Implementation of systematic screening for tuberculosis disease and tuberculosis preventive treatment among people living with HIV attending antiretroviral treatment clinics in Ghana: a national pilot study.

OBJECTIVES: To assess the yield and cost of implementing systematic screening for tuberculosis (TB) disease among people living with HIV (PLHIV) and initiation of TB preventive treatment (TPT) in Ghana. DESIGN: Prospective cohort study from August 2019 to December 2020. SETTING: One hospital from each of Ghana's regions (10 total). PARTICIPANTS: Any PLHIV already receiving or newly initiating antiretroviral treatment were eligible for inclusion. INTERVENTIONS: All participants received TB symptom screening and chest radiography. Those with symptoms and/or an abnormal chest X-ray provided a sputum sample for microbiological testing. All without TB disease were offered TPT. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated the proportion diagnosed with TB disease and proportion initiating TPT. We used logistic regression to identify factors associated with TB disease diagnosis. We used microcosting to estimate the health system cost per person screened (2020 US$). RESULTS: Of 12 916 PLHIV attending participating clinics, 2639 (20%) were enrolled in the study and screened for TB disease. Overall, 341/2639 (12.9%, 95% CI 11.7% to 14.3%) had TB symptoms and/or an abnormal chest X-ray; 50/2639 (1.9%; 95% CI 1.4% to 2.5%) were diagnosed with TB disease, 20% of which was subclinical. In multivariable analysis, only those newly initiating antiretroviral treatment were at increased odds of TB disease (adjusted OR 4.1, 95% CI 2.0 to 8.2). Among 2589 participants without TB, 2581/2589 (99.7%) initiated TPT. Overall, the average cost per person screened during the study was US$57.32. CONCLUSION: In Ghana, systematic TB disease screening among PLHIV was of high yield and modest cost when combined with TPT. Our findings support WHO recommendations for routine TB disease screening among PLHIV.

Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.

BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes. METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone. RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities. CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.

The prevalence of tuberculosis infection among foreign-born Canadians: a modelling study.

BACKGROUND: The prevalence of tuberculosis infection is critical to the design of tuberculosis prevention strategies, yet is unknown in Canada. We estimated the prevalence of tuberculosis infection among Canadian residents born abroad. METHODS: We estimated the prevalence of tuberculosis infection by age and year of migration to Canada for people from each of 168 countries by constructing country-specific and calendar year-specific trends for annual risk of infection using a previously developed model. We combined country-specific prevalence estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to estimate the overall prevalence of tuberculosis infection among foreign-born Canadian residents. RESULTS: The estimated overall prevalence of tuberculosis infection among foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%-35%) for census year 2001, 24% (95% UI 20%-33%) for 2006, 23% (95% UI 19%-30%) for 2011, 22% (95% UI 19%-28%) for 2016 and 22% (95% UI 19%-27%) for 2021. The prevalence increased with age at migration and incidence of tuberculosis in the country of origin. In 2021, the estimated prevalence of infection among foreign-born residents was lowest in Quebec (19%, 95% UI 16%-24%) and highest in Alberta (24%, 95% UI 21%-28%) and British Columbia (24%, 95% UI 20%-30%). Among all foreign-born Canadian residents with tuberculosis infection in 2021, we estimated that only 1 in 488 (95% UI 185-1039) had become infected within the 2 preceding years. INTERPRETATION: About 1 in 4 foreign-born Canadian residents has tuberculosis infection, but very few were infected within the 2 preceding years (the highest risk period for progression to tuberculosis disease). These data may inform future tuberculosis infection screening policies.

Identifying patients with multidrug-resistant tuberculosis who may benefit from shorter durations of treatment.

OBJECTIVE: Studying treatment duration for rifampicin-resistant and multidrug-resistant tuberculosis (MDR/RR-TB) using observational data is methodologically challenging. We aim to present a hypothesis generating approach to identify factors associated with shorter duration of treatment. STUDY DESIGN AND SETTING: We conducted an individual patient data meta-analysis among MDR/RR-TB patients restricted to only those with successful treatment outcomes. Using multivariable linear regression, we estimated associations and their 95% confidence intervals (CI) between the outcome of individual deviation in treatment duration (in months) from the mean duration of their treatment site and patient characteristics, drug resistance, and treatments used. RESULTS: Overall, 6702 patients with successful treatment outcomes from 84 treatment sites were included. We found that factors commonly associated with poor treatment outcomes were also associated with longer treatment durations, relative to the site mean duration. Use of bedaquiline was associated with a 0.51 (95% CI: 0.15, 0.87) month decrease in duration of treatment, which was consistent across subgroups, while MDR/RR-TB with fluoroquinolone resistance was associated with 0.78 (95% CI: 0.36, 1.21) months increase. CONCLUSION: We describe a method to assess associations between clinical factors and treatment duration in observational studies of MDR/RR-TB patients, that may help identify patients who can benefit from shorter treatment.

The association of SARS-CoV-2 infection and tuberculosis disease with unfavorable treatment outcomes: A systematic review.

BACKGROUND: Whether SARS-CoV-2 infection and its management influence tuberculosis (TB) treatment outcomes is uncertain. We synthesized evidence on the association of SARS-CoV-2 coinfection (Coinfection Review) and its management (Clinical Management Review) on treatment outcomes among people with tuberculosis (TB) disease. METHODS: We systematically searched the literature from 1 January 2020 to 6 February 2022. Primary outcomes included: unfavorable (death, treatment failure, loss-to-follow-up) TB treatment outcomes (Coinfection and Clinical Management Review) and/or severe or critical COVID-19 or death (Clinical Management Review). Study quality was assessed with an adapted Newcastle Ottawa Scale. Data were heterogeneous and a narrative review was performed. An updated search was performed on April 3, 2023. FINDINGS: From 9,529 records, we included 11 studies and 7305 unique participants. No study reported data relevant to our review in their primary publication and data had to be contributed by study authors after contact. Evidence from all studies was low quality. Eight studies of 5749 persons treated for TB (286 [5%] with SARS-CoV-2) were included in the Coinfection Review. Across five studies reporting our primary outcome, there was no significant association between SARS-CoV-2 coinfection and unfavorable TB treatment outcomes. Four studies of 1572 TB patients-of whom 291 (19%) received corticosteroids or other immunomodulating treatment-were included in the Clinical Management Review, and two addressed a primary outcome. Studies were likely confounded by indication and discordant findings existed among studies. When updating our search, we still did not identify any study reporting data relevant to this review in their primary publication. INTERPRETATION: No study was designed to answer our research questions of interest. It remains unclear whether TB/SARS-CoV-2 and its therapeutic management are associated with unfavorable outcomes. Research is needed to improve our understanding of risk and optimal management of persons with TB and SARS-CoV-2 infection. TRIAL REGISTRATION: Registration: PROSPERO (CRD42022309818).

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

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

The state of tuberculosis surveillance in Canada.

Tuberculosis incidence in Canada has remained essentially unchanged over the past decade. A strategic plan to reduce the burden of disease, underpinned by high-quality surveillance data, is sorely needed. However, tuberculosis surveillance data are lacking in Canada for multiple reasons. There is no single entity responsible for coordinating a tuberculosis response, including strategies for surveillance, thus inhibiting effective solutions. This in turn affects the timeliness and comprehensiveness of national tuberculosis surveillance reporting: between 2000 and 2020, there was an average 25-month delay to publication of annual surveillance data and the comprehensiveness of reports has precipitously fallen over time. Compounding these issues are case report forms for tuberculosis surveillance data which have not been updated since 2011, failing to keep up with the changing tuberculosis epidemiology and to provide information required for strategic planning. Common-sense steps can be taken to vastly improve the utility of collected tuberculosis surveillance data, and the development of a strategic plan for tuberculosis elimination. These include initiating a country-wide consultation on surveillance needs; allocating resources for data collection and analysis and data sharing; setting precise, measurable goals; and, importantly, establishing an oversight committee with representation from all provincial/territorial tuberculosis program leads who are held to account for performance.

RéSUMé: L'incidence de la tuberculose au Canada est demeurée essentiellement inchangée au cours de la dernière décennie. Un plan stratégique visant à réduire le fardeau de la maladie, étayé par des données de surveillance de haute qualité, est grandement nécessaire. Cependant, les données de surveillance de la tuberculose font défaut au Canada pour de multiples raisons. Il n'existe pas d'entité unique chargée de coordonner la réponse à la tuberculose, y compris les stratégies de surveillance, ce qui empêche de trouver des solutions efficaces. Cette situation a une incidence sur la rapidité et l'exhaustivité des rapports nationaux de surveillance de la tuberculose : entre 2000 et 2020, la publication des données annuelles de surveillance a été retardée de 25 mois en moyenne, et l'exhaustivité des rapports a chuté de façon vertigineuse au fil du temps. Ces problèmes sont aggravés par le fait que les formulaires de déclaration des cas pour les données de surveillance de la tuberculose n'ont pas été mis à jour depuis 2011, ce qui entrave leur capacité à suivre l'évolution de l'épidémiologie de la tuberculose et à fournir les informations nécessaires à la planification stratégique. Des mesures de bon sens peuvent être prises pour améliorer considérablement l'utilité des données de surveillance de la tuberculose collectées et le développement d'un plan stratégique pour l'élimination de la tuberculose. Il s'agit notamment de lancer une consultation à l'échelle du pays sur les besoins en matière de surveillance, d'allouer des ressources pour la collecte et l'analyse des données et leur partage, de fixer des objectifs précis et mesurables et, surtout, d'établir un comité de surveillance composé de représentants de tous les responsables provinciaux/territoriaux du programme de lutte contre la tuberculose qui sont tenus de rendre compte des performances.

Factors Associated With Discontinuation of Tuberculosis Preventive Treatment: Post Hoc Analysis of 2 Randomized, Controlled Trials.

BACKGROUND: Adherence to tuberculosis preventive treatment (TPT) is an important determinant of clinical benefit. We assessed the association of participant behaviors early in TPT with subsequent discontinuation. METHODS: We used data from a phase 3 randomized trial and the preceding phase 2 trial to compare 4 months of rifampin to 9 months of isoniazid for TPT. We excluded participants whose providers discontinued TPT due to adverse events or tuberculosis disease. We analyzed 4 outcomes: discontinuing TPT within the first month of treatment, discontinuing TPT between the first and second month, discontinuing TPT after the second month, and completing treatment but not per protocol. We analyzed the association of outcomes with regimen and participant characteristics and 4 behavioral predictors of discontinuation recorded at the month 1 and month 2 follow-up visits: reporting symptoms of intolerance, missing >20% of doses, rescheduling appointments, and not bringing their medication bottle. RESULTS: Overall, 6656 participants were included (phase 3, 5848; phase 2, 808), of whom 4318 (64.9%) completed treatment per protocol. Participant characteristics were inconsistently associated with discontinuation. Phase 3 trial participants with 1, 2, or 3-4 behavioral predictors at the month 1 follow-up had 5.0 (95% confidence interval, 3.6-6.7), 18.6 (13.3-26.1), and 79.4 (38.2-165.0), respectively, higher odds of discontinuing before the second month. The corresponding number of predictors at the month 2 follow-up had 1.8 (1.4-2.2), 4.7 (3.6-6.2), and 7.4 (4.6-11.9) higher odds of discontinuing before completing treatment; phase 2 findings were similar. CONCLUSIONS: Four behavioral predictors recorded early in therapy were more strongly associated with subsequent discontinuation than participant characteristics, particularly when more than 1 behavioral predictor was recorded. Clinical Trials Registration. NCT00170209; NCT00931736.

Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis.

BACKGROUND: 3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R. METHODS: We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs. FINDINGS: We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found. INTERPRETATION: In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment. FUNDING: None. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Evaluating the Effectiveness of a Novel Systematic Screening Approach for Tuberculosis among Individuals Suspected or Recovered from COVID-19: Experiences from Niger and Guinea.

Evidence suggests that the COVID-19 pandemic negatively impacts tuberculosis (TB) activities. As TB and COVID-19 have similar symptoms, we assessed the effectiveness of integrated TB/COVID-19 screening in Guinea and Niger. From May to December 2020, TB screening was offered to symptomatic patients after a negative COVID-19 PCR test or after recovery from COVID-19 in Guinea. From December 2020 to March 2021, all presumptive COVID-19 patients with respiratory symptoms were tested simultaneously for COVID-19 and TB in Niger. We assessed the TB detection yield and used micro-costing to estimate the costs associated with both screening algorithms. A total of 863 individuals (758 in Guinea, and 105 in Niger), who were mostly male (60%) and with a median age of 34 (IQR: 26-45), were screened for TB. Reported symptoms were cough ≥2 weeks (49%), fever (45%), and weight loss (30%). Overall, 61 patients (7%) tested positive for COVID-19 (13 in Guinea, 48 in Niger) and 43 (4.9%) were diagnosed with TB disease (35 or 4.6% in Guinea, and 8 or 7.6% in Niger). The cost per person initiating TB treatment was USD $367 in Guinea and $566 in Niger. Overall, the yield of both approaches was high, and the cost was modest. Optimizing integrated COVID-19/TB screening may support maintaining TB detection during the ongoing pandemic.

Costs of Tuberculosis at 3 Treatment Centers, Canada, 2010-2016.

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.

Occupational stress in industry setting in Benin 2019: A cross-sectional study.

BACKGROUND: Occupational stress is a psychosocial risk in the workplace. Working conditions in industrial settings may lead to occupational stress. In Benin, however, there is little epidemiological data on occupational stress in industrial settings. We aimed to determine the prevalence and factors associated with occupational stress in industrial settings in Benin in 2019. METHODS: This was a prospective, cross-sectional study conducted from January 31 to April 11, 2019, among 15 cotton ginning plants. Sampling was exhaustive for permanent workers and stratified in clusters by shift for occasional cotton gin workers. Data were collected through Karasek and Siegrist questionnaires. Data analysis was performed using R software. Binary multivariable logistic regression was performed. The significance level was p < 0.05. RESULTS: Of 1883 workers included, 90.8% were male. The median age was 38 years (IQR: 28 years to 49 years). The prevalence of occupational stress was 77.7% (95% CI: 75.8-79.6). Psychological demand was high in 93.0% of workers and 83.9% had low decision latitude. Among the workers, 16.3% had low social support and 89.9% had a low recognition score at work. Factors associated with occupational stress were: being an occasional vs. permanent worker (aOR 6.43, 95% CI 4.18 to 9.88); age less than 38 years (aOR 0.55, 95% CI 0.41 to 0.76); high intensity physical activity at work (aOR 1.33, 95% CI 1.03 to 1.73); working in production vs. administration (aOR 1.59, 95% CI 1.03 to 2.45); spending fewer than 4 years at the current work location (aOR 1.60, 95% CI 1.05 to 2.44); and scoring low for recognition at work (aOR 1.53, 95% CI 1.04 to 2.23). Noise exposure and being a shift worker were significant in univariable analysis, but not multivariable analysis. CONCLUSION: Occupational stress is very common among workers in industrial settings. The implementation and evaluation of preventive measures against these risk factors is necessary.

Scaling up target regimens for tuberculosis preventive treatment in Brazil and South Africa: An analysis of costs and cost-effectiveness.

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.

Safety of prolonged treatment with bedaquiline in programmatic conditions.

Bedaquiline is now considered a first-line medicine for treatment of rifampicin-resistant tuberculosis (RR-TB). We evaluated the safety of treatment with bedaquiline for longer than 190 days in individuals with RR-TB under programmatic conditions. In a prospective cohort study enrolling pulmonary RR-TB patients, we initiated bedaquiline-based treatment at a tertiary hospital in Belarus. We defined standard bedaquiline use as <190 days and prolonged as ≥190 days. We recorded adverse events (AEs) and classified their seriousness and relation to bedaquiline. Our primary outcome in regression analyses was the incidence of serious AEs occurring within 5 months of bedaquiline cessation. We used generalised estimating equations to estimate the adjusted incidence rate ratio (aIRR) of serious AEs between the prolonged and standard bedaquiline groups. We enrolled 113 patients, 83 (73%) of whom received standard and 30 (27%) received prolonged treatment. A total of 2030 AEs occurred during treatment. Of these, 63 (3.1%) were serious AEs occurring within 5 months of bedaquiline cessation; QTcF prolongation was the most common bedaquiline-related serious AE. The incidence of serious AEs per 100 person-months was 5.4 (3.9 to 7.2) in the standard group and 4.4 (2.6 to 7.0) in the prolonged group. In adjusted analyses, serious AEs were no different (aIRR: 0.82, 95% CI 0.42-1.61) in the prolonged group. One patient in the standard bedaquiline group died of acute cardiopulmonary failure deemed possibly related to bedaquiline. Prolonged use of bedaquiline under programmatic conditions appears safe. Clinicians should carefully monitor QTcF interval since its prolongation was commonly observed.

Systematic on-site testing for SARS-CoV-2 infection among asymptomatic essential workers in Montréal, Canada: a prospective observational and cost-assessment study.

BACKGROUND: Essential workers are at increased risk for SARS-CoV-2 infection. We aimed to estimate the yield, acceptability and cost of systematic workplace-based testing of asymptomatic essential workers for SARS-CoV-2 infection. METHODS: From Jan. 27 to Mar. 12, 2021, we prospectively recruited non-health care essential businesses in Montréal, Canada, through email or telephone contact. Two trained mobile teams, each composed of 2 non-health care professionals, visited businesses. Consenting asymptomatic employees provided saline gargle samples under supervision. Samples were analyzed by means of reverse transcription polymerase chain reaction (RT-PCR). At businesses with outbreaks (≥ 2 participants with a positive result), we retested all participants with a negative result on initial testing. Our primary outcomes were yield (proportion of test results that were positive), acceptability (proportion of participants estimated to be present at the business who agreed to participate) and costs (including training, sample collection and analysis, and communicating results). Our secondary outcome was identification of factors associated with a positive test result on multivariable logistic regression. RESULTS: Of the 366 businesses contacted, 69 (18.8%) agreed to participate. Nineteen businesses (28%) were manufacturers or suppliers, 12 (17%) were in auto sales or repair, and 11 (16%) were in childcare; the corresponding number of employees was 1225, 242 and 113. The median number of participants per business was 13 (interquartile range [IQR] 8-22). Of an estimated 2348 employees on site, 2128 (90.6%) participated (808 [38.0%] female, median age 48 [IQR 37-57] yr). Of the 2626 tests performed, 53 (2.0%) gave a positive result. Self-reported nonwhite ethnicity (adjusted odds ratio [OR] 3.7, 95% confidence interval [CI] 1.4-9.9) and a negative SARS-CoV-2 test result before the study (adjusted OR 0.4, 95% CI 0.2-0.8) were associated with a positive test result. Five businesses were experiencing an outbreak; at these businesses, 40/917 participants (4.4%) had a positive result on the initial test. We repeated testing for employees with initially negative results at 3 of these businesses over 2-3 weeks: 8/350 participants (2.3%) had a positive result on the second test, and none had a positive result on the third and fourth tests; no employer reported new positive results after our final visit (up to Mar. 26, 2021). At the remaining 64 businesses, 1211 participants were tested once, of whom 5 (0.4%) had a positive result. The per-person RT-PCR cost was $34, and all other costs, $8.67. INTERPRETATION: On-site saline gargle sampling of essential workers for SARS-CoV-2 testing was acceptable and of modest cost, and appears most useful in the context of outbreaks. This sampling strategy should be evaluated further as a component of efforts to prevent SARS-CoV-2 transmission. PREPRINT: medRxiv - doi:10.1101/2021.05.12.21256956.

Adequacy of Serial Self-performed SARS-CoV-2 Rapid Antigen Detection Testing for Longitudinal Mass Screening in the Workplace.

Importance: Longitudinal mass testing using rapid antigen detection tests (RADT) for serial screening of asymptomatic persons has been proposed for preventing SARS-CoV-2 community transmission. The feasibility of this strategy relies on accurate self-testing. Objective: To quantify the adequacy of serial self-performed SARS-CoV-2 RADT testing in the workplace, in terms of the frequency of correct execution of procedural steps and accurate interpretation of the range of possible RADT results. Design, Setting, and Participants: This prospective repeated cross-sectional study was performed from July to October 2021 at businesses with at least 2 active cases of SARS-CoV-2 infection in Montreal, Canada. Participants included untrained persons in their workplace, not meeting Public Health quarantine criteria (ie, required quarantine for 10 days after a moderate-risk contact with someone infected with SARS-CoV-2). Interpretation and performance were compared between participants who received instructions provided by the manufacturer vs those who received modified instructions that were informed by the most frequent or most critical errors we observed. Data were analyzed from October to November 2021. Exposures: RADT testing using a modified quick reference guide compared with the original manufacturer's instructions. Main Outcomes and Measures: The main outcome was the difference in correctly interpreted RADT results. Secondary outcomes included difference in proportions of correctly performed procedural steps. Additional analyses, assessed among participants with 2 self-testing visits, compared the second self-test visit with the first self-test visit using the same measures. Results: Overall, 1892 tests were performed among 647 participants, of whom 278 participants (median [IQR] age, 43 [31-55] years; 156 [56.1%] men) had at least 1 self-testing visit. For self-test visit 1, significantly better accuracy in test interpretation was observed among participants using the modified quick reference guide than those using the manufacturer's instructions for reading results that were weak positive (64 of 115 participants [55.6%] vs 20 of 163 participants [12.3%]; difference, 43.3 [95% CI, 33.0-53.8] percentage points), positive (103 of 115 participants [89.6%] vs 84 of 163 participants [51.5%]; difference, 38.1 [95% CI, 28.5-47.5] percentage points), strong positive (219 of 229 participants [95.6%] vs 274 of 326 participants [84.0%]; difference, 11.6 [95% CI, 6.8-16.3] percentage points), and invalid (200 of 229 participants [87.3%] vs 252 of 326 participants [77.3%]; difference, 10.0 [95% CI, 3.8-16.3] percentage points). Use of the modified guide was associated with improvements on self-test visit 2 for results that were weak positive (difference, 15.4 [95% CI, 0.7-30.1] percentage points), positive (difference, 19.0 [95% CI, 7.2-30.9] percentage points), and invalid (difference, 8.0 [95% CI, 0.8-15.4] percentage points). For procedural steps identified as critical for test validity, adherence to procedural testing steps did not differ meaningfully according to instructions provided or reader experience. Conclusions and Relevance: In this cross-sectional study of self-performed SARS-CoV-2 RADT in an intended-use setting, a modified quick reference guide was associated with significantly improved accuracy in RADT interpretations.

Treatment outcomes 24 months after initiating short, all-oral bedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study.

BACKGROUND: There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group). METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes. FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment. INTERPRETATION: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients. FUNDING: WHO Global TB Programme. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Prioritising attributes for tuberculosis preventive treatment regimens: a modelling analysis.

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.