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BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

Digital technologies are increasingly harnessed to support treatment of persons with tuberculosis (TB). Since in-person directly observed treatment (DOT) can be resource intensive and challenging to implement, these technologies may have the potential to improve adherence and clinical outcomes. We reviewed the effect of these technologies on TB treatment adherence and patient outcomes.We searched several bibliographical databases for studies reporting the effect of digital interventions, including short message service (SMS), video-observed therapy (VOT) and medication monitors (MMs), to support treatment for active TB. Only studies with a control group and which reported effect estimates were included.Four trials showed no statistically significant effect on treatment completion when SMS was added to standard care. Two observational studies of VOT reported comparable treatment completion rates when compared with in-person DOT. MMs increased the probability of cure (RR 2.3, 95% CI 1.6-3.4) in one observational study, and one trial reported a statistically significant reduction in missed treatment doses relative to standard care (adjusted means ratio 0.58, 95% CI 0.42-0.79).Evidence of the effect of digital technologies to improve TB care remains limited. More studies of better quality are needed to determine how such technologies can enhance programme performance.

Background: We hypothesized that investments to improve the control of tuberculosis in selected high-incidence countries would prove to be cost saving for the United States by reducing the incidence of the disease among migrants. Methods: Using decision analysis, we estimated tuberculosis-related morbidity, mortality, and costs among legal immigrants and refugees, undocumented migrants, and temporary visitors from Mexico after their entry into the United States. We assessed the current strategy of radiographic screening of legal immigrants plus current tuberculosis-control programs alone and with the addition of either U.S.-funded expansion of the strategy of directly observed treatment, short course (DOTS), in Mexico or tuberculin skin testing to screen legal immigrants from Mexico. We also examined tuberculosis-related outcomes among migrants from Haiti and the Dominican Republic using the same three strategies. Results: As compared with the current strategy, expanding the DOTS program in Mexico at a cost to the United States of 34.9 million dollars would result in 2591 fewer cases of tuberculosis in the United States, with 349 fewer deaths from the disease and net discounted savings of 108 million dollars over a 20-year period. Adding tuberculin skin testing to radiographic screening of legal immigrants from Mexico would result in 401 fewer cases of tuberculosis in the United States but would cost an additional 329 million dollars. Expansion of the DOTS program would remain cost saving even if the initial investment were doubled, if the United States paid for all antituberculosis drugs in Mexico, or if the decline in the incidence of tuberculosis in Mexico was less than projected. A 9.4 million dollars investment to expand the DOTS program in Haiti and the Dominican Republic would result in net U.S. savings of 20 million dollars over a 20-year period. Conclusions: U.S.-funded efforts to expand the DOTS program in Mexico, Haiti, and the Dominican Republic could reduce tuberculosis-related morbidity and mortality among migrants to the United States, producing net cost savings for the United States. [ABSTRACT FROM AUTHOR]

Abstract Background The development of a successful new tuberculosis (TB) vaccine would circumvent many limitations of current diagnostic and treatment practices. However, vaccine development is complex and costly. We aimed to assess the potential cost effectiveness of novel vaccines for TB control in a sub-Saharan African country - Zambia - relative to the existing strategy of directly observed treatment, short course (DOTS) and current level of bacille Calmette-Guérin (BCG) vaccination coverage. Methods We conducted a decision analysis model-based simulation from the societal perspective, with a 3% discount rate and all costs expressed in 2007 US dollars. Health outcomes and costs were projected over a 30-year period, for persons born in Zambia (population 11,478,000 in 2005) in year 1. Initial development costs for single vaccination and prime-boost strategies were prorated to the Zambian share (0.398%) of global BCG vaccine coverage for newborns. Main outcome measures were TB-related morbidity, mortality, and costs over a range of potential scenarios for vaccine efficacy. Results Relative to the status quo strategy, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to avert 932 TB cases and 422 TB-related deaths (prevention of 199 cases/100,000 vaccinated, and 90 deaths/100,000 vaccinated). This would result in estimated net savings of $3.6 million over 30 years for 468,073 Zambians born in year 1 of the simulation. The addition of a booster at age 10 results in estimated savings of $5.6 million compared to the status quo, averting 1,863 TB cases and 1,011 TB-related deaths (prevention of 398 cases/100,000 vaccinated, and of 216 deaths/100,000 vaccinated). With vaccination at birth alone, net savings would be realized within 1 year, whereas the prime-boost strategy would require an additional 5 years to realize savings, reflecting a greater initial development cost. Conclusions Investment in an improved TB vaccine is predicted to result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when added to existing control strategies. For a vaccine with waning efficacy, a prime-boost strategy is more cost-effective in the long term.

Abstract Background Implementation of the World Health Organization's DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives. Methods Using decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US$. Results Starting in 2003, DOTS expansion in Haiti is anticipated to cost $4.2 million and result in 63,080 fewer tuberculosis cases, 53,120 fewer tuberculosis deaths, and net societal savings of $131 million, over 20 years. Current government spending for tuberculosis is high, relative to the per capita income, and would be only slightly lower with DOTS. Societal savings would begin within 4 years, and would be substantial in all scenarios considered, including higher HIV seroprevalence or drug resistance, unchanged incidence following DOTS expansion, or doubling of initial and ongoing costs for DOTS expansion. Conclusion A modest investment for DOTS expansion in Haiti would provide considerable humanitarian benefit by reducing tuberculosis-related morbidity, mortality and costs for patients and their families. These benefits, together with projected minimal Haitian government savings, argue strongly for donor support for DOTS expansion.

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)., Competing Interests: Dr Fox reports receiving peer reviewed grants as PI for operating funds for other TB research projects from the Australian Medical Research Council (paid to institution), and receipt of a $50,000 in-kind donation of Rifapentine from Sanofi Inc, for a study outside of the scope of work of the current trial. Dr Menzies reports receiving peer reviewed grants as PI for operating funds for other TB research projects from the Canadian Institutes of Health Research, and from the TB Trials Consortium of Centres for Disease Control (USA) (paid to institution). Dr TA Nguyen reports receiving peer reviewed grants as PI for operating funds for other TB research projects from the Australian Medical Research Council (paid to institution), Dr Ruslami reports receiving honoraria from the Indonesian Pediatric Society. All other authors declare no competing interests relevant to this study. All other authors declare no relevant Conflicts of interest., (© 2024 The Authors.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alsdurf, Benedetti, Buu, Adjobimey, Cook, Fisher, Fox, Fregonese, Hadisoemarto, Johnston, Long, Obeng, Oxlade, Ruslami, Schwartzman, Strumpf and Menzies.)

Background: During the first year of the COVID-19 pandemic, the proportion of reported cases of COVID-19 among Canadians was under 6%. Although high vaccine coverage was achieved in Canada by fall 2021, the Omicron variant caused unprecedented numbers of infections, overwhelming testing capacity and making it difficult to quantify the trajectory of population immunity., Methods: Using a time-series approach and data from more than 900 000 samples collected by 7 research studies collaborating with the COVID-19 Immunity Task Force (CITF), we estimated trends in SARS-CoV-2 seroprevalence owing to infection and vaccination for the Canadian population over 3 intervals: prevaccination (March to November 2020), vaccine roll-out (December 2020 to November 2021), and the arrival of the Omicron variant (December 2021 to March 2023). We also estimated seroprevalence by geographical region and age., Results: By November 2021, 9.0% (95% credible interval [CrI] 7.3%-11%) of people in Canada had humoral immunity to SARS-CoV-2 from an infection. Seroprevalence increased rapidly after the arrival of the Omicron variant - by Mar. 15, 2023, 76% (95% CrI 74%-79%) of the population had detectable antibodies from infections. The rapid rise in infection-induced antibodies occurred across Canada and was most pronounced in younger age groups and in the Western provinces: Manitoba, Saskatchewan, Alberta and British Columbia., Interpretation: Data up to March 2023 indicate that most people in Canada had acquired antibodies against SARS-CoV-2 through natural infection and vaccination. However, given variations in population seropositivity by age and geography, the potential for waning antibody levels, and new variants that may escape immunity, public health policy and clinical decisions should be tailored to local patterns of population immunity., Competing Interests: Competing interests: Maureen Anderson reports receiving a Saskatchewan Health Research Foundation Establishment Grant, in support of the present manuscript. Lesley Behl reports receving funding from the CITF via a research grant paid to the University of Saskatchewan, in support of the present manuscript. Patrick Brown reports receiving grant support from the CITF. Carmen Charlton reports receiving grant funding from Merck and support for attending meetings or travel from AMMI Canada. Karen Colwill reports receiving an honorarium for a presentation to the Ontario Society of Clinical Chemists. Dr. Colwill is also the vice president of communications for the Canadian National Proteomics Network. Tim Evans reports receiving support for the present manuscript from the CITF, and holds the role of its executive director. Anne-Claude Gingras reports receiving support for automated equipment for ELISA, housed at the Lunenfeld-Tanenbaum Research Institute (a facility supported by Canada Foundation for Innovation funding, the Ontario Government, Genome Canada and Ontario Genomics); support from the Canadian Institutes of Health Research (CIHR) for general lab operations; salary support as a Canada Research Chair (Tier 1) in functional proteomics; and from CITF and the Public Health Agency of Canada (PHAC) for assay calibration at Mount Sinai, all in support of the present manuscript. Dr. Gingras has had a contract with Providence Therapeutics (no consultation fees received), and has received grant funding from CIHR for several SARS-CoV-2 studies and from the Ontario Research Fund, outside of the present work. Dr. Gingras has served as the chair of the Institute Advisory Board of the CIHR Institute of Genetics and is a member and chair of the Human Health Therapeutics Division advisory board, National Research Council of Canada. Dr. Gingras is a member of the CITF working parties on testing and immunology, and is pillar lead of the Functional Genomics and Structure Function of CoVaRR-Net (all roles unpaid). Steven Drews reports receiving grants or contracts from CIHR and Alberta Innovates, consulting fees from Roche, support for attending meetings or travel from the Canadian Immunization Research Network and other support from Abbott. Jaspreet Jain reports receiving support from the CITF for the present manuscript. Prabhat Jha reports receiving grant support from the CITF for the Action to Beat Coronavirus study. Amanda Lang reports receiving funding from the CITF, in support of the present manuscript, for assay reagents and technologist salary. Dr. Lang has also received support from the CITF to attend a CITF meeting. Stephen Lee reports receiving funding from the CITF, in support of the present manuscript. Sheila O’Brien reports receiving payment (paid to Canadian Blood Services [CBS]) from the Government of Canada, and laboratory infrastructure from CBS, in support of the present manuscript. Chantale Pambrun reports receiving salary support from CBS, and study funding from PHAC. Olivia Oxlade is an employee of the CITF Secretariat. David Stephens reports receiving funds for a graduate student from the National Science and Engineering Research Council Emerging Infectious Disease Modelling, in support of the present manuscript. Hanna Swail reports receiving support from the CITF for the present manuscript. David Buckeridge reports receiving funding from PHAC, in support of the present manuscript. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

We estimated costs of managing different forms of tuberculosis (TB) across Canada by conducting a retrospective chart review and cost assessment of patients treated for TB infection, drug-susceptible TB (DS TB), isoniazid-resistant TB, or multidrug-resistant TB (MDR TB) at 3 treatment centers. We included 90 patients each with TB infection and DS TB, 71 with isoniazid-resistant TB, and 62 with MDR TB. Median per-patient costs for TB infection (in 2020 Canadian dollars) were $804 (interquartile range [IQR] $587-$1,205), for DS TB $12,148 (IQR $4,388-$24,842), for isoniazid-resistant TB $19,319 (IQR $7,117-$41,318), and for MDR TB $119,014 (IQR $80,642-$164,015). Compared with costs for managing DS TB, costs were 11.1 (95% CI 9.1-14.3) times lower for TB infection, 1.7 (95% CI 1.3-2.1) times higher for isoniazid-resistant TB, and 8.1 (95% CI 6.1-10.6) times higher for MDR TB. Broadened TB infection treatment could avert high costs associated with managing TB disease.

Background: The World Health Organization recommends tuberculosis (TB) preventive treatment (TPT) for all people living with HIV (PLH) and household contacts (HHC) of index TB patients. Tests for TB infection (TBI) or to rule out TB disease (TBD) are preferred, but if not available, this should not be a barrier if access to these tests is limited for high-risk people, such as PLH and HHC under 5 years old. There is equipoise on the need for these tests in different risk populations, especially HHC aged over 5., Methods: This superiority cluster-randomized multicenter trial with three arms of equal size compares, in Benin and Brazil, three strategies for HHC investigation aged 0-50: (i) tuberculin skin testing (TST) or interferon gamma release assay (IGRA) for TBI and if positive, chest X-Ray (CXR) to rule out TBD in persons with positive TST or IGRA; (ii) same as (i) but GeneXpert (GX) replaces CXR; and (iii) no TBI testing. CXR for all; if CXR is normal, TPT is recommended. All strategies start with symptom screening. Clusters are defined as HHC members of the same index patients with newly diagnosed pulmonary TBD. The main outcome is the proportion of HHC that are TPT eligible who start TPT within 3 months of the index TB patient starting TBD treatment. Societal costs, incidence of severe adverse events, and prevalence of TBD are among secondary outcomes. Stratified analyses by age (under versus over 5) and by index patient microbiological status will be conducted. All participants provide signed informed consent. The study was approved by the Research Ethic Board of the Research Institute of the McGill University Health Centre, the Brazilian National Ethical Board CONEP, and the "Comité Local d'Éthique Pour la Recherche Biomédicale (CLERB) de l'Université de Parakou," Benin. Findings will be submitted for publication in major medical journals and presented in conferences, to WHO and National and municipal TB programs of the involved countries., Discussion: This randomized trial is meant to provide high-quality evidence to inform WHO recommendations on investigation of household contacts, as currently these are based on very low-quality evidence., Trial Registration: ClinicalTrials.gov NCT04528823., (© 2022. The Author(s).)

Background: Shorter, safer, and cheaper tuberculosis (TB) preventive treatment (TPT) regimens will enhance uptake and effectiveness. WHO developed target product profiles describing minimum requirements and optimal targets for key attributes of novel TPT regimens. We performed a cost-effectiveness analysis addressing the scale-up of regimens meeting these criteria in Brazil, a setting with relatively low transmission and low HIV and rifampicin-resistant TB (RR-TB) prevalence, and South Africa, a setting with higher transmission and higher HIV and RR-TB prevalence., Methods and Findings: We used outputs from a model simulating scale-up of TPT regimens meeting minimal and optimal criteria. We assumed that drug costs for minimal and optimal regimens were identical to 6 months of daily isoniazid (6H). The minimal regimen lasted 3 months, with 70% completion and 80% efficacy; the optimal regimen lasted 1 month, with 90% completion and 100% efficacy. Target groups were people living with HIV (PLHIV) on antiretroviral treatment and household contacts (HHCs) of identified TB patients. The status quo was 6H at 2019 coverage levels for PLHIV and HHCs. We projected TB cases and deaths, TB-associated disability-adjusted life years (DALYs), and costs (in 2020 US dollars) associated with TB from a TB services perspective from 2020 to 2035, with 3% annual discounting. We estimated the expected costs and outcomes of scaling up 6H, the minimal TPT regimen, or the optimal TPT regimen to reach all eligible PLHIV and HHCs by 2023, compared to the status quo. Maintaining current 6H coverage in Brazil (0% of HHCs and 30% of PLHIV treated) would be associated with 1.1 (95% uncertainty range [UR] 1.1-1.2) million TB cases, 123,000 (115,000-132,000) deaths, and 2.5 (2.1-3.1) million DALYs and would cost $1.1 ($1.0-$1.3) billion during 2020-2035. Expanding the 6H, minimal, or optimal regimen to 100% coverage among eligible groups would reduce DALYs by 0.5% (95% UR 1.2% reduction, 0.4% increase), 2.5% (1.8%-3.0%), and 9.0% (6.5%-11.0%), respectively, with additional costs of $107 ($95-$117) million and $51 ($41-$60) million and savings of $36 ($14-$58) million, respectively. Compared to the status quo, costs per DALY averted were $7,608 and $808 for scaling up the 6H and minimal regimens, respectively, while the optimal regimen was dominant (cost savings, reduced DALYs). In South Africa, maintaining current 6H coverage (0% of HHCs and 69% of PLHIV treated) would be associated with 3.6 (95% UR 3.0-4.3) million TB cases, 843,000 (598,000-1,201,000) deaths, and 36.7 (19.5-58.0) million DALYs and would cost $2.5 ($1.8-$3.6) billion. Expanding coverage with the 6H, minimal, or optimal regimen would reduce DALYs by 6.9% (95% UR 4.3%-95%), 15.5% (11.8%-18.9%), and 38.0% (32.7%-43.0%), respectively, with additional costs of $79 (-$7, $151) million and $40 (-$52, $140) million and savings of $608 ($443-$832) million, respectively. Compared to the status quo, estimated costs per DALY averted were $31 and $7 for scaling up the 6H and minimal regimens, while the optimal regimen was dominant. Study limitations included the focus on 2 countries, and no explicit consideration of costs incurred before the decision to prescribe TPT., Conclusions: Our findings suggest that scale-up of TPT regimens meeting minimum or optimal requirements would likely have important impacts on TB-associated outcomes and would likely be cost-effective or cost saving., Competing Interests: The authors have declared that no competing interests exist.

Background: Recent years have seen important improvements in available preventive treatment regimens for tuberculosis (TB), and research is ongoing to develop these further. To assist with the formulation of target product profiles for future regimens, we examined which regimen properties would be most influential in the epidemiological impact of preventive treatment., Methods: Following expert consultation, we identified 5 regimen properties relevant to the incidence-reducing impact of a future preventive treatment regimen: regimen duration, efficacy, ease-of-adherence (treatment completion rates in programmatic conditions), forgiveness to non-completion and the barrier to developing rifampicin resistance during treatment. For each regimen property, we elicited expert input for minimally acceptable and optimal (ideal-but-feasible) performance scenarios for future regimens. Using mathematical modelling, we then examined how each regimen property would influence the TB incidence reduction arising from full uptake of future regimens according to current WHO guidelines, in four countries: South Africa, Kenya, India and Brazil., Results: Of all regimen properties, efficacy is the single most important predictor of epidemiological impact, while ease-of-adherence plays an important secondary role. These results are qualitatively consistent across country settings; sensitivity analyses show that these results are also qualitatively robust to a range of model assumptions, including the mechanism of action of future preventive regimens., Conclusions: As preventive treatment regimens against TB continue to improve, understanding the key drivers of epidemiological impact can assist in guiding further development. By meeting these key targets, future preventive treatment regimens could play a critical role in global efforts to end TB., (© 2022. The Author(s).)

Background: In Brazil, investigation and treatment of tuberculosis infection (TBI) in households contacts (HHC) of TB patients is not a priority. We estimated the cost-effectiveness and budget-impact of scaling-up an enhanced HHC management in Brazil., Methods: We conceptualized a cascade-of-care that captures how HHC of tuberculosis patients are investigated in Brazil (status quo) and two enhanced strategies for management of HHC focusing on: (1) only tuberculosis disease (TBD) detection and, (2) TBD and TBI detection and treatment. Effectiveness was the number of HHC diagnosed with TBD and completing TBI treatment. Proportions in the cascades-of-care were derived from a meta-analysis. Health-system costs (2019 US$) were based on literature and official data from Brazil. The impact of enhanced strategies was extrapolated using reported data from 2019., Findings: With the status quo , 0 (95% uncertainty interval: 0-1) HHC are diagnosed with TBD and 2 (0-16) complete TBI treatment. With strategy(1), an additional 15 (3-45) HHC would be diagnosed with TBD at a cost of US$346 each. With strategy(2), 81 (19-226) additional HHC would complete TBI treatment at a cost of US$84 each. A combined strategy, implemented nationally to enhance TBD detection and TBI treatment would result in an additional 9,711 (845-28,693) TBD being detected, and 51,277 (12,028-143,495) more HHC completing TBI treatment each year, utilizing 10.9% and 11.6% of the annual national tuberculosis program budget, respectively., Interpretation: Enhanced detection and treatment of TBD and TBI among HHC in Brazil can be achieved at a national level using current tools at reasonable cost., Funding: None., Competing Interests: No conflict of interest to declare., (© 2021 The Authors.)

Background: In settings without access to rapid expert radiographic interpretation, artificial intelligence (AI)-based chest radiograph (CXR) analysis can triage persons presenting with possible tuberculosis (TB) symptoms, to identify those who require additional microbiological testing. However, there is limited evidence of the cost-effectiveness of this technology as a triage tool., Methods: A decision analysis model was developed to evaluate the cost-effectiveness of triage strategies with AI-based CXR analysis for patients presenting with symptoms suggestive of pulmonary TB in Karachi, Pakistan. These strategies were compared to the current standard of care using microbiological testing with smear microscopy or GeneXpert, without prior triage. Positive triage CXRs were considered to improve referral success for microbiologic testing, from 91% to 100% for eligible persons. Software diagnostic accuracy was based on a prospective field study in Karachi. Other inputs were obtained from the Pakistan TB Program. The analysis was conducted from the healthcare provider perspective, and costs were expressed in 2020 US dollars., Results: Compared to upfront smear microscopy for all persons with presumptive TB, triage strategies with AI-based CXR analysis were projected to lower costs by 19%, from $23233 per 1000 persons, and avert 3%-4% disability-adjusted life-years (DALYs), from 372 DALYs. Compared to upfront GeneXpert, AI-based triage strategies lowered projected costs by 37%, from $34346 and averted 4% additional DALYs, from 369 DALYs. Reinforced follow-up for persons with positive triage CXRs but negative microbiologic tests was particularly cost-effective., Conclusions: In lower-resource settings, the addition of AI-based CXR triage before microbiologic testing for persons with possible TB symptoms can reduce costs, avert additional DALYs, and improve TB detection., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Human immunodeficiency virus (HIV) is the strongest known risk factor for tuberculosis (TB) through its impairment of T-cell immunity. Tuberculosis preventive treatment (TPT) is recommended for people living with HIV (PLHIV) by the World Health Organization, as it significantly reduces the risk of developing TB disease. We conducted a systematic review and meta-analysis of modeling studies to summarize projected costs, risks, benefits, and impacts of TPT use among PLHIV on TB-related outcomes., Methods and Findings: We searched MEDLINE, Embase, and Web of Science from inception until December 31, 2020. Two reviewers independently screened titles, abstracts, and full texts; extracted data; and assessed quality. Extracted data were summarized using descriptive analysis. We performed quantile regression and random effects meta-analysis to describe trends in cost, effectiveness, and cost-effectiveness outcomes across studies and identified key determinants of these outcomes. Our search identified 6,615 titles; 61 full texts were included in the final review. Of the 61 included studies, 31 reported both cost and effectiveness outcomes. A total of 41 were set in low- and middle-income countries (LMICs), while 12 were set in high-income countries (HICs); 2 were set in both. Most studies considered isoniazid (INH)-based regimens 6 to 2 months long (n = 45), or longer than 12 months (n = 11). Model parameters and assumptions varied widely between studies. Despite this, all studies found that providing TPT to PLHIV was predicted to be effective at averting TB disease. No TPT regimen was substantially more effective at averting TB disease than any other. The cost of providing TPT and subsequent downstream costs (e.g. post-TPT health systems costs) were estimated to be less than $1,500 (2020 USD) per person in 85% of studies that reported cost outcomes (n = 36), regardless of study setting. All cost-effectiveness analyses concluded that providing TPT to PLHIV was potentially cost-effective compared to not providing TPT. In quantitative analyses, country income classification, consideration of antiretroviral therapy (ART) use, and TPT regimen use significantly impacted cost-effectiveness. Studies evaluating TPT in HICs suggested that TPT may be more effective at preventing TB disease than studies evaluating TPT in LMICs; pooled incremental net monetary benefit, given a willingness-to-pay threshold of country-level per capita gross domestic product (GDP), was $271 in LMICs (95% confidence interval [CI] -$81 to $622, p = 0.12) and was $2,568 in HICs (-$32,115 to $37,251, p = 0.52). Similarly, TPT appeared to be more effective at averting TB disease in HICs; pooled percent reduction in active TB incidence was 20% (13% to 27%, p < 0.001) in LMICs and 37% (-34% to 100%, p = 0.13) in HICs. Key limitations of this review included the heterogeneity of input parameters and assumptions from included studies, which limited pooling of effect estimates, inconsistent reporting of model parameters, which limited sample sizes of quantitative analyses, and database bias toward English publications., Conclusions: The body of literature related to modeling TPT among PLHIV is large and heterogeneous, making comparisons across studies difficult. Despite this variability, all studies in all settings concluded that providing TPT to PLHIV is potentially effective and cost-effective for preventing TB disease., Competing Interests: The authors have declared that no competing interests exist.

Background: Tuberculosis (TB) preventive therapy (TPT) is an essential component of care for people living with HIV (PLHIV). We compared efficacy, safety, completion, and drug-resistant TB risk for currently recommended TPT regimens through a systematic review and network meta-analysis (NMA) of randomized trials., Methods and Findings: We searched MEDLINE, Embase, and the Cochrane Library from inception through June 9, 2020 for randomized controlled trials (RCTs) comparing 2 or more TPT regimens (or placebo/no treatment) in PLHIV. Two independent reviewers evaluated eligibility, extracted data, and assessed the risk of bias. We grouped TPT strategies as follows: placebo/no treatment, 6 to 12 months of isoniazid, 24 to 72 months of isoniazid, and rifamycin-containing regimens. A frequentist NMA (using graph theory) was carried out for the outcomes of development of TB disease, all-cause mortality, and grade 3 or worse hepatotoxicity. For other outcomes, graphical descriptions or traditional pairwise meta-analyses were carried out as appropriate. The potential role of confounding variables for TB disease and all-cause mortality was assessed through stratified analyses. A total of 6,466 unique studies were screened, and 157 full texts were assessed for eligibility. Of these, 20 studies (reporting 16 randomized trials) were included. The median sample size was 616 (interquartile range [IQR], 317 to 1,892). Eight were conducted in Africa, 3 in Europe, 3 in the Americas, and 2 included sites in multiple continents. According to the NMA, 6 to 12 months of isoniazid were no more efficacious in preventing microbiologically confirmed TB than rifamycin-containing regimens (incidence rate ratio [IRR] 1.0, 95% CI 0.8 to 1.4, p = 0.8); however, 6 to 12 months of isoniazid were associated with a higher incidence of all-cause mortality (IRR 1.6, 95% CI 1.2 to 2.0, p = 0.02) and a higher risk of grade 3 or higher hepatotoxicity (risk difference [RD] 8.9, 95% CI 2.8 to 14.9, p = 0.004). Finally, shorter regimens were associated with higher completion rates relative to longer regimens, and we did not find statistically significant differences in the risk of drug-resistant TB between regimens. Study limitations include potential confounding due to differences in posttreatment follow-up time and TB incidence in the study setting on the estimates of incidence of TB or all-cause mortality, as well as an underrepresentation of pregnant women and children., Conclusions: Rifamycin-containing regimens appear safer and at least as effective as isoniazid regimens in preventing TB and death and should be considered part of routine care in PLHIV. Knowledge gaps remain as to which specific rifamycin-containing regimen provides the optimal balance of efficacy, completion, and safety., Competing Interests: The authors have declared that no competing interests exist.

Olivia Oxlade and co-authors introduce a Collection on tuberculosis preventive therapy in people with HIV infection., Competing Interests: The authors have declared that no competing interests exist.

Background: Tuberculosis preventive therapy (TPT) reduces TB-related morbidity and mortality in people living with HIV (PLHIV). Cascade-of-care analyses help identify gaps and barriers in care and develop targeted solutions. A previous latent tuberculosis infection (LTBI) cascade-of-care analysis showed only 18% of persons in at-risk populations complete TPT, but a similar analysis for TPT among PLHIV has not been completed. We conducted a meta-analysis to provide this evidence., Methods and Findings: We first screened potential articles from a LTBI cascade-of-care systematic review published in 2016. From this study, we included cohorts that reported a minimum of 25 PLHIV. To identify new cohorts, we used a similar search strategy restricted to PLHIV. The search was conducted in Medline, Embase, Health Star, and LILACS, from January 2014 to February 2021. Two authors independently screened titles and full text and assessed risk of bias using the Newcastle-Ottawa Scale for cohorts and Cochrane Risk of Bias for cluster randomized trials. We meta-analyzed the proportion of PLHIV completing each step of the LTBI cascade-of-care and estimated the cumulative proportion retained. These results were stratified based on cascades-of-care that used or did not use LTBI testing to determine eligibility for TPT. We also performed a narrative synthesis of enablers and barriers of the cascade-of-care identified at different steps of the cascade. A total of 71 cohorts were included, and 70 were meta-analyzed, comprising 94,011 PLHIV. Among the PLHIV included, 35.3% (33,139/94,011) were from the Americas and 29.2% (27,460/94,011) from Africa. Overall, 49.9% (46,903/94,011) from low- and middle-income countries, median age was 38.0 [interquartile range (IQR) 34.0;43.6], and 65.9% (46,328/70,297) were men, 43.6% (29,629/67,947) were treated with antiretroviral therapy (ART), and the median CD4 count was 390 cell/mm3 (IQR 312;458). Among the cohorts that did not use LTBI tests, the cumulative proportion of PLHIV starting and completing TPT were 40.9% (95% CI: 39.3% to 42.7%) and 33.2% (95% CI: 31.6% to 34.9%). Among cohorts that used LTBI tests, the cumulative proportions of PLHIV starting and completing TPT were 60.4% (95% CI: 58.1% to 62.6%) and 41.9% (95% CI:39.6% to 44.2%), respectively. Completion of TPT was not significantly different in high- compared to low- and middle-income countries. Regardless of LTBI test use, substantial losses in the cascade-of-care occurred before treatment initiation. The integration of HIV and TB care was considered an enabler of the cascade-of-care in multiple cohorts. Key limitations of this systematic review are the observational nature of the included studies, potential selection bias in the population selection, only 14 cohorts reported all steps of the cascade-of-care, and barriers/facilitators were not systematically reported in all cohorts., Conclusions: Although substantial losses were seen in multiple stages of the cascade-of-care, the cumulative proportion of PLHIV completing TPT was higher than previously reported among other at-risk populations. The use of LTBI testing in PLHIV in low- and middle-income countries was associated with higher proportion of the cohorts initiating TPT and with similar rates of completion of TPT., Competing Interests: The authors have declared that no competing interests exist.

The scale-up of tuberculosis (TB) preventive treatment (TPT) must be accelerated to achieve the targets set by the United Nations High-level Meeting on TB and the End TB Strategy. The scale-up of effective TPT is hampered by concerns about operational challenges to implement the existing tests for TB infection. New simpler tests could facilitate the scale-up of testing for TB infection. We present a framework for evaluation of new immunodiagnostic tests for the detection of TB infection, with an aim to facilitate their standardised evaluation and accelerate adoption into global and national policies and subsequent scale-up. The framework describes the principles to be considered when evaluating new tests for TB infection and provides guidance to manufacturers, researchers, regulators and other users on study designs, populations, reference standards, sample size calculation and data analysis and it is also aligned with the Global Strategy for TB Research and Innovation adopted by the World Health Assembly in 2020. In addition, we briefly describe technical issues that should be considered when evaluating new tests, including the safety for skin tests, costs incurred by patients and the health system, and operational characteristics., Competing Interests: Conflict of interest: Y. Hamada has nothing to disclose. Conflict of interest: S. den Boon has nothing to disclose. Conflict of interest: D.M. Cirillo has nothing to disclose. Conflict of interest: A. Penn-Nicholson: FIND has several clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These studies are for diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and contribute through unrestricted donations as per FIND policy and external SAC review. FIND has not allocated any financial value to know-how or access to equipment gained through these projects. Current projects are listed at www.finddx.org for more information. In addition, A. Penn-Nicholson has a patent WO2016123058A1 WIPO (PCT) (Biomarkers for detection of tuberculosis risk 2016-08-04) pending, and a patent WO2017081618A9 WIPO (PCT) (Biomarkers for prospective determination of risk for development of active tuberculosis 2017-07-13) pending. Conflict of interest: M. Ruhwald: FIND has several clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These studies are for diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and contribute through unrestricted donations as per FIND policy and external SAC review. FIND has not allocated any financial value to know-how or access to equipment gained through these projects. Current projects are listed at www.finddx.org for more information. In addition, M. Ruhwald has a patent WO2017084671A1 issued to Statens Serum Institute, and a patent O2008028489A2 issued to Statens Serum Institute. Conflict of interest: D. Menzies has nothing to disclose. Conflict of interest: O. Oxlade has nothing to disclose. Conflict of interest: D. Falzon has nothing to disclose. Conflict of interest: A. Kanchar has nothing to disclose. Conflict of interest: A. Korobitsyn has nothing to disclose. Conflict of interest: M. Zignol has nothing to disclose. Conflict of interest: A. Matteelli has nothing to disclose. Conflict of interest: T. Kasaeva has nothing to disclose., (Copyright ©The authors 2021.)

Background: There is a need for innovative strategies to improve TB testing uptake and patient retention along the continuum of TB care early-on in treatment without burdening under-resourced health systems. We used a mixed methods approach to develop and pilot test a tuberculosis literacy and counselling intervention at an urban clinic in KwaZulu Natal, South Africa, to improve TB testing uptake and retention in tuberculosis care., Methods: We engaged in discussions with clinic staff to plan and develop the intervention, which was delivered by senior social work students who received one-week training. The intervention included: 1) group health talks with all patients attending the primary clinic; and 2) individual counselling sessions, using motivational interviewing techniques, with newly diagnosed tuberculosis patients. We compared social work students' tuberculosis knowledge, attitudes, and practices before and after their training. We assessed the change in number of tuberculosis diagnostic tests performed after implementation via an interrupted time series analysis with a quasi-Poisson regression model. We compared pre- and post-intervention probabilities of treatment initiation and completion using regression analyses, adjusting for potential baseline confounders. We conducted focus groups with the students, as well as brief surveys and one-on-one interviews with patients, to assess acceptability, feasibility, and implementation., Results: During the study period, 1226 individuals received tuberculosis diagnostic testing and 163 patients started tuberculosis treatment, of whom 84 (51.5%) received individual counselling. The number of diagnostic tuberculosis tests performed increased by 1.36 (95%CI 1.23-1.58) times post-intervention, adjusting for background calendar trend. Probabilities of TB treatment initiation and treatment completion increased by 10.1% (95%CI 1.5-21.3%) and 4.4% (95%CI -7.3-16.0%), respectively. Patients found the counselling sessions alleviated anxiety and increased treatment self-efficacy. Social work students felt the clinic staff were collaborative and highly supportive of the intervention, and that it improved patient engagement and adherence., Conclusions: Engaging clinic staff in the development of an intervention ensures buy-in and collaboration. Education and counselling before and early-on in tuberculosis treatment can increase tuberculosis testing and treatment uptake. Training junior social workers can enable task-shifting in under-resourced settings, while addressing important service gaps in tuberculosis care.

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Tuberculosis (TB) is an important public health problem in Inuit communities across Canada, with an annual incidence rate in 2017 that was nearly 300 times higher than in Canadian-born non-Indigenous individuals. Social and behavioral factors that are prevalent in the North, such as commercial tobacco use, excessive alcohol use, food insecurity and overcrowded housing put individuals at higher risk for TB morbidity and mortality. We examined the potential impact of mitigation strategies for these risk factors, in reducing TB burden in this setting., Methods: We created a transmission model to simulate the epidemiology of TB in Nunavut, Canada. We then used a decision analysis model to assess the potential impact of several evidence-based strategies targeting tobacco use, excessive alcohol use, food insecurity and overcrowded housing. We predicted TB incidence, TB-related deaths, quality adjusted life years (QALYs), and associated costs and cost-effectiveness over 20 years. All costs were expressed in 2018 Canadian dollars., Results: Compared to a status quo scenario with no new interventions for these risk factors, the reduction strategy for tobacco use was most effective and cost-effective, reducing TB incidence by 5.5% (95% uncertainty range: 2.7-11%) over 20 years, with an estimated cost of $95,835 per TB case prevented and $49,671 per QALY gained. The addition of the food insecurity reduction strategy reduced incidence by a further 2% (0.5-3%) compared to the tobacco cessation strategy alone, but at significant cost., Conclusions: Strategies that aim to reduce commercial tobacco use and improve food security will likely lead to modest reductions in TB morbidity and mortality. Although important for the communities, strategies that address excess alcohol use and overcrowding will likely have a more limited impact on TB-related outcomes at current scale, and are associated with much higher cost. Their benefits will be more substantial with scale up, which will also likely have important downstream impacts such as improved mental health, educational attainment and food security.

Background: Less than 19% of those needing tuberculosis (TB) preventive treatment complete it, due to losses in several steps of the cascade of care for latent TB infection. A cluster randomized trial of a programmatic public health intervention to improve management of latent TB infection in household contacts was conducted in Rio de Janeiro. Interventions included contact registry, initial and in-service training, and a TB booklet. We conducted a follow-up study starting one month after the conclusion of this trial, to measure the effect of interventions implemented, and to identify remaining barriers and facilitators to latent TB infection treatment, from different perspectives., Methods: In two health clinics in Rio de Janeiro that received the interventions in the trial, data for the latent TB infection cascade of care for household contacts was collected over a five-month period. The number of household contacts initiating treatment per 100 index-TB patients was compared with the cascade of care data obtained before and during the intervention trial. Semi-structured open-ended questionnaires were administered to healthcare workers, household contacts and index-TB patients regarding knowledge and perceptions about TB and study interventions., Results: In this follow-up study, 184 household contacts per 100 index-TB patients were identified. When compared to the intervention period, there were 65 fewer household contacts per 100 index-TB patients, (95% CI -115, - 15) but the number starting latent TB infection treatment was sustained (difference -2, 95% CI -8,5). A total of 31 index-TB patients, 22 household contacts and 19 health care workers were interviewed. Among index-TB patients, 61% said all their household contacts had been tested for latent TB infection. All health care workers said it was very important to test household contacts, and 95% mentioned that possessing correct knowledge on the benefits of latent TB infection treatment was the main facilitator to enable them to recommend this treatment., Conclusion: In this follow-up study, we observed a sustained effect of interventions to strengthen the latent TB infection cascade of care on increasing the number of household contacts starting latent TB infection treatment.

Competing Interests: Intérêts concurrents: Alton Russell a fourni des services de consultation à Terumo BCT, une entreprise d’appareils médicaux qui ne fabrique pas de tests diagnostiques; ces services n’avaient aucun lien avec la présente étude et ont été offerts hors du cadre de celle-ci. Stephanie Law travaille à temps partiel à Carebook Technologies Inc., une entreprise d’applications technologiques mobiles qui met présentement à l’essai une application permettant de suivre les symptômes de la maladie à coronavirus 2019 (COVID-19). Ce travail n’a aucun lien avec la présente étude et a lieu en dehors de celle-ci. Jonathon Campbell a quant à lui reçu des honoraires de consultant du Groupe de travail sur l’immunité face à la COVID-19 (GTIC) pour des services non liés à la présente étude et rendus à l’extérieur de celle-ci; l’offre des services et la perception des honoraires ont eu lieu après la remise initiale du manuscrit. Olivia Oxlade est directrice scientifique associée (gestion) du GTIC. Sa contribution au manuscrit a eu lieu avant son arrivée à ce poste, alors qu’elle travaillait au Centre international de la tuberculose de McGill. Enfin, Timothy Evans est directeur administratif du GTIC. Aucun autre intérêt concurrent n’a été déclaré.

Background: Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely passive, which impedes epidemic control. We defined active testing strategies for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) for groups at increased risk of acquiring SARS-CoV-2 in all Canadian provinces., Methods: We identified 5 groups who should be prioritized for active RT-PCR testing: contacts of people who are positive for SARS-CoV-2, and 4 at-risk populations - hospital employees, community health care workers and people in long-term care facilities, essential business employees, and schoolchildren and staff. We estimated costs, human resources and laboratory capacity required to test people in each group or to perform surveillance testing in random samples., Results: During July 8-17, 2020, across all provinces in Canada, an average of 41 751 RT-PCR tests were performed daily; we estimated this required 5122 personnel and cost $2.4 million per day ($67.8 million per month). Systematic contact tracing and testing would increase personnel needs 1.2-fold and monthly costs to $78.9 million. Conducted over a month, testing all hospital employees would require 1823 additional personnel, costing $29.0 million; testing all community health care workers and persons in long-term care facilities would require 11 074 additional personnel and cost $124.8 million; and testing all essential employees would cost $321.7 million, requiring 25 965 added personnel. Testing the larger population within schools over 6 weeks would require 46 368 added personnel and cost $816.0 million. Interventions addressing inefficiencies, including saliva-based sampling and pooling samples, could reduce costs by 40% and personnel by 20%. Surveillance testing in population samples other than contacts would cost 5% of the cost of a universal approach to testing at-risk populations., Interpretation: Active testing of groups at increased risk of acquiring SARS-CoV-2 appears feasible and would support the safe reopening of the economy and schools more broadly. This strategy also appears affordable compared with the $169.2 billion committed by the federal government as a response to the pandemic as of June 2020., Competing Interests: Competing interests: Alton Russell has provided consulting services to Terumo BCT, a medical device company, unrelated to and outside the submitted work; Terumo BCT does not manufacture diagnostic tests. Stephanie Law is a part-time employee at Carebook Technologies Inc., a mobile app tech company; Carebook Technologies Inc. is currently pilot-testing an app for monitoring symptoms related to coronavirus disease 2019 (COVID-19); this is unrelated to and outside the submitted work. Jonathon Campbell reports that he has received consulting fees from the COVID-19 Immunity Task Force, outside and unrelated to the submitted work. The fees were received and the work performed after initial submission of the present manuscript. Olivia Oxlade reports being Associate Scientific Director (Management) for the COVID-19 Immunity Task Force. All of the work related to this manuscript was done while Dr. Oxlade was part of the McGill International TB Centre and before this position started. Timothy Evans is Executive Director of the COVID-19 Immunity Task Force. No other competing interests were declared., (© 2020 Joule Inc. or its licensors.)

Background: Four months of rifampin treatment for latent tuberculosis infection is safer, has superior treatment completion rates, and is as effective as 9 months of isoniazid. However, daily medication costs are higher for a 4-month rifampin regimen than a 9-month isoniazid regimen., Objective: To compare health care use and associated costs of 4 months of rifampin and 9 months of isoniazid., Design: Health system cost comparison using all health care activities recorded during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and NCT00170209)., Setting: High-income countries (Australia, Canada, Saudi Arabia, and South Korea), middle-income countries (Brazil and Indonesia), and African countries (Benin, Ghana, and Guinea)., Participants: Adults and children with clinical or epidemiologic factors associated with increased risk for developing tuberculosis that warranted treatment for latent tuberculosis infection., Measurements: Health system costs per participant., Results: A total of 6012 adults and 829 children were included. In both adults and children, greater health system use and higher costs were observed with 9 months of isoniazid than with 4 months of rifampin. In adults, the ratios of costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI, 0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings were observed in the pediatric population., Limitation: Costs may have been overestimated because the trial protocol required a minimum number of follow-up visits, although fewer than recommended by many authoritative guidelines., Conclusion: A 4-month rifampin regimen was safer and less expensive than 9 months of isoniazid in all settings. This regimen could be adopted by tuberculosis programs in many countries as first-line therapy for latent tuberculosis infection., Primary Funding Source: Canadian Institutes of Health Research.

Background: Loss of patients in the latent tuberculosis infection (LTBI) cascade of care is a major barrier to LTBI management. We evaluated the impact and acceptability of local solutions implemented to strengthen LTBI management of household contacts (HHCs) at an outpatient clinic in Ghana., Methods: Local solutions to improve LTBI management were informed by a baseline evaluation of the LTBI cascade and questionnaires administered to index patients, HHCs, and health care workers at the study site in Offinso, Ghana. Solutions aimed to reduce patient costs and improve knowledge. We evaluated the impact and acceptability of the solutions. Specific objectives were to: 1) Compare the proportion of eligible HHCs completing each step in the LTBI cascade of care before and after solution implementation; 2) Compare knowledge, attitude, and practices (KAP) before and after solution implementation, based on responses of patients and health care workers (HCW) to structured questionnaires; 3) Evaluate patient and HCW acceptability of solutions using information obtained from these questionnaires., Results: Pre and Post-Solution LTBI Cascades included 58 and 125 HHCs, respectively. Before implementation, 39% of expected < 5-year-old HHCs and 66% of ≥5-year-old HHCs were identified. None completed any further cascade steps. Post implementation, the proportion of eligible HHCs who completed identification, assessment, evaluation, and treatment initiation increased for HHCs < 5 to 94, 100, 82, 100%, respectively, and for HHCs ≥5 to 96, 69, 67, 100%, respectively. Pre and Post-Solutions questionnaires were completed by 80 and 95 respondents, respectively. Study participants most frequently mentioned financial support and education as the solutions that supported LTBI management., Conclusion: Implementation of locally selected solutions was associated with an increase in the proportion of HHCs completing all steps in the LTBI cascade. Tuberculosis programs should consider prioritizing financial support, such as payment for chest x-rays, to support LTBI cascade completion.

Background: The Tuberculin Skin Test (TST) is a relatively simple test for detecting latent tuberculosis infection (LTBI) but requires regular quality assurance to ensure proper technique for administration and reading. The objective of this study was to estimate the accuracy and reproducibility of an mhealth approach (the mTST) to measure the size of swelling immediately following TST administration (TST injection bleb) and after 48-72 hours (TST induration)., Methods: Five non-clinical and one clinical reviewer measured the size of TST injection blebs, and TST indurations using smartphone acquired photos of sites of TST administration and readings in patients, or saline injections in volunteers. The reference standard was the onsite measurement (measured by an experienced TB nurse) of the actual TST injection bleb, or induration. Agreement of reviewers' measurements with the reference standard, as well as agreement within and between reviewers, was estimated using Cohen's kappa coefficient., Results: Using the mTST method to assess bleb size in 64 photos of different TST injections, agreement between reviewers, and the reference standard was very good to excellent (κ ranged from 0.75 to 0.87), and within-reviewer reproducibility of readings was excellent (κ ranged from 0.86 to 0.96). Using the mTST method to assess TST induration in 72 photos, reviewers were able to detect no induration (<5mm) and induration of 15mm or greater with accuracy of 95% and 92% respectively, but accuracy was only 20% and 77% for reactions of 5-9mm and 10-14mm respectively., Conclusion: The mTST approach appears to be a reliable tool to assess TST administration. The mTST approach was accurate to read indurations of 0-4mm or 15+mm, but less accurate for reactions of 5-14mm. We believe the mTST approach could be useful for training and quality assurance in locations where on-site supervision is not possible., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Treatment of latent tuberculosis (TB) infection (LTBI) is an important component of the End-TB strategy. However, the number of individuals who successfully complete LTBI treatment remains low as there are losses at all steps in the LTBI 'cascade-of-care'. The reasons for these losses are variable and highly dependent on the setting. We have planned a trial of a standardised public health approach to strengthen the management of household contacts (HHCs) of newly diagnosed patients with pulmonary TB. Assessing costs related to approach is a secondary objective of the study., Methods and Analysis: A cluster randomised trial will be conducted in 24 randomisation units (health facilities or groups of health facilities) in five countries. In Phase 1, at intervention sites, we will conduct a standardised assessment of the current LTBI programme, with a focus on cascade-of-care endpoints. Standardised open-ended questionnaires on practices, knowledge, attitudes and beliefs regarding TB prevention are then administered to key patient groups and healthcare workers. At each site, local stake-holders will review study findings and select solutions based on their acceptability, cost and effectiveness. In Phase 2, intervention clinics will implement the selected solutions, along with contact measurement registries and regular in-service LTBI management training. Control sites will continue their usual LTBI care with no explicit evaluation, strengthening or training activities. The primary study outcome is the number of HHC initiating LTBI treatment per newly diagnosed active TB patient, within 3 months of diagnosis of the index patient. An intention-to-treat analysis will be performed, using a Poisson regression approach., Ethics and Dissemination: Ethics approval from the MUHC ethical review board (ERB) was obtained in November 2015. During the study standardised tools will be developed and made publicly available. Key study findings and novel methodologic contributions will be detailed in publications and other dissemination activities., Trial Registration Number: NCT02810678; Pre-Results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tuberculosis (TB) remains a significant public health problem in Canadian Inuit communities. In 2016, Canadian Inuit had an incidence rate 35 times the Canadian average. Tobacco use is an important risk factor for TB, and over 60% of Inuit adults smoke. We aimed to estimate changes in TB-related outcomes and costs from reducing tobacco use in Inuit communities., Methods: Using a transmission model to estimate the initial prevalence of latent TB infection (LTBI), followed by decision analysis modelling, we conducted a cost-effectiveness analysis that compared the current standard of care for management of TB and LTBI without additional tobacco reduction intervention (Status Quo) with (1) increased tobacco taxation, (2) pharmacotherapy and counselling for smoking cessation, (3) pharmacotherapy, counselling plus mass media campaign, and (4) the combination of all these. Projected outcomes included the following: TB cases, TB-related deaths, quality-adjusted life years (QALYs), and health system costs, all over 20 years., Results: The combined strategy was projected to reduce active TB cases by 6.1% (95% uncertainty range 4.9-7.0%) and TB deaths by 10.4% (9.5-11.4%) over 20 years, relative to the status quo. Increased taxation was the only cost-saving strategy., Conclusions: Currently available strategies to reduce commercial tobacco use will likely have a modest impact on TB-related outcomes in the medium term, but some may be cost saving.

Introduction: Isoniazid-resistant, rifampin susceptible tuberculosis (INHR-TB) is the most common form of drug resistant TB globally. Treatment of INHR-TB with standard first-line therapy is associated with high rates of multidrug resistant TB (MDR-TB). We modelled the potential impact of INHR-TB detection and appropriate treatment on MDR-TB prevalence., Methods: A decision analysis model was developed to compare three different strategies for the detection of TB (AFB smear, Xpert MTB/RIF, and Line-Probe Assays (LPA)), combined with appropriate treatment. The population evaluated were patients with a globally representative prevalence of newly diagnosed, drug-susceptible (88.6%), isoniazid-resistant (7.3%), and multidrug resistant (4.1%) pulmonary TB. Our primary outcome was the proportion of patients with MDR-TB after initial attempt at diagnosis and treatment within a 2-year period. Secondary outcomes were the proportion of i) individuals with detected TB who acquired MDR-TB ii) individuals who died after initial attempt at diagnosis and treatment., Results: After initial attempt at diagnosis and treatment, LPA combined with appropriate INHR-TB therapy resulted in a lower proportion of prevalent MDR-TB (1.61%; 95% Uncertainty Range (UR: 2.5th and 97.5th percentiles generated from 10 000 Monte Carlo simulation trials) 1.61-1.65), when compared to Xpert (1.84%; 95% UR 1.82-1.85) and AFB smear (3.21%; 95% UR 3.19-3.26). LPA also resulted in fewer cases of acquired MDR-TB in those with detected TB (0.35%; 95% UR 0.34-0.35), when compared to Xpert (0.67%; 95% UR 0.65-0.67) and AFB smear (0.68%; 95% UR 0.67-0.69). The majority of acquired MDR-TB arose from the treatment of INHR-TB in all strategies. Xpert-based strategies resulted in a lower proportion of death (2.89%; 95% UR 2.87-2.90) compared to LPA (2.93%; 95% UR 2.91-2.94) and AFB smear (3.21%; 95% UR 3.19-3.23)., Conclusion: Accurate diagnosis and tailored treatment of INHR-TB with LPA led to an almost 50% relative decrease in acquired MDR-TB when compared with an Xpert MTB/RIF strategy. Continued reliance on diagnostic and treatment protocols that ignore INHR-TB will likely result in further generation of MDR-TB., Competing Interests: The authors have declared that no competing interests exist.

Background: Indigenous peoples worldwide carry a disproportionate tuberculosis burden. There is an increasing awareness of the effect of social determinants and proximate determinants such as alcohol use, overcrowding, type 1 and type 2 diabetes, substance misuse, HIV, food insecurity and malnutrition, and smoking on the burden of tuberculosis. We aimed to understand the potential contribution of such determinants to tuberculosis in Indigenous peoples and to document steps taken to address them., Methods: We did a systematic review using seven databases (MEDLINE, Embase, CINAHL, Global Health, BIOSIS Previews, Web of Science, and the Cochrane Library). We identified English language articles published from Jan 1, 1980, to Dec 20, 2017, reporting the prevalence of proximate determinants of tuberculosis and preventive programmes targeting these determinants in Indigenous communities worldwide. We included any randomised controlled trials, controlled studies, cohort studies, cross-sectional studies, case reports, and qualitative research. Exclusion criteria were articles in languages other than English, full text not available, population was not Indigenous, focused exclusively on children or older people, and studies that focused on pharmacological interventions., Findings: Of 34 255 articles identified, 475 were eligible for inclusion. Most studies confirmed a higher prevalence of proximate determinants in Indigenous communities than in the general population. Diabetes was more frequent in Indigenous communities within high-income countries versus in low-income countries. The prevalence of alcohol use was generally similar to that among non-Indigenous groups, although patterns of drinking often differed. Smoking prevalence and smokeless tobacco consumption were commonly higher in Indigenous groups than in non-Indigenous groups. Food insecurity was highly prevalent in most Indigenous communities evaluated. Substance use was more frequent in Indigenous inhabitants of high-income countries than of low-income countries, with wide variation across Indigenous communities. The literature pertaining to HIV, crowding, and housing conditions among Indigenous peoples was too scant to draw firm conclusions. Preventive programmes that are culturally appropriate targeting these determinants appear feasible, although their effectiveness is largely unproven., Interpretation: Indigenous peoples were generally reported to have a higher prevalence of several proximate determinants of tuberculosis than non-Indigenous peoples, with wide variation across Indigenous communities. These findings emphasise the need for community-led, culturally appropriate strategies to address smoking, food insecurity, and diabetes in Indigenous populations as important public health goals in their own right, and also to reduce the burden of tuberculosis., Funding: Canadian Institutes of Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Ensuring adherence and support during treatment of tuberculosis (TB) is a major public health challenge. Digital health technologies could help improve treatment outcomes. We considered their potential cost and impact on treatment for active or latent TB in Brazil.Decision analysis models simulated two adult cohorts with 1) drug-susceptible active TB, and 2) multidrug-resistant TB, and two cohorts treated with isoniazid for latent TB infection (LTBI): 1) close contacts of persons with active TB, and 2) others newly diagnosed with LTBI. We evaluated four digital support strategies: two different medication monitors, synchronous video-observed therapy (VOT), and two-way short message service (SMS). Comparators were standard directly observed treatment for active TB and self-administered treatment for LTBI. Projected outcomes included costs (2016 US dollars), plus active TB cases and disability-adjusted life years averted among persons with LTBI.For individuals with active TB, medication monitors and VOT are projected to lead to substantial (up to 58%) cost savings, in addition to alleviating inconvenience and cost to patients of supervised treatment visits. For LTBI treatment, SMS and medication monitors are projected to be the most cost-effective interventions. However, all projections are limited by the scarcity of published estimates of clinical effect for the digital technologies., Competing Interests: Conflict of interest: N.P. Nsengiyumva reports grants from the European Respiratory Society, during the conduct of the study. Conflict of interest: B. Mappin-Kasirer has nothing to disclose. Conflict of interest: O. Oxlade has nothing to disclose. Conflict of interest: M. Bastos has nothing to disclose. Conflict of interest: A. Trajman has nothing to disclose. Conflict of interest: D. Falzon reports a grant from the European Respiratory Society for activities in support of the digital health agenda for the End TB Strategy (funder not involved in decisions made on the content of the current manuscript), during the conduct of the study. Conflict of interest: K. Schwartzman reports grants from the European Respiratory Society through the Global TB Programme of the World Health Organization, which paid for some research expenses associated with this work, during the conduct of the study., (Copyright ©ERS 2018.)