (tenofovir) $6,109 $5,000 $7,000 62,63
  Medications (lamivudine) $1,865 $1,000 $2,500 39
  Medications (pegylated interferon) 48 weeks $12,528 $9,504 $14,256 64
Compensated cirrhosis
  Diagnostic tests and laboratory tests $562 $518 $617 61
  Procedures (professional fees only) $89 $72 $113 61
  Outpatient visits $399 $349 $460 61
  Inpatient admissions $929 $397 $2,500 61
  Medications (entecavir) $8,000 $7,000 $9,000 39,47,62
  Medications (tenofovir) $6,109 $5,000 $7,000 62,63
  Medications (lamivudine) $1,865 $1,000 $2,500 39
  Medications (pegylated interferon) 52 weeks $13,572 $10,296 $15,444 64
Decompensated cirrhosis
  Diagnostic tests and laboratory tests $993 $916 $1,090 61
  Procedures (professional fees only) $388 $324 $472 61
  Outpatient visits $550 $440 $707 61
  Inpatient admissions $9,221 $6,145 $14,635 61
  Home care $24 $18 $35 61
  Medications $699 $626 $777 39,47
Liver transplant
  Diagnostic tests and laboratory tests $1,990 $1,809 $2,208 61
  Procedures (professional fees only) $6,784 $6,285 $7,289 61
  Outpatient visits $833 $682 $1,037 61
  Inpatient admissions $58,418 $54,480 $65,871 61
  Home care $44 $34 $58 61
  Medications $36,712 $34,203 $40,131 61
Post-transplant
  Diagnostic tests and laboratory tests $1,265 $1,128 $1,468 61
  Procedures (professional fees only) $228 $155 $343 61
  Outpatient visits $764 $688 $860 61
  Inpatient admissions $11,011 $6,254 $19,079 61
  Home care $28 $21 $37 61
  Medications $27,153 $25,887 $29,353 61
Hepatocellular carcinoma
  Diagnostic tests and laboratory tests $937 $845 $1,062 61
  Procedures (professional fees only) $1,042 $927 $1,175 61
  Outpatient visits $746 $629 $902 61
  Inpatient admissions $9,857 $6,970 $13,939 61
  Home care $533 $354 $793 61
  Medications $1,006 $921 $1,100 61
Cost of screening $84 $10 $400 65
Average health care $4,119 $3,707 $4,530 19
Utilities
  Canadian population average 0.93 0.85 1 20
  Noncirrhotic chronic hepatitis B 0.87 0.85 0.88 20
  Compensated cirrhosis 0.81 0.75 0.86 20
  Decompensated cirrhosis 0.49 0.22 0.75 20
  Hepatocellular carcinoma 0.85 0.76 0.95 20
  Post-transplant 0.72 0.60 0.83 20
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*

2008 Canadian dollars (CAD $1 = US $0.813 using purchasing power parity conversion rate)

Utility data were obtained from a previous study involving more than 400 patients with CHB across different CHB health states (20), from early disease stage to HCC and/or post-liver transplantation (Table 2). The utilities used in the analysis were based on published Health Utilities Index Mark 3 scores (20). It was assumed that patients who spontaneously clear HBV infection and those who have never been infected had utility scores similar to the general Canadian adult population (21). For the control cohort, average health care cost and average utility scores for the general Canadian adult population were used.

Economic assumptions

The analysis was conducted from the health care payer perspective. Future costs and health benefits were discounted at a rate of 5% (22). Non-Canadian cost data were converted to Canadian dollars at the purchasing power parity conversion rate (23). All cost data were adjusted to 2008 using the Statistics Canada Consumer Price Index for health care and personal items (24).

RESULTS

Base case

At the baseline estimate (Table 3), the present model projected that the cohort of immigrants with CHB would, on average, live 28.43 years as of 2006. Also projected was that the age-matched control cohort of immigrants without CHB would live 33.21 years. With respect to life expectancy adjusted for quality of life, our models projected that health gains were smaller, but still very substantial at 1.49 QALY per person over the lifetime of the cohort when compared with the control cohort of immigrants without CHB. In terms of lifetime direct medical costs, the model suggested that the cohort of immigrants with CHB increased by an average of $24,249 over the lifetime of the cohort when compared with the control cohort of immigrants without CHB. To demonstrate the magnitude of disease burden from 297,572 individuals who were born abroad and are currently living in Canada with CHB, the model calculated that individuals with CHB could lose a total of approximately 1.3 million LYs or 0.4 million QALYs, and increase the burden on the health care system in Canada by $7 billion as a direct result of CHB.

TABLE 3.

Baseline disease burden of chronic hepatitis B (CHB) among immigrants living in Canada

Indicators for disease burden With CHB Without CHB Difference
Treatment using tenofovir only
Average LY (year) 28.64 33.21 −4.57
Average QALY (year) 11.93 13.42 −1.49
Average lifetime direct medical costs, $ 83,706 59,457 24,249
Total LY (year) 8,523,753 9,882,598 −1,358,845
Total QALY (year) 3,550,436 3,994,710 −444,274
Total lifetime direct medical costs, $ 24,908,432,988 17,692,698,536 7,215,734,452
Treatment using entecavir only
Average LY (year) 28.47 33.21 −4.74
Average QALY (year) 11.90 13.42 −1.53
Average lifetime direct medical costs, $ 86,637 59,457 27,180
Total LY (year) 8,473,278 9,882,598 −1,409,320
Total QALY (year) 3,540,213 3,994,710 −454,497
Total lifetime direct medical costs, $ 25,780,649,619 17,692,698,536 8,087,951,083
Treatment using lamivudine and tenofovir
Average LY (year) 28.60 33.21 −4.61
Average QALY (year) 11.91 13.42 −1.51
Average lifetime direct medical costs, $ 80,042 59,457 20,585
Total LY (year) 8,511,417 9,882,598 −1,371,181
Total QALY (year) 3,545,421 3,994,710 −449,289
Total lifetime direct medical costs, $ 23,818,128,984 17,692,698,536 6,125,430,448
Treatment using lamivudine and entecavir
Average LY (year) 28.43 33.21 −4.78
Average QALY (year) 11.88 13.42 −1.54
Average lifetime direct medical costs, $ 81,166 59,457 21,709
Total LY (year) 8,458,783 9,882,598 −1,423,815
Total QALY (year) 3,536,087 3,994,710 −458,623
Total lifetime direct medical costs, $ 24,152,615,241 17,692,698,536 6,459,916,704
Treatment using pegylated interferon
Average LY (year) 27.69 33.21 −5.52
Average QALY (year) 11.73 13.42 −1.69
Average lifetime direct medical costs, $ 78,286 59,457 18,829
Total LY (year) 8,240,972 9,882,598 −1,641,626
Total QALY (year) 3,491,102 3,994,710 −503,608
Total lifetime direct medical costs, $ 23,295,642,649 17,692,698,536 5,602,944,113
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*

Note: 2008 Canadian dollars (CAD $1 = US $0.813 using purchasing power parity conversion rate). LY Life year; QALY Quality-adjusted life year

The present model also simulated the average annual direct medical costs per person starting in 2006 for the cohort of immigrants with CHB and the cohort of immigrants without CHB (Figure 1). The annual health care cost for immigrants without CHB was $3,878 per person. The annual incremental health care cost per person for the CHB cohort was $472 in 2006, rising to a maximum of $959 in 2014.

Figure 1).

Figure 1)

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Comparison in average annual direct medical costs between immigrants with chronic hepatitis B (CHB) and immigrants without CHB since 2006

Also projected was the annual distribution of CHB-related clinical outcomes in the cohort of immigrants with CHB since 2006 (Table 4). From the simulated results, 44% of immigrants with CHB remained undiagnosed after 20 years of follow-up and silently progressed to advanced liver disease. The prevalence of advanced liver disease among immigrants with CHB will peak over the next 25 years in those not diagnosed and/or not given treatment even if needed. The prevalence of compensated cirrhosis peaked at 11% at year 25, the prevalence of decompensated cirrhosis peaked at 1.2% at year 20 and the prevalence of HCC peaked at 1.2% at year 10. Among patients with CHB who were aware of their diagnosis, the present model projected that the uptake of antiviral therapy was low, at only 9%, because the timing of antiviral therapy is poorly understood. The cumulative risks of liver-related adverse outcomes are depicted in Figure 2. One in five (21%) CHB patients alive in 2006 will die from liver disease. One in six (16%) will develop liver cancer and one in 20 (5%) will require a liver transplant.

TABLE 4.

Baseline annual distribution of major clinical outcomes among immigrants with chronic hepatitis B (CHB)

Year Population, n Undiagnosed CHB Patients undergoing treatment Cirrhosis
HCC Liver transplant CHB-related death
Compensated Decompensated
2006 297,572 73.38 4.35 1.16 0.00 0.43 0.00 0.00
2010 281,807 66.66 7.55 5.07 0.48 1.07 0.11 0.40
2015 253,964 59.65 8.62 8.26 1.04 1.24 0.15 0.61
2020 222,442 53.85 8.35 9.89 1.24 1.17 0.15 0.65
2025 191,247 48.82 7.75 10.56 1.20 1.01 0.14 0.59
2030 161,286 44.28 7.17 10.69 1.05 0.82 0.11 0.50
2035 133,251 36.54 6.06 9.64 0.88 0.64 0.09 0.41
2040 107,342 32.96 5.63 9.32 0.70 0.49 0.07 0.32
2045 84,249 26.10 4.59 7.85 0.54 0.35 0.05 0.24
2050 63,942 23.34 4.26 7.43 0.41 0.25 0.03 0.17
2055 46,981 16.84 3.11 5.58 0.30 0.17 0.02 0.12
2060 33,159 14.93 2.86 5.19 0.22 0.11 0.02 0.08
2065 22,612 9.70 1.83 3.46 0.16 0.07 0.01 0.05
2070 14,501 5.15 0.96 1.87 0.11 0.04 0.01 0.03
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Data presented as % unless otherwise indicated. HCC Hepatocellular carcinoma

Figure 2).

Figure 2)

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Cumulative risks of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver transplant and chronic hepatitis B (CHB)-related death among immigrants with CHB since 2006

In terms of different antiviral therapies, the Canadian guideline (13) indicated entecavir or tenofovir should be used as first-line therapy. Because the pattern of care is not clear, additional disease burden analyses were performed on different antiviral therapies (Table 3). Among different antiviral therapies, the baseline analysis (using tenofovir as first-line therapy) generated the lowest LY or QALY lost, while lamivudine prescribed as first-line therapy and switching to tenofovir when resistance occurred generated average lifetime direct medical costs ($20,867 per person), but the consequence of this strategy is a higher average LY lost (4.72 years per person) and a higher average QALY lost (1.53 years per person). Using tenofovir as first-line therapy led to a gain of 0.15 LY per person, and an aggregated cost increase of $3,380 per person.

Sensitivity analysis

One-way sensitivity analysis was performed to evaluate the impact of uncertainty for all parameters in the model.

The projection results changed according to the following:

  1. Effectiveness of antiviral treatment: if we decreased the rate of suppressing HBV viral load in HBeAg-negative patients by one-half of the value, the LY and QALY will be approximately decreased by 0.5 years for immigrants with CHB;

  2. The progression rates to advanced liver disease: if the progression rates to advanced liver disease was reduced, the LY and QALY will be increased among immigrants with CHB while the average direct medical cost would be decreased;

  3. Known to be infected: If it is assumed all the immigrants with CHB had no knowledge about their infection, the LY and QALY would be decreased while the average direct medical cost would be increased, because most of the immigrants with CHB will remain undiagnosed and usually progress into late-phase liver disease (ie, cirrhosis and/or HCC).

Appendix Figure 3 summarizes the most sensitive variables using tornado diagrams for LY, QALY and cost.

DISCUSSION

In the present study, we developed two Markov cohort models – one for immigrants with CHB and one for immigrants without CHB – to compare and project the disease burden of CHB among immigrants. Our analysis indicates that immigrants in Canada with CHB could live 4.6 years less than those without CHB under current care in Canada. Our analysis also suggests that the economic burden of CHB among immigrants living in Canada was substantial. The total increase in lifetime direct medical costs due to CHB among immigrants in Canada could be $7 billion.

The most recent economic burden of illness reported by Health Canada was completed in 1998 (25). In this report, infectious and parasitic diseases cost $909 million (direct cost) in the Canadian health system in 1998. If we adjust this cost to 2008 cost using the Consumer Price Index, infectious and parasitic diseases would cost $1,057 million in 2008. From our model, the annual incremental health care cost per person for the CHB cohort is $732 in 2008. With the estimated 297,572 individuals who were born abroad and are currently living in Canada with CHB, CHB contributed $218 million (approximately 20% of the total estimated $1,057 million in the infectious and parasitic diseases category) in 2008.

The direct medical costs caused by CHB among immigrants living in Canada are significant if compared with other disease categories (Appendix 5). CHB represents approximately 7.6% of the estimated total direct cancer cost or 2.7% of the estimated total direct cost of cardiovascular disease in 2008. However, there are only limited policies on screening and promoting early recognition regarding CHB in Canada. Currently, routine vaccination of adolescents and infants born to infected mothers are in place. HBV immunization coverage among one-year-olds in Canada in 2008 was only 17% (26). Serological screening for CHB is recommended for all pregnant woman, children adopted from highly endemic countries, and some high-risk groups (27,28). However, serological screening for CHB is not routinely conducted in immigrants at entrance to Canada. In addition, HBV-related stigma is common in immigrants (29–31), which can become a barrier to screening and treatment.

Our findings are consistent with other disease burden studies, although comparing CHB disease burden with other infectious diseases was difficult because of the different outcome measures (eg, QALYs, disability-adjusted LYs [DALYs], etc) and different assumptions (eg, discount rate, target population). According to the WHO global burden of disease study (32), the economic burden of hepatitis B is ranked sixth among all infectious diseases in Canada in terms of DALYs. A recent disease burden study from Ontario in 2010 (33) ranked hepatitis B fourth among all infectious diseases in terms of DALYs. The infectious diseases that have higher burden ranking than hepatitis B were hepatitis C, Streptococcus pneumoniae and human papillomavirus. Recent studies from the United States (6) and Germany (34) also reported increasing CHB disease burden from immigrants. In both studies, imported CHB cases from immigrants account for a significant proportion of new cases found in the studied countries.

In our study, we compared the disease burden in the population with the disease with a matched control group without the disease. Together with our comprehensive disease history model, our study could exclude the burden of other diseases or conditions existing in the study population. Furthermore, because our utility data were primarily derived from the immigrant population, we can more accurately estimate the disease burden of CHB among immigrants in Canada.

Our analysis has several limitations. Due to the lack of data, our analysis assumed that the prevalence of CHB among immigrants was the same as that reported in their home countries. In addition, our analysis also assumed that the distribution of disease progression states among immigrants with CHB in Canada was the same as the cohort of immigrants with CHB who attended the tertiary referral liver clinic at the Toronto Western Hospital. These assumptions could have significantly biased the results of the present study.

According to our analysis, the economic burden of CHB among immigrants living in Canada was substantial. There were significant loss of LYs and QALYs, and increases in direct medical costs caused by CHB among immigrants living in Canada. Governments and health systems should develop policies that promote early recognition and raise public awareness regarding hepatitis B to extend the lives of CHB-infected immigrants.

Acknowledgments

The authors express their appreciation to Dr Jordan Feld, Dr David Wong, Unsal Acarsu and Colina Yim for their valuable suggestions and insight in this study.

APPENDIX 1.

Estimated hepatitis B prevalence for immigrants in Canada

Hepatitis B immigrant rate (estimated), % Hepatitis B immigrant population (estimated), n
Low Mid High Low Mid High
Total - Place of birth of respondent 6,136,520 2.94 4.81 6.79 182,185 297,701 420,352
United States of America 250,535 0.10 0.30 0.40 251 752 1,002
Central America 130,460 0.98 1.88 3.46 1,273 2,449 4,519
Caribbean and Bermuda 317,765 1.19 2.44 3.85 3,784 7,757 12,248
South America 250,710 0.90 1.51 2.12 2,263 3,788 5,318
Europe 2,278,345 0.76 1.79 2.84 17,387 40,722 64,606
  Western 424,645 0.20 0.89 1.80 849 3,795 7,640
  Eastern 511,095 1.60 3.42 4.94 8,171 17,459 25,223
  Southern 698,080 1.02 2.35 3.83 7,120 16,416 26 714
  Italy 296,850 0.70 2.40 3.50 2,078 7,124 10,390
  Other Southern Europe 401,220 1.26 2.32 4.07 5,043 9,292 16,325
  Northern Europe 644,525 0.19 0.47 0.78 1,247 3,052 5,029
  United Kingdom 579,620 0.20 0.50 0.80 1,159 2,898 4,637
  Other Northern Europe 64,900 0.13 0.24 0.60 87 154 392
Africa 374,565 7.46 10.42 15.13 27,925 39,037 56,676
  Western Africa 48,645 7.00 14.08 21.97 3,404 6,849 10,686
  Eastern Africa 129,920 10.00 11.80 17.00 12,992 15,331 22,086
  Northern Africa 134,505 4.00 7.10 10.00 5,380 9,550 13,451
  Central Africa 22,405 10.00 13.60 17.00 2,241 3,047 3,809
  Southern Africa 39,085 10.00 10.90 17.00 3,908 4,260 6,644
Asia and the Middle East 2,525,155 5.03 7.92 10.75 126,968 200,068 271,526
  West Central Asia and the Middle East 370,515 1.98 3.52 4.99 7,331 13,422 18,507
Eastern Asia 874,365 9.05 12.38 15.78 79,153 108,249 137,962
  China 466,940 10.00 13.60 17.00 46,694 63,504 79,380
  Hong Kong, Special Administrative Region 215,430 10.00 13.60 17.00 21,543 29,298 36,623
  Other Eastern Asia 185,990 5.55 7.87 11.26 10,316 14,631 20,939
Southeast Asia 560,995 4.97 9.13 12.04 27,854 51,237 67,538
  Philippines 303,195 4.20 7.00 9.00 12,734 21,224 27,288
  Other Southeast Asia 257,790 5.87 11.64 15.61 15,120 30,013 40,250
Southern Asia 719,280 1.76 3.78 6.61 12,629 27,161 47,518
  India 443,690 1.00 2.80 6.00 4,437 12,423 26,621
  Other Southern Asia 242,365 2.90 5.40 7.53 7,029 13,076 18,239
Oceania and other 58,985 3.98 5.34 7.60 2,347 3,149 4,486
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APPENDIX 2.

Health states used in the Markov model

Health state number Short description Serological status, liver inflammation and viral load details
HBsAg status HBeAg status ALT level (×ULN) Viral load, IU/mL
1 HBeAg-negative chronic hepatitis B state Positive Negative <1.5 ≥2000
2 HBeAg-negative chronic hepatitis B state Positive Negative ≥1.5 <2000
3 Immune tolerant Positive Positive <1.5 ≥20,000
4 HBeAg-positive chronic hepatitis B state Positive Positive ≥1.5 ≥20,000
5 Inactive chronic hepatitis B Positive Negative <1.5 <2000
6 HBeAg-negative chronic hepatitis B state Positive Negative ≥1.5 ≥2000
7 HBeAg-positive chronic hepatitis B state on treatment Positive Positive <1.5 <20,000
8 HBeAg-positive chronic hepatitis B state on treatment Positive Positive ≥1.5 <20,000
9 HBeAg-negative chronic hepatitis B state on treatment Positive Negative <1.5 ≥2000
10 HBeAg-negative chronic hepatitis B state on treatment Positive Negative ≥1.5 <2000
11 HBeAg-positive chronic hepatitis B state on treatment Positive Positive <1.5 ≥20,000
12 HBeAg-positive chronic hepatitis B state on treatment Positive Positive ≥1.5 ≥20,000
13 HBeAg-negative chronic hepatitis B state on treatment Positive Negative <1.5 <2000
14 HBeAg-negative chronic hepatitis B state on treatment Positive Negative ≥1.5 ≥2000
15 HBeAg-negative chronic hepatitis B state with compensated cirrhosis Positive Negative <1.5 ≥2000
16 HBeAg-negative chronic hepatitis B state with compensated cirrhosis Positive Negative ≥1.5 <2000
17 HBeAg-positive chronic hepatitis B state with compensated cirrhosis on treatment Positive Positive <1.5 ≥2000
18 HBeAg-positive chronic hepatitis B state with compensated cirrhosis on treatment Positive Positive ≥1.5 ≥2000
19 Inactive Chronic hepatits B with compensated cirrhosis Positive Negative <1.5 <2000
20 HBeAg-negative chronic hepatitis B state with compensated cirrhosis Positive Negative ≥1.5 ≥2000
21 HBeAg-positive chronic hepatitis B state with compensated cirrhosis on treatment Positive Positive <1.5 <2000
22 HBeAg-positive chronic hepatitis B state with compensated cirrhosis on treatment Positive Positive ≥1.5 <2000
23 HBeAg-negative chronic hepatitis B state with compensated cirrhosis on treatment Positive Negative <1.5 ≥2000
24 HBeAg-negative chronic hepatitis B state with compensated cirrhosis on treatment Positive Negative ≥1.5 <2000
25 HBeAg-positive chronic hepatitis B state with compensated cirrhosis on treatment Positive Positive <1.5 ≥2000
26 HBeAg-positive chronic hepatitis B state with compensated cirrhosis on treatment Positive Positive ≥1.5 ≥2000
27 HBeAg-negative chronic hepatitis B state with compensated cirrhosis on treatment Positive Negative <1.5 <2000
28 HBeAg-negative chronic hepatitis B state with compensated cirrhosis on treatment Positive Negative ≥1.5 ≥2000
29 Decompensated cirrhosis
30 Hepatocellular carcinoma
31 Liver transplant
32 Immune
33 Vaccine-induced immunity
34 No previous exposure
35 Naturally Immune
36 Post-liver transplant
37 Death
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HBeAg Hepatitis B e antigen; HBsAg Hepatitis B surface antigen; ULN Upper limit of normal

APPENDIX 3.

Estimated distribution of disease progression states among immigrants with chronic hepatitis B (CHB) using the medical records of immigrant patients with CHB who attended the liver clinic at Toronto Western Hospital, Toronto, Ontario

Disease states Age, years
<20 21–30 31–40 41–50 51–65 >65
Immune tolerant (HBsAg+; HBeAg+; viral load: high; ALT level: normal) 47.83 42.86 21.08 17.26 9.77 15.94
Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high) 21.74 26.32 24.10 16.07 4.65 2.90
Inactive hepatitis B (HBsAg+; HBeAg−; viral load: low; ALT level: normal) 21.74 21.05 39.76 50.00 67.44 65.22
Chronic HBeAg− hepatitis B (HBsAg+; HBeAg−; viral load: high; ALT level: high) 8.70 9.77 15.06 16.67 18.14 15.94
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Data presented as % unless otherwise specified. − Negative; + Positive; ALT Alanine aminotransferase; HBeAg Hepatitis B e antigen; HBsAg Hepatitis B surface antigen

APPENDIX 4.

Estimated probability of treatment using the medical records of immigrant patients with chronic hepatitis B who attended the liver clinic at Toronto Western Hospital, Toronto, Ontario

Disease states Age, years
Age <20 21–30 31–40 41–50 51–65 >65
Immune tolerant (HBsAg+; HBeAg+; viral load: high; ALT level: normal) 9.09 12.28 14.29 41.38 42.86 45.45
Chronic HBeAg+ hepatitis B (HBsAg+; HBeAg+; viral load: high; ALT level: high) 20.00 14.29 45.00 66.67 70.00 50.00
Inactive hepatitis B (HBsAg+; HBeAg−; viral load: low; ALT level: normal) 40.00 3.57 10.61 25.00 44.14 55.56
Chronic HBeAg− hepatitis B (HBsAg+; HBeAg−; viral load: high; ALT level: high) 0.00 30.77 40.00 32.14 53.85 45.45
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Data presented as %. − Negative; + Positive; ALT Alanine aminotransferase; HBeAg Hepatitis B e antigen; HBsAg Hepatitis B surface antigen

APPENDIX 5.

Comparing disease burden of illness in Canada according to diagnostic category against chronic hepatitis B (CHB)

Disease category Estimated total direct cost 2008 (in millions), $ Proportion of CHB from immigrant direct cost, %
CHB from immigrant 217.8 100
Birth defects 204.35 106.6
Blood diseases 248.05 87.8
Cancer 2,862.28 7.6
Cardiovascular diseases 7,925.31 2.7
Digestive diseases 4,114.87 5.3
Endocrine and related diseases 1,841.93 11.8
Genitourinary diseases 3,019.08 7.2
Ill-defined conditions 2,046.16 10.6
Infectious and parasitic diseases 1,056.62 20.6
Injuries 3,748.49 5.8
Mental disorders 5,440.93 4.0
Musculoskeletal diseases 3,078.48 7.1
Nervous system/sense organ diseases 3,280.86 6.6
Perinatal conditions 355.46 61.3
Pregnancy 1,507.74 14.4
Respiratory diseases 4,023.51 5.4
Skin and related diseases 1,713.72 12.7
Well patient care 3,049.31 7.1
Others 3,744.65 5.8
Unattributable 44,326.82 0.5
Overall Total 97,588.6 0.2
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Appendix Figure 1).

Appendix Figure 1)

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Markov model of hepatitis B virus (HBV) infection and progression. CHB Chronic hepatitis B; HCC Hepatocellular carcinoma

Appendix Figure 2).

Appendix Figure 2)

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Detailed Markov model of chronic hepatitis B virus (HBV) infection and progression. −Negative; + Positive; ALT Alanine amino-transferase; HBeAg Hepatitis B e antigen; HBsAg Hepatitis B surface antigen

Appendix Figure 3).

Appendix Figure 3)

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Result of sensitivity analysis: Tornado diagrams for life years (LY), quality-adjusted LYs (QALY) and cost (2008 Canadian dollars [CAD $1 = US $0.813]). CHB Chronic hepatitis B

Footnotes

FINANCIAL DISCLOSURES: The present study was supported by an unrestricted grant from Gilead Sciences. None of the funding organizations or sponsors had any role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review or approval of the manuscript.

FUNDING/SUPPORT: Dr Heathcote has received consulting fees and grant support from Axcan, Ortho Biotech, Idenix Pharmaceuticals, Human Genome Sciences, Gilead Sciences, GlaxoSmithKline, Novartis, Merck, Vertex, Hoffmann-La Roche, Tibotec, Boehringer Ingelheim and Bristol-Myers Squibb. Dr Krahn received a grant to fund this study from Gilead Sciences.

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