James Cameron Johnston

Background: People receiving immunosuppressive medications are at increased risk of tuberculosis. Tuberculosis preventive treatment (TPT) can reduce risk; however, its safety among these populations is uncertain. We conducted a meta-analysis to evaluate adverse events (AEs) associated with TPT among people receiving or about to initiate immunosuppressive medications. Methods: We searched Medline, Cochrane, Health Star, and Embase (1952–1 May 2025), for studies reporting AEs during TPT among people receiving or about to initiate immunosuppressive medications. We used random-effects generalized linear mixed models with Hartung–Knapp 95% confidence intervals (CIs) to estimate our primary outcome: pooled proportion of AE-related discontinuation, stratified by TPT regimen. Results: We included 27 studies (3184 participants). Populations included biologics/steroids recipients and solid organ/hematopoietic transplant candidates/recipients. For the primary outcome (25 studies, 2802 participants), TPT regimens included 6- to 12-month mono-isoniazid regimens (1511 participants), 4-month mono-rifamycin regimens (228 participants), 3-month isoniazid-rifamycin combination regimens (990 participants), and 6- to 9-month fluoroquinolone-based regimens (73 participants). Only mono-isoniazid regimens were provided while receiving immunosuppressive medications. Pooled AE-related discontinuation was 5.3% (95% CI, 3.1%–8.9%; I2 = 65.4%) for mono-isoniazid regimens, 4.4% (95% CI, .1%–75.4%; I2 = 86.3%) for mono-rifamycin regimens, 2.0% (1.0%–4.1%; I2 = 0.0%) for isoniazid-rifamycin combination regimens, and 6.9% (95% CI, 0–92.3%; I2 = 65.4%) for fluoroquinolone-based regimens. Proportions were similar when stratified by biologics/steroids and transplant populations. Conclusions: Overall, AE-related TPT discontinuation was similar to that in the broader TPT literature. AE-related discontinuation of TPT was lowest with rifamycin-containing regimens, but these were only provided prior to initiating immunosuppressive medications. Data on the safety of non-isoniazid regimens among people receiving immunosuppressive medications are needed.

We report on 2 patients with drug-resistant tuberculous meningitis diagnosed and treated in a high-resource, low-incidence setting. Both patients were treated with multidrug regimens including bedaquiline, a nitroimidazole, cycloserine, and linezolid. Drug selection was informed by molecular diagnostics, susceptibility testing, and pharmacokinetic and clinical data. Adverse events included suicidal ideation, cytopenias, ototoxicity, and neuropathy. There was discordance between phenotypic (susceptible) and genotypic (resistant) drug susceptibility testing for rifampin. After treatment, both patients had excellent clinical outcomes, with at least 12 months of post-treatment follow-up. These clinical cases provide an opportunity to explore the role of molecular diagnostics in the diagnosis of drug-resistant tuberculous meningitis, drug regimen selection in the era of novel oral regimens, and clinical decision-making in the setting of discordance between genotypic and phenotypic drug susceptibility testing.

Background: High-dose rifampicin could potentially shorten tuberculosis preventive therapy (TPT) and improve outcomes. We aimed to characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT among individuals with tuberculosis infection. Methods: Intensive and sparse pharmacokinetic substudies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared 2 months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with 4 months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥ 10 years. Venous blood samples were collected after 4 weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling in NONMEM. Results: Among 1368 trial participants, 440 were included in model development (51 intensive and 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A 1-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. All disposition parameters were allometrically scaled using fat-free mass. Country-specific differences, particularly variation in drug formulation, were associated with lower bioavailability in Canada {−21.8% (95% confidence interval [CI] −27.9 to −18.0%)} and Vietnam (−12.3% [95% CI −17.7 to −7.9%]) compared with Indonesia. The 24-hour area under the concentration–time curve increased more than proportionally with dose and was higher across treatment arms in Indonesia, followed by Vietnam and Canada. Conclusions: High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to nonlinear clearance at higher doses. Substantial between-country variability in exposure was observed, which may have been due to multiple factors, including differences in country-specific formulations, fat-free mass, and unmeasured confounders.

Background: Treatment-related adverse events are one of the leading barriers to tuberculosis treatment completion but have not been the focus of late-phase clinical trials. We performed a scoping review to identify interventions to improve the safety and tolerability of rifampin-susceptible tuberculosis. Our objective was to determine what interventions have been evaluated to prevent or manage adverse events, as well as what research is underway. Methods and findings: We searched Embase, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from 1970 to December 2024 using a broad set of terms regarding adverse events, as well as citation searches to identify additional studies in topic areas that were not well-represented in the initial title search. To identify research in progress we searched Clintrials.gov, Cochrane reviews, and International Clinical Trials Registry Platform for trials reported to be active between January 2015 to April 2025. Of 7314 titles reviewed, 119 papers were available and eligible for this scoping review: 37 (31%) evaluated changes in the tuberculosis treatment regimen, 55 (46%) evaluated other interventions to prevent adverse events, and 27 (23%) evaluated treatment of adverse events. Only 7 studies reported enrollment of children < 12 years old. Of the 49 clinical trials, 20 (41%) had sample sizes < 50 participants/arm. Notable gaps in research in this field: uncertainty about the safety of pyrazinamide, lack of research on prevention and management of nausea/vomiting, uncertainty about the impact of hepatoprotectants, and lack of inclusion of children. Of the 8 study proposals that appear to be in progress, five were for a single topic: isoniazid dosing based on N-actyltransferase-2 status. Conclusions: There has been considerable research on improving the safety and tolerability of tuberculosis treatment, but its impact is limited by under-powered studies, the lack of inclusion of key subgroups, and important gaps in the research portfolio (uncertainties about the safety of pyrazinamide and the efficacy of hepatoprotectants, lack of research on ways to manage and prevent treatment-related nausea). It is concerning that the research pipeline for interventions to improve safety and tolerability appears to be quite limited Our review has identified promising interventions that may make treatment better tolerated, and hence, more effective.

Routine screening of new immigrants for tuberculosis (TB) infection is being adopted or considered in high-income countries with a low burden of TB disease

People migrating to Canada are disproportionately impacted by tuberculosis (TB) disease. Prior to arrival, Immigration, Refugees and Citizenship Canada (IR

Tuberculosis (TB) is an infectious disease closely intertwined with stigma, discrimination, and the social determinants of health. Communities of people affected by TB are experts in their care pathways, but the TB field continues to fall short of meaningfully engaging communities in TB research. This is a missed opportunity to improve the quality, relevance, person-centeredness, positive impact, and sustainability of TB research outputs. We acknowledge the important progress that has been made to date regarding community engagement in TB, but emphasize persisting barriers to meaningful engagement, and the urgent need for updated and comprehensive TB-specific standards for such engagement in research. We highlight that core components of these standards should include the mobilisation of communities affected by TB, bilateral training in community engagement (for researchers and communities), as well as ensuring appropriate remuneration, representation of priority groups, and the use of non-stigmatising language in the engagement process. In addition, to meaningfully incorporate the experiences and expertise of communities affected by TB, their engagement in the research process should occur as early as possible, ideally before research priorities and directions are set, and the scope of the research should encompass questions and outputs relevant to the community. Further, knowledge-sharing between researchers and the community should be ensured, not only of the research outputs but also regarding the engagement process itself, so that lessons learned can be carried forward. Lastly, the sustainability of community engagement processes (whether within institutions or projects) should be ensured, including through adequate funding for such engagement and the training, community mobilisation and relationship-building that this requires.

Background: Recent studies suggest that triple-dose rifampin (TDR; ≥30 mg/kg/d) may be unsafe. We updated a systematic review to investigate the safety and efficacy of TDR. Methods: We searched Embase, MEDLINE, Cochrane CENTRAL, Cochrane Database for Systematic Reviews, and clinicaltrials.gov for randomized, controlled trials from 1 January 1965 to 10 February 2024 that compared standard-dose rifampin (SDR) with TDR and/or double-dose rifampin (DDR) in human tuberculosis treatment. The primary outcome was pooled incidence rate ratio (IRR) of severe adverse events (SevAEs) between participants who received TDR and those who received SDR. Pooled relative risk (RR) of death was a key secondary outcome. Meta-analysis was performed using the inverse variance method. Heterogeneity was assessed using I2, and bias was assessed using Cochrane Risk of Bias 2. The protocol was prospectively registered (osf.io/kfn5a). Results: Of the 11 315 articles identified, 17 met inclusion criteria, enrolling 2313 SDR participants (17 studies), 2238 receiving DDR (12 studies), and 1199 receiving TDR (11 studies). Six studies had a high risk of bias. There was an increase in pooled SevAEs among participants who received TDR compared with those who received SDR (IRR, 1.48; 95% confidence interval [CI], 1.12–1.96; I2, 23%), driven by hepatic events (IRR, 1.96; 95% CI, 1.21–3.18). Death did not differ between participants who received TDR and SDR (RR, 1.19; 95% CI, .71–1.99). One limitation is that only 2 included studies were blinded. Conclusions: Regimens that used TDR were associated with an increase in SevAEs, raising concerns regarding safety of TDR regimens.

Background: Tuberculosis (TB) incidence remains disproportionately high in people who migrate to Canada and other countries with low TB incidence, but systematic TB screening and prevention in migrants are often cost-prohibitive for TB programs. We aimed to develop and validate a TB risk-prediction model to inform TB screening decisions in foreign-born permanent residents of Canada. Methods: We developed and validated a proportional baselines landmark supermodel for TB risk prediction using health administrative data from British Columbia and Ontario, 2 distinct provincial healthcare systems in Canada. Demographic (age, sex, refugee status, year of entry, TB incidence in country of origin), TB exposure, and medical (human immunodeficiency virus, kidney disease, diabetes, solid organ transplantation, cancer) covariates were used to derive and test models in British Columbia; 1 model was chosen for external validation in the Ontario cohort. The model's ability to predict 2- and 5-year TB risk in the Ontario cohort was assessed using discrimination and calibration statistics. Results: The study included 715 423 individuals (including 1407 people with TB disease) in the British Columbia derivation cohort and 958 131 individuals (including 1361 people with TB disease) in the Ontario validation cohort. The 2- and 5-year concordance statistic in the validation cohort was 0.77 (95% confidence interval [CI]: .75 to .78) and 0.77 (95% CI: .76 to .78), respectively. Calibration-in-the-large values were 0.14 (95% CI: .08 to .21) and −0.05 (95% CI: −.12 to .02) in 2- and 5-year prediction windows. Conclusions: This prediction model, available online at https://tb-migrate.com, may improve TB risk stratification in people who migrate to low-incidence countries and may help inform TB screening policy and guidelines.

In the Perspective, William Burman and colleagues advocate improving the safety and acceptability of treatment, rather than treatment-shortening, of rifampin-susceptible tuberculosis.