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Health care costs associated with hepatitis C virus infection in First Nations populations in Ontario: a retrospective matched cohort study

Background: Colonization and marginalization have affected the risk for and experience of hepatitis C virus (HCV) infection for First Nations people in Canada. In partnership with the Ontario First Nations HIV/AIDS Education Circle, we estimated the publicly borne health care costs associated with HCV infection among Status First Nations people in Ontario. Methods: In this retrospective matched cohort study, we used linked health administrative databases to identify Status First Nations people in Ontario who tested positive for HCV antibodies or RNA between 2004 and 2014, and Status First Nations people who had no HCV testing records or only a negative test result (control group, matched 2:1 to case participants). We estimated total and net costs (difference between case and control participants) for 4 phases of care: prediagnosis (6 mo before HCV infection diagnosis), initial (after diagnosis), late (liver disease) and terminal (6 mo before death), until death or Dec. 31, 2017, whichever occurred first. We stratified costs by sex and residence within or outside of First Nations communities. All costs were measured in 2018 Canadian dollars. Results: From 2004 to 2014, 2197 people were diagnosed with HCV infection. The mean net total costs per 30 days of HCV infection were $348 (95% confidence interval [CI] $277 to $427) for the prediagnosis phase, $377 (95% CI $288 to $470) for the initial phase, $1768 (95% CI $1153 to $2427) for the late phase and $893 (95% CI −$1114 to $3149) for the terminal phase. After diagnosis of HCV infection, net costs varied considerably among those who resided within compared to outside of First Nations communities. Net costs were higher for females than for males except in the terminal phase. Interpretation: The costs per 30 days of HCV infection among Status First Nations people in Ontario increased substantially with progression to advanced liver disease and finally to death. These estimates will allow for planning and evaluation of provincial and territorial population-specific hepatitis C control efforts.


Methods Partnership
This study was conducted in partnership with the Ontario First Nations HIV/AIDS Education Circle and included First Nations community partners, ICES and academic researchers. Similar collaborations between First Nations organizations and researchers using ICES administrative data sets are described elsewhere. [10][11][12][13][14] Access to the Indian Register was granted by the Chiefs of Ontario First Nations Data Gover nance Committee after the study was reviewed for compliance with the First Nations principles of ownership, control, access and possession (OCAP) and by Grand Council Treaty #3. Permission to access data for members of communities in the Kenora Chiefs Advisory was not granted; thus, they were excluded from the analysis.

Study design and population
We conducted a retrospective matched cohort study to evaluate health care costs from the provincial public payer perspective. We identified First Nations people in Ontario registered under the Indian Act 15 using the Indian Register. The Indian Register includes demographic and administrative information for all First Nations people who have successfully applied for Indian status under the Indian Act (i.e., "Status First Nations"). We obtained HCV testing records from Public Health Ontario.
We identified Status First Nations people who had tested positive for HCV antibodies or RNA between Jan. 1, 2004, andDec. 31, 2014, at age 18-105 years, and followed them until death or Dec. 31, 2017, whichever occurred first. Partic ipants were linked to administrative data sets held at ICES (Appendix 1, available at www.cmajopen.ca/content/9/3/ E897/suppl/DC1) by means of unique encoded identifiers and analyzed at ICES. People who had a valid Ontario Health Insurance Plan number at cohort entry and end of followup were included. People were excluded if they were potentially coinfected with HIV or hepatitis B virus, or if their HVC infection was presumed to be spontaneously cleared or acute resolved (Table 1).
Control participants were Status First Nations people with no HCV testing record or only negative results of HCV test ing. For the terminal phase of care (6 mo before death from any cause), control participants who died during the observa tion period were matched 2:1 at 6 months before death to case participants who had died. All remaining unmatched control participants were censored 6 months before death or on Dec. 31, 2017, whichever occurred first, and were randomly assigned pseudo diagnosis dates based on the month and year distribution of the case participants' HCV infection diagnosis dates. Control participants with at least 6 months of observa tion time between their pseudo diagnosis date and censor date were matched 2:1 to case participants at the start of the pre diagnosis phase (6 mo before HCV infection diagnosis date), initial phase (period following diagnosis with no liver disease) and late phase (liver disease). Each control participant was matched only once. Case and control participants for whom First Nations community residence was not known during the year of each match were excluded.
Control and case participants were greedy matched by hardmatching on sex and age within 2 years. They were then matched within a caliper width of 0.2 standardized difference of the logit of the propensity score based on Johns Hopkins ACG System, Aggregated Diagnosis Groups (ADGs) cate gory 16 (excluding ADG 32 -Malignancy for late phase), and records of mental health or substance abuse conditions dur ing the year before matching date, age at HCV infection diagnosis, community residence status and rurality. 17 We evaluated the quality of each match using descriptive statistics and the weighted standardized differences of matching vari ables between case and control participants. 18

Cohort characteristics
We identified residence within or outside of a First Nations community at the year of phase entry using postal and resi dence codes from the Registered Persons Database, Discharge Abstract Database and National Ambulatory Care Reporting System. 13 We used validated algorithms within the adminis trative data sets to detect complications related to liver dis ease, and HCVspecific drug prescription claims were cap tured (Appendix 2). 19 We scored multimorbidity using ADGs.
Severe mental illnesses may be overrepresented in people at high risk for HCV infection. 20 Depression, bipolar mood disorder, anxiety and stressrelated disorders are prevalent and may be complicated by infection. [21][22][23] We identified flags for mental health and substance abuse disorders using methods developed by ICES (Appendix 2), supplemented with Ontario Health Insurance Plan service codes. 24 As alcohol use can have a compounded effect with HCV infection, further affecting deterioration of the liver, we identified alcohol use disorder separately using related diagnostic codes (Appendix 2). 25

Outcomes
We used a phasebased approach to estimate costs over the natural history of disease. 4,[26][27][28] Patients who had a record of decompensated cirrhosis, hepatocellular carcinoma or liver transplantation (Appendix 2) were allocated to the late phase 3 months before the date of the first record. If that date was before their HCV infection diagnosis, they entered the late phase on their diagnosis date. The phase lengths were defined by means of joinpoint analyses and expert opinion from phys icians with indepth knowledge of HCV infection (J.J.F., M.K.) (Appendix 3, available at www.cmajopen.ca/content/9/ 3/E897/suppl/DC1). We estimated provincial total and resourcespecific costs for inpatient and ambulatory care, physician and diagnostic services, drugs for those aged 65 years or more, complex con tinuing care, home care and longterm care for case and control participants using standard personlevel costing meth ods for administrative data ( Table 2). 29 We adjusted costs to 2018 Canadian dollars using healthsector-specific consumer price indices 29,30 and standardized them to per 30 days within each phase by dividing each patientlevel cost by each per son's time in phase.

Statistical analysis
We used clustered analyses by matched set using generalized estimating equations (γ family and log link) to estimate net costs (difference between case and control participants) with each cost category as the dependent variable and HCV infec tion status as the independent variable. 31 We used clustered bootstrap sampling, where matched sets were resampled, with 1000 replications and the percentile method to estimate 95% confidence intervals (CIs). Results were stratified by sex and by case participant residence within or outside of a First Nations community at matching date. All analyses were done with R version 3.6.3 (R Foundation for Statistical Comput ing), SAS version 9.2 (SAS Institute) and Stata version 15.1 (StataCorp).

Ethics approval
This study was approved by the University of Toronto Health Sciences Research Ethics Board.
The sociodemographic characteristics, mental health con ditions and comorbidity data of the case and control partici pants in each phase at matching dates are presented in Table 3. For the prediagnosis and initial phases, the weighted standardized differences were 0.1 or less for all matching variables. Despite efforts to improve matching, case and con trol participants were less well matched on some ADGs for the late and terminal phases (Appendix 5, Supplemental Table S7, available at www.cmajopen.ca/content/9/3/E897/ suppl/DC1), likely owing to the small number of people with these conditions. People with HCV infection spent, on average, 179, 2714, 1281 and 168 days in the prediagnosis, initial, late and termi nal phases, respectively. They were older in the late and ter minal phases (about 50 yr) than in the initial and prediagnosis phases (about 37 yr). In all phases, the majority were male and lived outside of First Nations communities. Substance abuse and addiction disorders were the most common comorbid conditions.
During the initial and late phases, 195 case participants (9.4%) and 23 case participants (17.7%), respectively, had records of an HCVrelated prescription, and 155 (7.5%) and 21 (16.2%), respectively, received directacting antiviral treatment.   (Table 4). Inpatient care accounted for 30%-50% of the health care costs in the prediagnosis, initial and late care phases, and 60%-70% of total costs in the terminal phase. For the pre diagnosis, initial and late phases, costs were higher among case participants than control participants for nearly all resource categories. In the terminal phase, control partici pants had higher costs for outpatient services ($738 v. $667), sameday surgery ($31 v. $17) and emergency department visits ($271 v. $249).

Total costs
Other cost outcomes are described in Appendix 5, Supple mental Tables S8 to S11, and below.

Net costs
The mean net cost per 30 days increased from $348 (95% CI $277 to $427) in the prediagnosis phase to $893 (95% CI -$1114 to $3149) in the terminal phase (Table 5). Figure 2 summarizes the net costs per 30 days for case par ticipants who resided within and outside of First Nations com munities in the year of matching date. Total net costs were higher in the initial, late and terminal phases for those who resided outside of versus within First Nations commun ities. Negative net costs indicate that the costs were higher for the control participants than for the case participants. In the terminal phase, the mean net total costs per 30 days were -$1844 (95% CI -$5182 to $1419) and $1289 (95% CI -$892 to $3515) for those who resided within and outside of First Nations communities, respectively.
Net total costs per 30 days were higher for females than males in the prediagnosis, initial and late phases ( Figure 3). In particular, females had consistently higher net costs for phys ician services, inpatient care and outpatient prescription drugs. In the terminal phase, net costs were higher for males than for females (

Interpretation
Using administrative data to estimate the phasespecific pro vincial health care costs attributable to HCV infection among Status First Nations people in Ontario, we found that costs per 30 days increased with disease progression. Inpatient ser vices, outpatient prescription drugs and physician services were the most costly resources. Female participants had higher net costs than male participants in the prediagnosis, initial and late phases of care, but males had higher net costs in the terminal phase. Net costs were consistently higher among those who resided outside of versus within First Nations communities, with the largest difference in the termi nal phase. However, the large CIs around the net cost esti mates indicate wide variations, and, therefore, definitive con clusions should be made with caution.
In our study, the average annual cost for Status First Nations people with HCV infection, before latestage liver dis ease, was $10 500, 1.5 times the average Canadian health care cost of $6867 in 2018. 32

Research
The mean endoflife costs for case and control partici pants in our study were higher than costs in the last year of life for patients with heart failure, renal disease or mental health disorders. 34 An Ontario study showed that patients with endstage liver disease incurred an additional $4201 in the last 90 days of life compared to other decedents. 34 Extrapolating 30day costs from our study shows that Status First Nations people with HCV infection incurred $2679 more in their last 90 days of life than other Status First Nations people.
Differences in costs between people with HCV infection who lived within and outside of First Nations communities may indicate unique patterns of use of health care resources and health care policy by the 2 populations. 35 A history of government mistrust, marginalization and alienation has cre ated hesitancy among First Nations people to seek main stream medical care, especially in rurally isolated communities with barriers to access to care. 36 The largest difference in net costs was in the terminal phase, which may indicate that      Error bars represent 95% confidence intervals. Mean cost and net cost results stratified by sex can be found in Appendix 5, Supplemental Tables S10 and S11.
endoflife care within First Nations communities is associ ated with family support rather than hospital or hospice care. 36 The lower cost of endoflife care within First Nations communities may also be attributable to funding constraints, resulting in unavailable or limited access to endoflife health care services. 36 In addition, 1 in 4 First Nations communities in Ontario are in remote areas accessible only by air year round or by ice road in winter. 37 These barriers can translate to people having to leave their community to seek care or, in certain cases, receiving no endoflife care at all. 36 In the prediagnosis, initial and late phases, female case par ticipants exhibited higher costs of care than male case partici pants. Verde and Li 38 found that First Nations women were more likely to have a family physician and seek health care services than First Nations men, perhaps owing to cultural norms regarding male strength and perception of less severe physical symptoms. Similarly, using ICES data, Green and colleagues 39 studied the monitoring, treatment and control of blood glucose and lipids in Status First Nations people with diabetes in Ontario and observed that women were more likely than men to be engaged in diabetesrelated care. The higher net cost for males during the terminal phase in our study may indicate that males seek health care only when dis ease progresses to a critical stage. 38 Also, females may choose traditional medicine and community supports rather than hospital or hospice care at the end of life (Evelynne Hill, Ontario First Nations HIV/AIDS Education Circle: personal communication, 2020).
Safe, effective and curative directacting antiviral treat ments for HCV infection were introduced in Canada in 2012. 40 However, Indigenous people face barriers in access to treatment. 41 Although progression to advanced liver disease can take decades, 42 the higher net costs in the late and termi nal phases compared to the prediagnosis and initial phases forecast the potential economic impact if HCV infection remains untreated or is diagnosed late. Understanding health care expenditures in First Nations people with HCV infec tion can stimulate research, planning and evaluation of cul turally specific services for combatting hepatitis C in this population. 43

Limitations
Although matching minimized differences between case and control participants, residual confounding and differences in health care-seeking behaviour potentially existed and may have introduced bias. The Public Health Ontario laboratory data set does not include all private diagnostic laboratory results. The Indian Register includes only First Nations peo ple who are registered with the Canadian government. 13 Our study included those who could be linked to ICES databases but excluded data for those who are members of communities in the Kenora Chiefs' Advisory.
Costs may be underestimated because ICES data sets do not capture federally funded or outofprovince health care services, including those covered by the NonInsured Health Benefit program (drug coverage and certain health care ser vices). The Ontario Drug Benefit program, our source of prescription information, covers only people aged 65 years or more, receiving social assistance or in longterm care homes.
We included allcause mortality; thus, our terminalphase net costs are not entirely attributable to HCV infection. 4 Many mental health conditions could not be distinguished as being a cause or consequence of HCV infection. Because determination of residence in a given Local Health Integra tion Network and within a First Nations community relied on annual postal and residence codes updated at health card use or renewal, residence may have been misclassified.
As HCV infection can remain asymptomatic, control partic ipants may have had undiagnosed infection. By excluding case participants with HIV and HBV infection, our study estimates reflect the cost of diagnosed monoinfection. Coinfection has been associated with potentially rapid fibrosis progression 44 and different treatment of infection. Coinfection with HIV in par ticular has been associated with increased health care costs. 4,45

Conclusion
Our results suggest that the costs of HCV infection in Status First Nations people vary by phase of care and increase as the disease progresses. Canada's commitment to partnership with First Nations people to eliminate hepatitis C will require measures that comprehensively depict its populationspecific impact. Our populationspecific health care costs can support research, planning and formulation of First Nations-specific prevention and treatment interventions for HCV infection.