Disease burden of chronic hepatitis B among immigrants in Canada

1Toronto Health Economics and Technology Assessment Collaborative (THETA); 2 Department of Medicine; 3Department of Health Policy, Management and Evaluation and Faculty of Pharmacy, University of Toronto; 4University Health Network, Toronto General Research Institute and Toronto Western Research Institute, Toronto, Ontario Correspondence: Dr William WL Wong, Toronto Health Economics and Technology Assessment (THETA) Collaborative, University of Toronto, Suite 658, 144 College Street, Toronto, Ontario M5S 3M2. Telephone 416-946-0868, fax 416-946-3719 e-mail william.wong@theta.utoronto.ca Received for publication May 31, 2012. Accepted July 22, 2012 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.

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, CHBinfected 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.

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.
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).

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.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.
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.
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)(30)(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)   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.

Figure 2) Cumulative risks of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver transplant and chronic hepatitis B (CHB)-related death among immigrants with
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.

aCKnOWLEDGEMEnT:
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.
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.

Table 2 Costs and utilities used in the model Costs and utilities
*2008 Canadian dollars (CAD $1 = US $0.813 using purchasing power parity conversion rate)

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

Table 4 baseline annual distribution of major clinical outcomes among immigrants with chronic hepatitis b (CHb)
(6)a presented as % unless otherwise indicated.HCC Hepatocellular carcinoma 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 (

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
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 age, years
TransiƟon appendix Figure 1) Markov model of hepatitis B virus (HBV) infection and progression.CHB Chronic hepatitis B; HCC Hepatocellular carcinoma appendix Figure 2) Detailed Markov model of chronic hepatitis B virus (HBV) infection and progression.-Negative; + Positive; ALT Alanine aminotransferase; HBeAg Hepatitis B e antigen; HBsAg Hepatitis B surface antigen appendix Figure 3) 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