Jonathon R. Campbell

Screening immigrants for latent tuberculosis: Do we have the resources?

The recently released seventh edition of the Canadian tuberculosis standards was extensively revised to reflect new information on control of tuberculosis in low-incidence countries.[1][1] The new edition comprehensively addresses screening for latent tuberculosis infection in migrant populations,

Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis.

BACKGROUND Therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes, but there is little evidence to guide TDM in clinical practice. DESIGN We performed a systematic review and meta-analysis to summarise existing literature on TDM in first-line drugs. RESULTS We identified 41 studies that reported 2 h post-dose drug concentrations (C2h) for first-line drugs and 12 studies that reported clinical outcomes. We pooled data by study quality, design, region, dosing modality and patient characteristics. The pooled proportion of subjects with low isoniazid C2h was 0.43 (95%CI 0.32-0.55), 0.67 (95%CI 0.60-0.74) had low rifampicin C2h, 0.27 (95%CI 0.17-0.38) had low ethambutol C2h, and 0.12 (95%CI 0.07-0.19) had low pyrazinamide C2h. Patients with diabetes had a non-significant increase in the proportion of subjects with low C2h levels across all four drugs. Only three of 12 studies that examined clinical outcomes demonstrated an association between low C2h and unsuccessful treatment outcomes. CONCLUSION Across a wide variety of studies, a high proportion of patients undergoing first-line anti-tuberculosis treatment had 2 h drug concentrations below the accepted normal threshold. These findings point to a discrepancy between accepted 2 h TDM thresholds and TB drug dosing recommendations.

Effect of Intermittency on Treatment Outcomes in Pulmonary Tuberculosis: An Updated Systematic Review and Metaanalysis

Background Intermittent regimens offer operational advantages in tuberculosis treatment, but their efficacy has been questioned. We updated a systematic review and metaanalysis to examine the efficacy of different intermittent dosing schedules in first-line pulmonary tuberculosis therapy. Methods An updated search included randomized control trials (RCTs) that reported on first-line pulmonary tuberculosis therapy between June 2008 and March 2016. We pooled proportions of failure, relapse, and acquired drug resistance (ADR) for 4 dosing schedules: daily throughout, thrice weekly throughout, daily (intensive phase) then thrice weekly (continuation phase), and daily (intensive phase) then twice weekly (continuation phase). Metaregression was performed using a negative binomial regression model. Results After screening 5874 citations, 7 RCTs with 10 arms were added for a total of 56 RCTs with 110 arms. The pooled proportion of relapse was significantly higher in arms with thrice weekly therapy throughout (6.8; 95% confidence interval [CI], 3.8-9.9) and twice weekly therapy in the continuation phase (7.3; 95% CI, 3.5-11.1) when compared with daily therapy (2.5; 95% CI, 1.8-3.2; P < .01). Metaregression revealed higher rates of relapse (2.2; 95% CI, 1.2-4.0), failure (3.7; 95% CI, 1.1-12.6), and ADR (10.0; 95% CI, 2.1-46.7) in arms with thrice weekly throughout and higher rates of failure (3.0; 95% CI, 1.0-8.8) with twice weekly in the continuation phase when compared with daily therapy. Conclusion Thrice weekly dosing throughout therapy, and twice weekly dosing in the continuation phase appear to have worse microbiological treatment outcomes when compared with daily therapy.

Demographic predictors of active tuberculosis in people migrating to British Columbia, Canada: a retrospective cohort study

BACKGROUND: Canadian tuberculosis (TB) guidelines recommend targeting postlanding screening for and treatment of latent tuberculosis infection (LTBI) in people migrating to Canada who are at increased risk for TB reactivation. Our objectives were to calculate robust longitudinal estimates of TB incidence in a cohort of people migrating to British Columbia, Canada, over a 29-year period, and to identify groups at highest risk of developing TB based on demographic characteristics at time of landing. METHODS: We included all individuals (n = 1 080 908) who became permanent residents of Canada between Jan. 1, 1985, and Dec. 31, 2012, and were resident in BC at any time between 1985 and 2013. Multiple administrative databases were linked to the provincial TB registry. We used recursive partitioning models to identify populations with high TB yield. RESULTS: Active TB was diagnosed in 2814 individuals (incidence rate 24.2/100 000 person-years). Demographic factors (live-in caregiver, family, refugee immigration classes; higher TB incidence in country of birth; and older age) were strong predictors of TB incidence in BC, with elevated rates continuing many years after entry into the cohort. Recursive partitioning identified refugees 18–64 years of age from countries with a TB incidence greater than 224/100 000 population as a high-yield group, with 1% developing TB within the first 10 years. INTERPRETATION: These findings support recommendations in Canadian guidelines to target postlanding screening for and treatment of LTBI in adult refugees from high-incidence countries. Because high-yield populations can be identified at entry via demographic data, screening at this point may be practical and high-impact, particularly if the LTBI care cascade can be optimized.

Cost-effectiveness of post-landing latent tuberculosis infection control strategies in new migrants to Canada

Background The majority of tuberculosis in migrants to Canada occurs due to reactivation of latent TB infection. Risk of tuberculosis in those with latent tuberculosis infection can be significantly reduced with treatment. Presently, only 2.4% of new migrants are flagged for post-landing surveillance, which may include latent tuberculosis infection screening; no other migrants receive routine latent tuberculosis infection screening. To aid in reducing the tuberculosis burden in new migrants to Canada, we determined the cost-effectiveness of using different latent tuberculosis infection interventions in migrants under post-arrival surveillance and in all new migrants. Methods A discrete event simulation model was developed that focused on a Canadian permanent resident cohort after arrival in Canada, utilizing a ten-year time horizon, healthcare system perspective, and 1.5% discount rate. Latent tuberculosis infection interventions were evaluated in the population under surveillance (N = 6100) and the total cohort (N = 260,600). In all evaluations, six different screening and treatment combinations were compared to the base case of tuberculin skin test screening followed by isoniazid treatment only in the population under surveillance. Quality adjusted life years, incident tuberculosis cases, and costs were recorded for each intervention and incremental cost-effectiveness ratios were calculated in relation to the base case. Results In the population under surveillance (N = 6100), using an interferon-gamma release assay followed by rifampin was dominant compared to the base case, preventing 4.90 cases of tuberculosis, a 4.9% reduction, adding 4.0 quality adjusted life years, and saving

Latent tuberculosis diagnostic tests to predict longitudinal tuberculosis during dialysis: a meta-analysis.

353,013 over the ensuing ten-years. Latent tuberculosis infection screening in the total population (N = 260,600) was not cost-effective when compared to the base case, however could potentially prevent 21.8% of incident tuberculosis cases. Conclusions Screening new migrants under surveillance with an interferon-gamma release assay and treating with rifampin is cost saving, but will not significantly impact TB incidence. Universal latent tuberculosis infection screening and treatment is cost-prohibitive. Research into using risk factors to target screening post-landing may provide alternate solutions.

Predicting tuberculosis risk in the foreign-born population of British Columbia, Canada: study protocol for a retrospective population-based cohort study

SETTING Tuberculosis (TB) rates in dialysis patients are more than 10 times greater than in the general population. Recent recommendations advise the use of interferon-gamma release assays (IGRAs) over the tuberculin skin test (TST) to aid in the diagnosis of latent tuberculous infection (LTBI); however, their longitudinal predictive ability for TB development has not been assessed. OBJECTIVE To determine whether the TST or IGRA are able to predict longitudinal TB development in dialysis patients. DESIGN We performed a systematic review to determine the longitudinal risk of TB in dialysis patients. Random-effects meta-analysis was used to determine the incidence rate ratio (IRR) of longitudinal TB development and the predictive value of such tests. RESULTS Eight studies were included. An IRR of 2.59 (95%CI 1.20-5.57) for longitudinal TB was seen in patients with a TST ⩾ 10 mm compared to patients with a TST < 10 mm. The positive predictive value (PPV) of a TST ⩾ 10 mm was 11.93% and the negative predictive value was 94.03%. We were unable to analyse the studies that used IGRAs, as only one study had TB events. CONCLUSION A TST with a 10 mm cut-off point appears to offer the capability to distinguish long-term risk of TB, with a modest PPV. The predictive value of IGRAs could not be quantified.

Comorbidities and treatment outcomes in multidrug resistant tuberculosis: a systematic review and meta-analysis

Introduction Improved understanding of risk factors for developing active tuberculosis (TB) will better inform decisions about diagnostic testing and treatment for latent TB infection (LTBI) in migrant populations in low-incidence regions. We aim to examine TB risk factors among the foreign-born population in British Columbia (BC), Canada, and to create and validate a clinically relevant multivariate risk score to predict active TB. Methods and analysis This retrospective population-based cohort study will include all foreign-born individuals who acquired permanent resident status in Canada between 1 January 1985 and 31 December 2013 and acquired healthcare coverage in BC at any point during this period. Multiple administrative databases and disease registries will be linked, including a National Immigration Database, BC Provincial Health Insurance Registration, physician billings, hospitalisations, drugs dispensed from community pharmacies, vital statistics, HIV testing and notifications, cancer, chronic kidney disease and dialysis treatment, and all TB and LTBI testing and treatment data in BC. Extended proportional hazards regression will be used to estimate risk factors for TB and to create a prognostic TB risk score. Ethics and dissemination Ethical approval for this study has been obtained from the University of British Columbia Clinical Ethics Review Board. Once completed, study findings will be presented at conferences and published in peer-reviewed journals. An online TB risk score calculator will also be created.

Burden of non-adherence to latent tuberculosis infection drug therapy and the potential cost-effectiveness of adherence interventions in Canada: a simulation study

Little is known about the impact of comorbidities on multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) treatment outcomes. We aimed to examine the effect of human immunodeficiency virus (HIV), diabetes, chronic kidney disease (CKD), alcohol misuse, and smoking on MDR/XDRTB treatment outcomes. We searched MEDLINE, EMBASE, Cochrane Central Registrar and Cochrane Database of Systematic Reviews as per PRISMA guidelines. Eligible studies were identified and treatment outcome data were extracted. We performed a meta-analysis to generate a pooled relative risk (RR) for unsuccessful outcome in MDR/XDRTB treatment by co-morbidity. From 2457 studies identified, 48 reported on 18,257 participants, which were included in the final analysis. Median study population was 235 (range 60–1768). Pooled RR of unsuccessful outcome was higher in people living with HIV (RR = 1.41 [95%CI: 1.15–1.73]) and in people with alcohol misuse (RR = 1.45 [95%CI: 1.21–1.74]). Outcomes were similar in people with diabetes or in people that smoked. Data was insufficient to examine outcomes in exclusive XDRTB or CKD cohorts. In this systematic review and meta-analysis, alcohol misuse and HIV were associated with higher pooled OR of an unsuccessful outcome in MDR/XDRTB treatment. Further research is required to understand the role of comorbidities in driving unsuccessful treatment outcomes.

A Systematic Review on TST and IGRA Tests Used for Diagnosis of LTBI in Immigrants

Objective Pharmaceutical treatment of latent tuberculosis infection (LTBI) reduces the risk of progression to active tuberculosis (TB); however, poor adherence tempers the protective effect. We aimed to estimate the health burden of non-adherence, the maximum allowable cost of hypothetical new adherence interventions to be cost-effective and the potential value of existing adherence interventions for patients with low-risk LTBI in Canada. Design A microsimulation model of LTBI progression over 25 years. Setting General practice in Canada. Participants Individuals with LTBI who are initiating drug therapy. Interventions A hypothetical intervention with a range of effectiveness was evaluated. Existing drug adherence interventions including peer support, two-way text messaging support, enhanced adherence counselling and adherence incentives were also evaluated. Primary and secondary outcome measures Simulation outcomes included healthcare costs, TB incidence, TB deaths and quality-adjusted life years (QALYs). Base case results were interpreted against a willingness-to-pay threshold of