Sustainability and impact of an intervention to improve initiation of tuberculosis preventive treatment: results from a follow-up study of the ACT4 randomized trial.

Background: In a cluster randomized trial (clinicaltrials.gov: NCT02810678) a flexible but comprehensive health system intervention significantly increased the number of household contacts (HHC) identified and started on tuberculosis preventive treatment (TPT). A follow-up study was conducted one year later to test the hypotheses that these effects were sustained, and were reproducible with a simplified intervention. Methods: We conducted a follow-up study from May 1, 2018 until April 30, 2019, as part of a multinational cluster randomized trial. Eight sites in 4 countries that had received the intervention in the original trial received no further intervention; eight other sites in the same countries that had not received the intervention (control sites in the original trial) now received a simplified version of the intervention. This consisted of repeated local evaluation of the Cascade of care for TB infection, and stakeholder decision making. The number of HHC identified and starting TPT were repeatedly measured at all 16 sites and expressed as rates per 100 newly diagnosed index TB patients. The sustained effect of the original intervention was estimated by comparing these rates after the intervention in the original trial with the last 6 months of the follow-up study. The reproducibility was estimated by comparing the pre-post intervention changes in rates at sites receiving the original intervention with the pre-post changes in rates at sites receiving the later, simplified intervention. Findings: With regard to the sustained impact of the original intervention, compared to the original post-intervention period, the number of HHC identified and treated per 100 newly diagnosed TB patients was 10 more (95% confidence interval: 84 fewer to 105 more), and 1 fewer (95% CI: 22 fewer to 20 more) respectively up to 14 months after the end of the original intervention. With regard to the reproducibility of the simplified intervention, at sites that had initially served as control sites, the number of HHC identified and treated per 100 TB patients increased by 33 (95% CI: -32, 97), and 16 (-69, 100) from 3 months before, to up to 6 months after receiving a streamlined intervention, although differences were larger, and significant if the post-intervention results were compared to all pre-intervention periods. Interpretation: Up to one year after it ended, a health system intervention resulted in sustained increases in the number of HHC identified and starting TPT. A simplified version of the intervention was associated with non-significant increases in the identification and treatment of HHC. Inferences are limited by potential bias due to other temporal effects, and the small number of study sites. Funding: Funded by the Canadian Institutes of Health Research (Grant number 143350).

High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial.

BACKGROUND: Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. METHODS: This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with ClinicalTrials.gov, NCT03988933 (active). RESULTS: Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (-0·5% [95% CI -2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (-7·8% [95% CI -13·6 to -2·0]) and the 30 mg/kg group (-15·4% [-21·4 to -9·4]) than in the standard-dose group. INTERPRETATION: In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. FUNDING: Canadian Institutes of Health Research.

Distinct healthcare utilization profiles of high healthcare use tuberculosis survivors: A latent class analysis.

BACKGROUND: Recent data have demonstrated that healthcare use after treatment for respiratory tuberculosis (TB) remains elevated in the years following treatment completion. However, it remains unclear which TB survivors are high healthcare users and whether any variation exists within this population. Thus, the primary objective of this study was to identify distinct profiles of high healthcare-use TB survivors to help inform post-treatment support and care. METHODS: Using linked health administrative data from British Columbia, Canada, we identified foreign-born individuals who completed treatment for incident respiratory TB between 1990 and 2019. We defined high healthcare-use TB survivors as those in the top 10% of annual emergency department visits, hospital admissions, or general practitioner visits among the study population during the five-year period immediately following TB treatment completion. We then used latent class analysis to categorize the identified high healthcare-use TB survivors into subgroups. RESULTS: Of the 1,240 people who completed treatment for respiratory TB, 258 (20.8%) people were identified as high post- TB healthcare users. Latent class analysis results in a 2-class solution. Class 1 (n = 196; 76.0%) included older individuals (median age 71.0; IQR 59.8, 79.0) with a higher probability of pre-existing hypertension and diabetes (41.3% and 33.2%, respectively). Class 2 (n = 62; 24.0%) comprised of younger individuals (median age 31.0; IQR 27.0, 41.0) with a high probability (61.3%) of immigrating to Canada within five years of their TB diagnosis and a low probability (11.3%) of moderate to high continuity of primary care. DISCUSSION: Our findings suggest that foreign-born high healthcare-use TB survivors in a high-resource setting may be categorized into distinct profiles to help guide the development of person-centred care strategies targeting the long-term health impacts TB survivors face.

Risk of Tuberculosis Disease in People With Chronic Kidney Disease Without Kidney Failure: A Systematic Review and Meta-analysis.

BACKGROUND: Kidney failure is an established risk factor for tuberculosis (TB), but little is known about TB risk in people with chronic kidney disease (CKD) who have not initiated kidney replacement therapy (CKD without kidney failure). Our primary objective was to estimate the pooled relative risk of TB disease in people with CKD stages 3-5 without kidney failure compared with people without CKD. Our secondary objectives were to estimate the pooled relative risk of TB disease for all stages of CKD without kidney failure (stages 1-5) and by each CKD stage. METHODS: This review was prospectively registered (PROSPERO CRD42022342499). We systematically searched MEDLINE, Embase, and Cochrane databases for studies published between 1970 and 2022. We included original observational research estimating TB risk among people with CKD without kidney failure. Random-effects meta-analysis was performed to obtain the pooled relative risk. RESULTS: Of the 6915 unique articles identified, data from 5 studies were included. The estimated pooled risk of TB was 57% higher in people with CKD stages 3-5 than in people without CKD (adjusted hazard ratio: 1.57; 95% CI: 1.22-2.03; I2 = 88%). When stratified by CKD stage, the pooled rate of TB was highest in stages 4-5 (incidence rate ratio: 3.63; 95% CI: 2.25-5.86; I2 = 89%). CONCLUSIONS: People with CKD without kidney failure have an increased relative risk of TB. Further research and modeling are required to understand the risks, benefits, and CKD cutoffs for screening people for TB with CKD prior to kidney replacement therapy.

Healthcare Utilization After Respiratory Tuberculosis: A Controlled Interrupted Time Series Analysis.

BACKGROUND: Despite data suggesting elevated morbidity and mortality among people who have survived tuberculosis disease, the impact of respiratory tuberculosis on healthcare utilization in the years following diagnosis and treatment remains unclear. METHODS: Using linked health administrative data from British Columbia, Canada, we identified foreign-born individuals treated for respiratory tuberculosis between 1990 and 2019. We matched each person with up to four people without a tuberculosis diagnosis from the same source cohort using propensity score matching. Then, using a controlled interrupted time series analysis, we measured outpatient physician encounters and inpatient hospital admissions in the 5 years following respiratory tuberculosis diagnosis and treatment. RESULTS: We matched 1216 individuals treated for respiratory tuberculosis to 4864 non-tuberculosis controls. Immediately following the tuberculosis diagnostic and treatment period, the monthly rate of outpatient encounters in the tuberculosis group was 34.0% (95% confidence interval [CI]: 30.7%, 37.2%) higher than expected, and this trend was sustained for the duration of the post-tuberculosis period. The excess utilization represented an additional 12.2 (95% CI: 10.6, 14.9) outpatient encounters per person over the post-tuberculosis period, with respiratory morbidity a large contributor to the excess healthcare utilization. Results were similar for hospital admissions, with an additional 0.4 (95% CI: .3, .5) hospital admissions per person over the post-tuberculosis period. CONCLUSIONS: Respiratory tuberculosis appears to have long-term impacts on healthcare utilization beyond treatment. These findings underscore the need for screening, assessment, and treatment of post-tuberculosis sequelae, as it may provide an opportunity to improve health and reduce resource use.

Role of latent tuberculosis infection on elevated risk of cardiovascular disease: a population-based cohort study of immigrants in British Columbia, Canada, 1985-2019.

We investigated cardiovascular disease (CVD) risk associated with latent tuberculosis infection (LTBI) (Aim-1) and LTBI therapy (Aim-2) in British Columbia, a low-tuberculosis-incidence setting. 49,197 participants had valid LTBI test results. Cox proportional hazards model was fitted, adjusting for potential confounders. Compared with the participants who tested LTBI negative, LTBI positive was associated with an 8% higher CVD risk in complete case data (adjusted hazard ratio (HR): 1.08, 95% CI: 0.99-1.18), a statistically significant 11% higher risk when missing confounder values were imputed using multiple imputation (HR: 1.11, 95% CI: 1.02-1.20), and 10% higher risk when additional proxy variables supplementing known unmeasured confounders were incorporated in the highdimensional disease risk score technique to reduce residual confounding (HR: 1.10, 95% CI: 1.01-1.20). Also, compared with participants who tested negative, CVD risk was 27% higher among people who were LTBI positive but incomplete LTBI therapy (HR: 1.27, 95% CI: 1.04-1.55), whereas the risk was similar in people who completed LTBI therapy (HR: 1.04, 95% CI: 0.87-1.24). Findings were consistent in different sensitivity analyses. We concluded that LTBI is associated with an increased CVD risk in low-tuberculosis-incidence settings, with a higher risk associated with incomplete LTBI therapy and attenuated risk when therapy is completed.

Human resource implications of expanding latent tuberculosis patient care activities.

Introduction: The World Health Organization (WHO) declared increasing services for latent tuberculosis infection (LTBI) a priority to eliminate tuberculosis (TB) by 2035. Yet, there is little information about thehuman resource needs required to implement LTBI treatment scale-up. Our study aimed to estimate the change in healthcare workers (HCW) time spent on different patient care activities, following an intervention to strengthen LTBI services. Methods: We conducted a time and motion (TAM) study, observing HCW throughout a typical workday before and after the intervention (Evaluation and Strengthening phases, respectively) at 24 health facilities in five countries. The precise time spent on pre-specified categories of work activities was recorded. Time spent on direct patient care was subcategorized as relating to one of three conditions: LTBI, active or suspected TB, and non-TB (i.e., patients with any other medical condition). A linear mixed model (LMM) was fit to estimate the change in HCW time following the intervention. Results: A total of 140 and 143 HCW participated in the TAMs during the Evaluation and Strengthening phases, respectively. Results from intervention facilities showed an increase of 9% (95% CI: 3%, 15%) in the proportion of HCW time spent on LTBI-related services, but with a corresponding change of -11% (95% CI: -21%, -1%) on active TB services. There was no change in the proportion of time spent on LTBI care in control facilities; this remained low in both phases of the study. Discussion: Our findings suggest that additional HCW personnel will be required for expansion of LTBI services to ensure that this expansion does not reduce the time available for care of active TB patients.

Evaluation of the implementation process of the mobile health platform 'WelTel' in six sites in East Africa and Canada using the modified consolidated framework for implementation research (mCFIR).

BACKGROUND: Health systems globally are investing in integrating secure messaging platforms for virtual care in clinical practice. Implementation science is essential for adoption, scale-up, spread and maintenance of complex evidence-based solutions in clinics with evolving priorities. In response, the mobile Health (mHealth) Research Group modified the existing consolidated framework for implementation research (CFIR) to evaluate implementation of virtual health tools in clinical settings. WelTel® is an evidence-based digital health platform widely deployed in various geographical and health contexts. The objective is to identify the facilitators and barriers for implementing WelTel and to assess the application of the mCFIR tool in facilitating focus groups in different geographical and health settings. METHODS: Both qualitative and descriptive quantitative approaches were employed. Six mCFIR sessions were held in three countries with 51 key stakeholders. The mCFIR tool consists of 5 Domains and 25 constructs and was distributed through Qualtrics Experience Management (XM). "Performance" and "Importance" scores were valued on a scale of 0 to 10 (Mean ± SD). Descriptive analysis was conducted using R computing software. NVivo 12 Pro software was used to analyze mCFIR responses and to generate themes from the participants' input. RESULTS: We observed a parallel trend in the scores of Importance and Performance. Of the five Domains, Domain 4 (End-user Characteristics) and Domain 3 (Inner Settings) scored highest in Importance (8.9 ± 0.5 and 8.6 ± 0.6, respectively) and Performance (7.6 ± 0.7 and 7.2 ± 1.3, respectively) for all sites. Domain 2 (Outer Setting) scored the lowest in both Importance and Performance for all sites (7.6 ± 0.4 and 5.6 ± 1.8). The thematic analysis produced the following themes: for areas of strengths, the themes brought up were timely diagnosis and response, cost-effectiveness, and user-friendliness. As for areas for improvement, the themes discussed were training, phone accessibility, stakeholder engagement, and literacy. CONCLUSION: The mCFIR tool allowed for a comprehensive understanding of the barriers and facilitators to the implementation, reach, and scale-up of digital health tools. Amongst several important findings, we observed the value of bringing the perspectives of both end users (HCPs and patients) to the table across Domains. TRIAL REGISTRATION: NCT02603536 - November 11, 2015: WelTelOAKTREE: Text Messaging to Support Patients With HIV/AIDS in British Columbia (WelTelOAKTREE). NCT01549457 - March 9, 2012: TB mHealth Study-Use of Cell Phones to Improve Compliance in Patients on LTBI Treatment.

Epidemiology, clinical features and outcomes of incident tuberculosis in children in Canada in 2013-2016: results of a national surveillance study.

PURPOSE: Childhood tuberculosis disease is difficult to diagnose and manage and is an under-recognised cause of morbidity and mortality. Reported data from Canada do not focus on childhood tuberculosis or capture key epidemiologic, clinical and microbiologic details. The purpose of this study was to assess demographics, presentation and clinical features of childhood tuberculosis in Canada. METHODS: We conducted prospective surveillance from 2013 to 2016 of over 2700 paediatricians plus vertical tuberculosis programmes for incident tuberculosis disease in children younger than 15 years in Canada using the Canadian Paediatric Surveillance Program (CPSP). RESULTS: In total, 200 cases are included in this study. Tuberculosis was intrathoracic in 183 patients of whom 86% had exclusively intrathoracic involvement. Central nervous system tuberculosis occurred in 16 cases (8%). Fifty-one per cent of cases were hospitalised and 11 (5.5%) admitted to an intensive care unit. Adverse drug reactions were reported in 9% of cases. The source case, most often a first-degree relative, was known in 73% of cases. Fifty-eight per cent of reported cases were Canadian-born Indigenous children. Estimated study rates of reported cases (per 100 000 children per year) were 1.2 overall, 8.6 for all Indigenous children and 54.3 for Inuit children. CONCLUSION: Childhood tuberculosis may cause significant morbidity and resource utilisation. Key geographies and groups have very high incidence rates. Elimination of childhood tuberculosis in Canada will require well-resourced community-based efforts that focus on these highest risk groups.

Tuberculosis-associated depression: a population-based cohort study of people immigrating to British Columbia, Canada, 1985-2015.

PURPOSE: To estimate the risk of tuberculosis (TB)-associated depression. A second aim was to estimate the extent to which any increased risk of depression among TB patients may be mediated by the length of hospital length stay (LOS) METHODS: Retrospective cohort study of linked healthcare claims and public health surveillance data. Our primary outcome, time-to-depression, was analyzed using Cox proportional hazards (PH) regressions. Causal mediation analysis was used to estimate the natural direct and indirect effect of TB mediated by hospital LOS. RESULTS: Among 755,836 participants (52.2% female, median age=35 years, median follow-up=8.75 years), 2295 were diagnosed with TB (exposure), and 128,963 were diagnosed with depression (outcome). We observed a covariate-adjusted hazard ratio (aHR) of 1.24 (95% CI, 1.14-1.34) for depression by TB. The total effect of TB on depression was decomposed into a natural direct effect of TB of aHR=1.11 (95% CI, 1.02-1.21) and an indirect effect through hospital LOS of aHR=1.11 (95% CI, 1.10-1.12), indicating that TB's total effect was mediated by 50% (95% CI, 35-82%) through hospital LOS. CONCLUSIONS: TB patients had a 24% higher risk of developing depression. TB's effect was mediated substantially by hospital LOS, requiring further study. Depression screening among TB patients is warranted.

Post-tuberculosis airway disease: A population-based cohort study of people immigrating to British Columbia, Canada, 1985-2015.

BACKGROUND: Current epidemiological evidence of post-TB airway disease is largely cross-sectional and derived from high-TB-incidence settings. We present the first cohort study of post-TB airway disease in a low-TB-incidence setting. AIMS: (1) analyze the risk of airway disease by respiratory TB, (2) assess potential unmeasured confounding between TB and airway disease, and (3) investigate TB effect measure modification. METHODS: A population-based cohort study using healthcare claims data for immigrants to British Columbia (BC), Canada, 1985-2015. Airway disease included chronic airway obstruction, asthma, bronchitis, bronchiolitis, and emphysema. Respiratory TB was defined from TB registry data. Cox proportional hazards (PH) regressions were used to analyze time-to-airway disease by respiratory TB. Sensitivity analyses included varying definitions of TB and airway disease. Potential unmeasured confounding by smoking was evaluated by E-value and hybrid least absolute shrinkage and selection operator (LASSO)-high-dimensional propensity score (hdPS). FINDINGS: In our cohort (N = 1 005 328; nTB=1141) there were 116 840 incident cases of airway disease during our 30-year study period (10.43 per 1,000 person-years of follow-up), with cumulative incidence of 42·5% among respiratory TB patients compared with 11·6% among non-TB controls. The covariate-adjusted hazard ratio (aHR) for airway disease by respiratory TB was 2·08 (95% CI: 1·91-2·28) with E-value=3·58. The LASSO-hdPS analysis produced aHR=2·26 (95% CI: 2·07-2·47). INTERPRETATION: A twofold higher risk of airway disease was observed among immigrants diagnosed with respiratory TB, compared with non-TB controls, in a low-TB-incidence setting. Unmeasured confounding is unlikely to explain this relationship. Models of post-TB care are needed. FUNDING: Canadian Institutes of Health Research.

Effectiveness and cost-effectiveness of a health systems intervention for latent tuberculosis infection management (ACT4): a cluster-randomised trial.

BACKGROUND: Reaching the UN General Assembly High-Level Meeting on Tuberculosis target of providing tuberculosis preventive treatment to at least 30 million people by 2022, including 4 million children under the age of 5 years and 20 million other household contacts, will require major efforts to strengthen health systems. The aim of this study was to evaluate the effectiveness and cost-effectiveness of a health systems intervention to strengthen management for latent tuberculosis infection (LTBI) in household contacts of confirmed tuberculosis cases. METHODS: ACT4 was a cluster-randomised, open-label trial involving 24 health facilities in Benin, Canada, Ghana, Indonesia, and Vietnam randomly assigned to either a three-phase intervention (LTBI programme evaluation, local decision making, and strengthening activities) or control (standard LTBI care). Tuberculin and isoniazid were provided to control and intervention sites if not routinely available. Randomisation was stratified by country and restricted to ensure balance of index patients with tuberculosis by arm and country. The primary outcome was the number of household contacts who initiated tuberculosis preventive treatment at each health facility within 4 months of the diagnosis of the index case, recorded in the first or last 6 months of our 20-month study. To ease interpretation, this number was standardised per 100 newly diagnosed index patients with tuberculosis. Analysis was by intention to treat. Masking of staff at the coordinating centre and sites was not possible; however, those analysing data were masked to assignment of intervention or control. An economic analysis of the intervention was done in parallel with the trial. ACT4 is registered at ClinicalTrials.gov, NCT02810678. FINDINGS: The study was done between Aug 1, 2016, and March 31, 2019. During the first 6 months of the study the crude overall proportion of household contacts initiating tuberculosis preventive treatment out of those eligible at intervention sites was 0·21. After the implementation of programme strengthening activities, the proportion initiating tuberculosis preventive treatment increased to 0·35. Overall, the number of household contacts initiating tuberculosis preventive treatment per 100 index patients with tuberculosis increased between study phases in intervention sites (adjusted rate difference 60, 95% CI 4 to 116), while control sites showed no statistically significant change (-12, -33 to 10). There was a difference in rate differences of 72 (95% CI 10 to 134) contacts per 100 index patients with tuberculosis initiating preventive treatment associated with the intervention. The total cost for the intervention, plus LTBI clinical care per additional contact initiating treatment was estimated to be CA$1348 (range 724 to 9708). INTERPRETATION: A strategy of standardised evaluation, local decision making, and implementation of health systems strengthening activities can provide a mechanism for scale-up of tuberculosis prevention, particularly in low-income and middle-income countries. FUNDING: Canadian Institutes of Health Research.

Risk of active tuberculosis in migrants diagnosed with cancer: a retrospective cohort study in British Columbia, Canada.

OBJECTIVES: To describe the association between types of cancer and active tuberculosis (TB) risk in migrants. Additionally, in order to better inform latent TB infection (LTBI) screening protocols, we assessed proportion of active TB cases potentially preventable through LTBI screening and treatment in migrants with cancer. DESIGN: Population-based, retrospective cohort study. SETTING: British Columbia (BC), Canada. PARTICIPANTS: 1 000 764 individuals who immigrated to Canada from 1985 to 2012 and established residency in BC at any point up to 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: Using linked health administrative databases and disease registries, data on demographics, comorbidities, cancer type, TB exposure and active TB diagnosis were extracted. Primary outcomes included: time to first active TB diagnoses, and risks of active TB following cancer diagnoses which were estimated using Cox extended hazard regression models. Potentially preventable TB was defined as active TB diagnosed >6 months postcancer diagnoses. RESULTS: Active TB risk was increased in migrants with cancer ((HR (95% CI)) 2.5 (2.0 to 3.1)), after adjustment for age, sex, TB incidence in country of origin, immigration classification, contact status and comorbidities. Highest risk was observed with lung cancer (HR 11.2 (7.4 to 16.9)) and sarcoma (HR 8.1 (3.3 to 19.5)), followed by leukaemia (HR 5.6 (3.1 to 10.2)), lymphoma (HR 4.9 (2.7 to 8.7)) and gastrointestinal cancers (HR 2.7 (1.7 to 4.4)). The majority (65.9%) of active TB cases were diagnosed >6 months postcancer diagnosis. CONCLUSION: Specific cancers increase active TB risk to varying degrees in the migrant population of BC, with approximately two-thirds of active TB cases identified as potentially preventable.

Latent Tuberculosis Therapy Outcomes in Dialysis Patients: A Retrospective Cohort.

RATIONALE & OBJECTIVES: Maintenance dialysis patients are at an increased risk for active tuberculosis (TB). In 2012, British Columbia, Canada, began systematically screening maintenance dialysis patients for latent TB infection (LTBI) and treating people with evidence of LTBI when appropriate. We examined LTBI treatment outcomes and compared treatment outcomes before and after rollout of the systematic screening program. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: The study comprised 365 people in British Columbia, Canada, initiating at least 90 days of dialysis from January 1, 2001, to May 31, 2017, and starting LTBI therapy: 290 (79.5%) people in the recent cohort and 75 (20.5%) in the historical cohort. People starting LTBI therapy from January 1, 2012, onward were classified as the recent cohort, whereas people starting LTBI therapy before January 1, 2012, were classified as the historical cohort. EXPOSURE: Systematic LTBI screening and therapy. OUTCOMES: Proportion of people who experience grade 3 to 5 adverse events (AEs) or any grade rash and end-of-treatment outcomes. ANALYTICAL APPROACH: Outcomes were reported using descriptive statistics. 2-sample test of proportions using χ2 distribution was used to test for statistical significance between the recent and historical cohorts. RESULTS: 298 (81.6%) people successfully completed LTBI therapy. The proportion of people experiencing a grade 3 to 4 AE or any grade rash was 21.1%. Most AEs were related to gastrointestinal events, general malaise, or pruritus that resulted in regimen changes. 2 (0.5%) people were hospitalized for AEs related to LTBI therapy. No significant difference was found between the recent and historical cohorts in all outcomes of interest. No grade 5 AEs (deaths) were attributed to LTBI therapy. LIMITATIONS: Retrospective data and generalizability outside low-TB-burden settings. CONCLUSIONS: Our findings suggest that a high proportion of people receiving maintenance dialysis can complete LTBI therapy. The rate of grade 3 to 4 AEs was high and associated with frequent medication changes during therapy. LTBI therapy in maintenance dialysis may be safe but requires close monitoring.

Safety and Efficacy of Rifampin or Isoniazid Among People With Mycobacterium tuberculosis Infection and Living With Human Immunodeficiency Virus or Other Health Conditions: Post Hoc Analysis of 2 Randomized Trials.

BACKGROUND: The safety and efficacy of rifampin among people living with human immunodeficiency virus (PLHIV) or other health conditions is uncertain. We assessed completion, safety, and efficacy of 4 months of rifampin vs 9 months of isoniazid among PLHIV or other health conditions. METHODS: We conducted post hoc analysis of 2 randomized trials that included 6859 adult participants with Mycobacterium tuberculosis infection. Participants were randomized 1:1 to 10 mg/kg/d rifampin or 5 mg/kg/d isoniazid. We report completion, drug-related adverse events (AE), and active tuberculosis incidence among people living with HIV; with renal failure or receiving immunosuppressants; using drugs or with hepatitis; with diabetes mellitus; consuming >1 alcoholic drink per week or current/former smokers; and with no health condition. RESULTS: Overall, 270 (3.9%) people were living with HIV (135 receiving antiretroviral therapy), 2012 (29.3%) had another health condition, and 4577 (66.8%) had no condition. Rifampin was more often or similarly completed to isoniazid in all populations. AEs were less common with rifampin than isoniazid among PLHIV (risk difference, -2.1%; 95% confidence interval [CI], -5.9 to 1.6). This was consistent for others except people with renal failure or on immunosuppressants (2.1%; 95% CI, -7.2 to 11.3). Tuberculosis incidence was similar among people receiving rifampin or isoniazid. Among participants receiving rifampin living with HIV, incidence was comparable to those with no health condition (rate difference, 4.1 per 1000 person-years; 95% CI, -6.4 to 14.7). CONCLUSIONS: Rifampin appears to be safe and as effective as isoniazid across many populations with health conditions, including HIV. CLINICAL TRIALS REGISTRATION: NCT00170209; NCT00931736.

Post-tuberculosis mortality risk among immigrants to British Columbia, Canada, 1985-2015: a time-dependent Cox regression analysis of linked immigration, public health, and vital statistics data.

OBJECTIVE: To compare non-tuberculosis (non-TB)-cause mortality risk overall and cause-specific mortality risks within the immigrant population of British Columbia (BC) with and without TB diagnosis through time-dependent Cox regressions. METHODS: All people immigrating to BC during 1985-2015 (N = 1,030,873) were included with n = 2435 TB patients, and the remaining as non-TB controls. Outcomes were time-to-mortality for all non-TB causes, respiratory diseases, cardiovascular diseases, cancers, and injuries/poisonings, and were ascertained using ICD-coded vital statistics data. Cox regressions were used, with a time-varying exposure variable for TB diagnosis. RESULTS: The non-TB-cause mortality hazard ratio (HR) was 4.01 (95% CI 3.57-4.51) with covariate-adjusted HR of 1.69 (95% CI 1.50-1.91). Cause-specific covariate-adjusted mortality risk was elevated for respiratory diseases (aHR = 2.96; 95% CI 2.18-4.00), cardiovascular diseases (aHR = 1.63; 95% CI 1.32-2.02), cancers (aHR = 1.40; 95% CI 1.13-1.75), and injuries/poisonings (aHR = 1.85; 95% CI 1.25-2.72). CONCLUSIONS: In any given year, if an immigrant to BC was diagnosed with TB, their risk of non-TB mortality was 69% higher than if they were not diagnosed with TB. Healthcare providers should consider multiple potential threats to the long-term health of TB patients during and after TB treatment. TB guidelines in high-income settings should address TB survivor health.

RéSUMé: OBJECTIF: Au moyen de régressions de Cox avec une covariable temporalisée, comparer le risque global de mortalité non due à la tuberculose et les risques de mortalité par cause au sein de la population immigrante de la Colombie-Britannique (C.-B.) avec et sans diagnostic de tuberculose. MéTHODE: Toutes les personnes ayant immigré en C.-B. entre 1985 et 2015 (N = 1 030 873) ont été incluses, dont n = 2 435 patients tuberculeux, le reste étant des témoins non tuberculeux. Nos résultats incluaient le temps jusqu'à la mortalité de toute cause autre que la tuberculose, soit les maladies respiratoires, les maladies cardiovasculaires, les cancers et les blessures/empoisonnements, déterminé à l'aide des statistiques de l'état civil codées selon la CIM. Nous avons utilisé des régressions de Cox avec une variable d'exposition temporalisée pour le diagnostic de tuberculose. RéSULTATS: Le coefficient de danger (CD) de mortalité non due à la tuberculose était de 4,01 (IC de 95 % : 3,57-4,51) avec un CD ajusté selon la covariable de 1,69 (IC de 95 % : 1,50-1,91). Le risque de mortalité par cause ajusté selon la covariable était élevé pour : les maladies respiratoires (CDa = 2,96; IC de 95 % : 2,18-4,00), les maladies cardiovasculaires (CDa = 1,63; IC de 95 % : 1,32-2,02), les cancers (CDa = 1,40; IC de 95 % : 1,13-1,75) et les blessures/empoisonnements (CDa = 1,85; IC de 95 % : 1,25-2,72). CONCLUSIONS: Chaque année, si une personne ayant immigré en C.-B. avait un diagnostic de tuberculose, son risque de mortalité non due à la tuberculose était supérieur de 69 % à celui d'une personne sans diagnostic de tuberculose. Les professionnels de santé devraient tenir compte des multiples menaces possibles à la santé à long terme de leurs patients tuberculeux pendant et après le traitement de la tuberculose. Les lignes directrices sur la tuberculose dans les milieux à revenu élevé devraient tenir compte de la santé des survivants de la tuberculose.

Using Whole-genome Sequencing to Determine the Timing of Secondary Tuberculosis in British Columbia, Canada.

Combined with epidemiological data, whole-genome sequencing (WGS) can help better resolve individual tuberculosis (TB) transmission events to a degree not possible with traditional genotyping. We combine WGS data with patient-level data to calculate the timing of secondary TB among contacts of people diagnosed with active TB in British Columbia, Canada.

Ethical challenges in the treatment of non-refugee migrants with tuberculosis in Canada.

While attention to the ethical issues that migrants face in accessing tuberculosis care has increased in the last few years, most of the attention has focused on challenges that refugees face when emigrating. Less attention has been given to ethical challenges that arise in the context of providing tuberculosis treatment and care to non-refugee migrants in high-income countries (HIC), particularly those that do not face immediate danger or violence. In this paper, we analyze some of the ethical challenges associated with treating migrants with tuberculosis in the Canadian context. In particular, we will discuss (i) inter- and intra-jurisdictional issues that challenge quotidian public health governance structures, and (ii) the ethical imperative for the Canadian government and its provinces to clearly differentiate access to healthcare from a person's immigration status to help overcome power imbalances that may exist between public health workers and their clients. The arguments presented herein could potentially apply to other HIC with some form of universal health coverage.

Effectiveness of Latent TB Screening and Treatment in People Initiating Dialysis in British Columbia, Canada.

BACKGROUND: People undergoing chronic dialysis are at an increased risk of active tuberculosis (TB). In 2012, the Canadian province of British Columbia began systematically screening people initiating dialysis for latent TB using interferon-gamma release assay (IGRA), and treating when appropriate. OBJECTIVE: The objective of this study was to compare active TB rate in people who initiated dialysis and were screened using an IGRA compared with those not screened during the same period. DESIGN: Retrospective cohort study. SETTING: British Columbia (BC), a Canadian province of 5.0 million people with an active TB incidence of 5.1 per 100 000 population. PARTICIPANTS: All people in BC who initiated at least 90 days of dialysis between January 2012 and May 2017 were included in the study. People were excluded if they were <18 years of age or had a prior history of active TB diagnosis or treatment for latent TB. METHODS: A retrospective cohort was created of British Columbians who initiated dialysis between 2012 and 2017. Individuals were stratified into a screened and nonscreened group. Multivariable Cox regression was used to determine the association between latent TB screening and the development of active TB. The primary outcome was incident active TB, either microbiologically confirmed or clinically diagnosed. RESULTS: Of the 3190 people included in the study, 1790 (56.1%) were screened, of which 152 (8.5%) initiated latent TB treatment postscreening. During follow-up, incident active TB was diagnosed in 6 (0.3%) of the 1790 people screened, compared with 11 (0.8%) of the 1400 people who received no screening. In multivariable analysis, latent TB screening and treatment was associated with a significant reduction in the rate of active TB (adjusted hazard ratio = 0.3, 95% confidence interval = 0.1-0.8; P < .01). LIMITATIONS: This was an observational retrospective study and the potential for unmeasured confounding should be carefully assessed. CONCLUSIONS: These findings suggest that systematically screening and treating people initiating dialysis can significantly decrease the rate of active TB in this high-risk population. Given the importance of screening high-risk groups, the results from this analysis could inform scale-up of TB screening in dialysis programs in other low incidence regions. Trial registration is not applicable as this was a retrospective cohort analysis and not a randomized trial.

CONTEXTE: Les patients sous dialyse chronique sont plus susceptibles de développer une tuberculose (TB) active. En 2012, la Colombie-Britannique (province canadienne) a entrepris de dépister systématiquement la TB latente chez les patients qui amorcent un traitement de dialyse. Le dépistage s'effectue à l'aide du test sanguin de libération d'interféron gamma (test IGRA­Interferon Gamma Release Assay) et les patients sont traités lorsque nécessaire. OBJECTIF: L'objectif de l'étude était de comparer le taux de TB active chez les patients dépistés par le test IGRA à celui des individus non testés au cours de la même période. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: L'étude s'est tenue en Colombie-Britannique, une province canadienne de cinq millions d'habitants dont l'incidence de TB active est de 5,1 cas pour 100 000 habitants. PARTICIPANTS: Ont été inclus tous les Britanno-Colombiens ayant amorcé une dialyse de plus de 90 jours entre janvier 2012 et mai 2017. Les mineurs et les individus avec des antécédents de TB active ou ayant déjà été traités pour une TB latente ont été exclus. MÉTHODOLOGIE: Une étude de cohorte rétrospective a été menée auprès des Britanno-Colombiens ayant amorcé une dialyse entre 2012 et 2017. Les individus ont été divisés en deux groupes: un groupe dépisté et un groupe non dépisté. Une régression de Cox à variables multiples a servi à établir l'association entre une TB latente et le développement d'une TB active. Le principal résultat d'intérêt était une TB active confirmée par analyse microbiologique ou diagnostiquée cliniquement. RÉSULTATS: Des 3 190 individus retenus pour l'étude, 1 790 (56,1 %) ont été testés et de ceux-ci, 152 (8,5 %) ont été traités pour une TB latente après l'examen. Pendant le suivi, parmi les 1 790 individus dépistés, 6 patients (0,3 %) ont reçu un diagnostic de TB active comparativement à onze (0,8 %) parmi les 1400 qui n'avaient pas été examinés. Dans l'analyse multivariée, le traitement et le dépistage de la TB latente ont été associés à une réduction significative du taux de TB active (aHR 0,3; IC 95%: 0,1 à 0,8; p <0,01). LIMITES: Il s'agit d'une étude observationnelle rétrospective et le risque de confusion devrait être rigoureusement évalué. CONCLUSION: Ces résultats suggèrent que le taux de TB active chez les patients dialysés pourrait être réduit significativement par le dépistage et le traitement systématique des individus qui entreprennent un traitement de dialyse. Vu l'importance du dépistage des populations à haut risque, les résultats de cette étude sont susceptibles d'éclairer l'augmentation du dépistage de la TB au sein des programmes de dialyse dans d'autres régions de faible incidence.