Study Design and Participating TB Treatment Centers

We conducted a retrospective chart review of persons initiating treatment for TB infection, drug-susceptible TB (DS TB) disease, isoniazid-resistant TB disease, or multidrug-resistant TB (MDR TB) disease; we defined MDR TB as TB resistant to at least isoniazid and rifampin. We extracted data at 3 TB treatment centers in Canada: the British Columbia Centre for Disease Control (BCCDC), West Park Healthcare Centre (WPHC) in Toronto, Ontario, and the Montreal Chest Institute (MCI) in Quebec. In Canada, healthcare, including TB management, is a provincial and territorial responsibility.

BCCDC operates 2 TB clinics in the greater Vancouver region, treating all persons with TB infection and TB disease in the region. In 2016, BCCDC treated 241 persons for TB disease (all forms) and 676 persons for TB infection. WPHC, a rehabilitation and complex care hospital in Toronto, Ontario, housing a 20-bed dedicated inpatient TB unit and an ambulatory TB clinic, is recognized as a referral center for complex and drug-resistant TB. WPHC treated 119 persons for TB disease (all forms) and 33 persons for TB infection in 2016. MCI is located within the McGill University Health Centre, and is a center for TB screening and surveillance for newly arrived adult migrants to Canada. MCI treated 51 persons for TB disease (all forms) and 488 persons for TB infection in 2016.

Study Inclusion and Exclusion Criteria

We included persons of any age who initiated treatment at any participating site during July 1, 2010–June 30, 2016; we reviewed consecutive patients, working backward from the end date, to permit adequate time to complete treatment and follow-up owing to the approximate 18–20-month duration of MDR TB treatment. All forms of TB disease required microbiologic confirmation (i.e., positive culture or positive nucleic acid amplification test). In addition, DS TB required confirmed susceptibility by phenotypic or genotypic means to all first-line TB drugs (i.e., isoniazid, rifampin, ethambutol, and pyrazinamide); isoniazid-resistant TB required confirmed resistance to isoniazid and susceptibility to rifampin; and MDR TB required confirmed resistance to at least isoniazid and rifampin. We excluded persons who initiated treatment at a participating site but later transferred to another treatment site where we could not access their charts.

For MDR TB disease, all persons meeting inclusion criteria at each site were included because of the low incidence in Canada. For TB infection, DS TB disease, and isoniazid-resistant TB disease, incidence is higher and treatment is more standardized; at each site we included up to 30 consecutive persons meeting inclusion criteria (14). This group included patients who had initiated treatment closest to June 30, 2016, for WPHC and MCI, and closest to December 31, 2015, for BCCDC.

Procedures

For each person, we entered data into standardized forms (Appendix Table 1). In brief, for each person we collected detailed information on demographic and clinical characteristics, TB-related diagnostic tests performed, TB-related monitoring tests performed, TB-related inpatient and outpatient visits (including any visits requiring specialists), TB medication dose, frequency, and duration, including adverse events (and, if applicable, reasons for discontinuation), method of treatment administration (directly observed vs. self-administered), adjunct medications administered during treatment, use of interpreters, number of contacts traced (for all groups except those with TB infection), and posttreatment monitoring visits and evaluations. We completed data extraction during August 2018–May 2020.

At each site, we tabulated costs for services, consumables, and overheads (Appendix Table 2). We documented costs from the health system perspective in 2020 Canadian dollars (1.00 CAD ≈ 0.75 USD). When a cost item was unavailable from a given center, we used the mean from the other centers to impute it (Appendix Table 2). To determine drivers of cost, we grouped costs in 5 different categories: diagnosis, treatment, posttreatment follow-up, hospitalization, and public health costs. We did not include costs associated with healthcare seeking before TB diagnosis or for post-TB disease complications. To estimate true resource use, we performed microcosting where possible; in all other cases, we used top-down approaches.

In the diagnosis category, we performed microcosting and considered costs associated with initial physician consultations, nurse and interpreter time, and overheads, as well as costs of diagnostic tests (e.g., tuberculin skin test, chest radiograph, smear microscopy, sputum culture, drug-susceptibility testing, and computed tomography scans) and of routine screening for other related conditions (e.g., HIV infection and viral hepatitis).

In the treatment category, we performed microcosting and considered costs associated with TB and adjunct medications, tests for treatment and adverse event monitoring (e.g., for liver transaminases, complete blood count, therapeutic drug monitoring, and audiometry), tests for treatment response (e.g., sputum culture), and personnel and overhead associated with follow-up visits with nurses, physicians, and specialists. Bedaquiline and clofazimine are given under compassionate-use programs in Canada and are not associated with costs to programs.

In the posttreatment follow-up category, we performed microcosting and only considered costs associated with surveillance for TB recurrence. These costs included chest imaging and costs of routine follow-up appointments.

In the hospitalization category, we performed microcosting and considered per-diem costs attributed to each day of hospitalization according to setting. We also considered costs associated with visits by physicians during the stay and with investigations and medications.

In the public health category, we considered costs of delivering directly observed therapy (DOT), when performed, and costs associated with contact investigation. For costs of delivering DOT, we performed microcosting at MCI and BCCDC, considering personnel (nurse, pharmacist, or both) and other costs (e.g., travel). We used a top-down approach at WPHC on the basis of data from Toronto Public Health. Because of the varied nature of contact investigations across sites, we used a top-down approach on the basis of data from Toronto Public Health because they had the most systematic and comprehensive data for contact investigation (Appendix).

Data Analysis

We performed descriptive analysis of patient characteristics by TB treatment center and form of TB (TB infection, DS TB, isoniazid-resistant TB, or MDR TB). For persons with TB infection, we also described those receiving different regimens: 9 months of isoniazid, 4 months of rifampin, or other isoniazid-containing regimens. For persons with MDR TB, we further described persons with additional resistance to a fluoroquinolone (ofloxacin, moxifloxacin, or levofloxacin), resistance to a second-line injectable drug (amikacin, kanamycin, or capreomycin), or both.

For each person, we used the itemized costs to estimate the costs associated with each cost category defined previously and summed them to arrive at an overall cost. We estimated median costs and interquartile range (IQR) to illustrate cost variation, but also estimated mean costs, because these data are most useful for policymakers. We estimated costs for each form of TB overall and in different subgroups (as relevant): sex, age at treatment initiation (dichotomous, based on median age in all persons), presence versus absence of adverse events causing drug cessation, duration of hospitalization (dichotomous, based on median hospitalization duration in all persons hospitalized), completion of treatment, acid-fast bacilli smear status, presence of cavities, and location of TB disease.

We performed regression by using linear mixed models to identify predictors of cost for all forms of TB together (using DS TB as the reference category). We conducted a subgroup analysis where we excluded TB infection to assess the impact of clinical characteristics such as radiography and microbiologic findings. We also conducted stratified analyses for each form of TB separately. We treated each site as a random intercept. For each analysis, we log-transformed costs and performed univariable analysis on several predictors (Appendix Table 3). We included age and sex as a priori predictors in all multivariable models and any predictor with a p value <0.2 in univariable analysis. We back-transformed the resultant estimates and 95% CIs, which we interpreted as cost ratios (15). Because costs are probably associated with treatment completion or noncompletion, we did a post hoc sensitivity analysis, in which we repeated all analyses but excluded persons who did not complete treatment. We performed all analyses in R version 4.1.0 (16) using package lme4 (version 1.1–23) (17).

This study was approved by the research ethics boards of the sites where data were collected. These boards were the Research Institute of the McGill University Health Centre (approval no. 2019-4811), the University of British Columbia (approval no. H18-01700), and West Park Healthcare Centre (approval no. 18-017-WP).

Total Population

We included a total of 313 persons in the study: 101 (32%) from BCCDC, 132 (42%) from WPHC, and 80 (26%) from MCI. We tabulated the characteristics of included persons (Table 1) and the estimated costs of their management, stratified by form of TB (Table 2). We also stratified costs by patient characteristics (Appendix Tables 4–7). We determined mean costs for all analyses (Appendix Table 8). Overall, the median cost of TB infection was $804 (IQR $587–$1,205), of DS TB disease was $12,148 (IQR $4,388–$24,842), of isoniazid-resistant TB disease was $19,319 (IQR $7,117–$41,318), and of MDR TB disease was $119,014 (IQR $80,642–$164,015).

Figure

Figure. Relative contribution of each cost category to overall cost of managing different forms of TB at 3 treatment centers, Canada, July 2010–June 2016. DOT, directly observed therapy; DS, drug-susceptible; INHR,...

We determined the relative contribution of each cost category to the overall cost of management, again stratified by form of TB (Figure). Although diagnosis costs were a substantial contributor to overall costs in TB infection, their contribution was comparatively smaller for other forms of TB. For TB disease (DS TB, isoniazid-resistant TB, and MDR TB), hospitalization costs accounted for a substantial proportion of all costs (54.4% for DS TB, 61.7% for isoniazid-resistant TB, and 37.2% for MDR TB).

Among the 313 persons, multivariable regression estimated costs of managing TB infection were 11.1 times lower (adjusted cost ratio 0.09 [95% CI 0.07–0.11]) than costs of managing DS TB. Conversely, costs of managing isoniazid-resistant TB were 1.7 times higher (95% CI 1.3–2.1) than DS TB, whereas costs of managing MDR TB were 8.1 times higher (95% CI 6.1–10.6) than DS TB (Table 3; univariable regression results [Appendix Table 9]). When we excluded TB infection from multivariable regression and included clinical characteristics (Appendix Table 10), adjusted cost ratios were reduced for isoniazid-resistant TB (1.3 [95% CI 1.1–1.7]) and MDR TB (3.6 [95% CI 2.6–5.1]). Estimates were not substantially different when we excluded persons who did not complete treatment (Appendix Table 11).

TB Infection

Overall, we included 90 persons treated for TB infection (30 at each center) (Table 1). Of these persons, 53 (59%) initiated 9 months of isoniazid, 35 (39%) initiated 4 months of rifampin, and 2 (2%) initiated isoniazid and rifampin (Appendix Tables 12, 13).

Approximately two-thirds of costs for TB infection were associated with treatment (Figure); absolute treatment costs were correlated with duration (Appendix Table 13). Persons initiating an isoniazid-containing regimen had overall costs 1.3-times (95% CI 0.98–1.7) higher than persons initiating a rifampin-only regimen (Table 3).

DS TB Disease

We included 90 persons treated for DS TB disease (30 at each center) (Table 1). Approximately half (46 [51%]) were hospitalized for a median duration of 24 (IQR 9–36) days. The median duration of treatment was 8.9 (IQR 6.1–9.6) months; treatment was shorter for persons who were smear-negative and without cavities (6.6 months [IQR 6.1–9.1]) compared with persons who were smear-positive or had cavities, or both (9.1 months [IQR 6.4–10.0]) (Appendix Table 14).

More than half the cost of DS TB disease management was related to hospitalization, whereas approximately one third reflected contact investigations and DOT administration (Figure). Costs of managing DS TB disease were much lower at MCI (median $4,987) than at WPHC ($13,328) and BCCDC ($15,201), largely because of variation in disease severity and attendant differences in hospitalization among persons treated at these centers (Appendix Table 14). Costs were 3.7 (95% CI 1.9–7.4) times higher for persons hospitalized for >2 months compared with persons not hospitalized at all or hospitalized <2 months (Table 3).

Isoniazid-Resistant TB Disease

We included 71 persons treated for isoniazid-resistant TB disease (30 at BCCDC, 27 at WPHC, and 14 at MCI) (Table 1). Of those, 47 (66%) were hospitalized, with median duration 23 (IQR 17–69) days. The median treatment duration was 11.7 (IQR 9.1–16.7) months and varied substantially by TB treatment center (Appendix Table 15). Fifty-four (76%) persons received regimens containing a fluoroquinolone, and 8 (11%) received a second-line injectable (Appendix Table 15).

Over 60% of costs associated with isoniazid-resistant TB disease were because of hospitalization (Figure). Treatment was shortest and costs lowest at MCI (median duration 8 months; median cost $6,504) and treatment longest and costs highest at WPHC (median duration 17.6 months; median cost $34,400). Costs were 3.2 (95% CI 2.1–4.7) times higher for persons hospitalized >2 months compared with patients not hospitalized at all or hospitalized <2 months (Table 3).

MDR TB Disease

We included 62 persons treated for MDR TB disease (11 at BCCDC, 45 at WPHC, and 6 at MCI) (Table 1). Of these, 2 (3%) had additional fluoroquinolone resistance, 6 (10%) had additional resistance to a second-line injectable, and 4 (6%) had both. Nearly all (60 [97%]) were hospitalized for a median duration of 99 (IQR 66–159) days. The median treatment duration was 21.2 (IQR 20.0–24.7) months and was similar across centers (Appendix Table 16). About half (34 [55%]) of the patients received linezolid, whereas few received the newer drugs bedaquiline (3 [5%]) or delamanid (4 [6%]) (Appendix Tables 16, 17).

Costs associated with treatment (56.5%) and hospitalization (37.2%) were the largest cost components for MDR TB management (Figure). In adjusted analyses, resistance to a fluoroquinolone, a second-line injectable, or both were associated with 1.4 (95% CI 1.02–2.0) times higher costs (Table 3).

We analyzed median duration and cost of each medication received (Table 4). Cycloserine was the most expensive drug, costing a median of $57,658 (IQR $28,942–$91,935) per person. New and repurposed drugs (i.e., linezolid, delamanid, and carbapenems) were also expensive (median cost range $8,459–$22,437). Fluoroquinolones and second-line injectables were less expensive (median cost range $330–$4,024). Compassionate-use drugs (clofazimine and bedaquiline) did not contribute to costs to TB programs.