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

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

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

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

Long-Term Protective Effect of Tuberculosis Preventive Therapy in a Medium/High Tuberculosis Incidence Setting.

BACKGROUND: The duration of the protective effect of tuberculosis preventive therapy (TPT) is controversial. Some studies have found that the protective effect of TPT is lost after cessation of therapy among people with human immunodeficiency virus (HIV) in settings with very high tuberculosis incidence, but others have found long-term protection in low-incidence settings. METHODS: We estimated the incidence rate (IR) of new tuberculosis disease for up to 12 years after randomization to 4 months of rifampin or 9 months of isoniazid, among 991 Brazilian participants in a TPT trial in the state of Rio de Janeiro, with an incidence of 68.6/100 000 population in 2022. The adjusted hazard ratios (aHRs) of independent variables for incident tuberculosis were calculated. RESULTS: The overall tuberculosis IR was 1.7 (95% confidence interval [CI], 1.01- 2.7) per 1000 person-years (PY). The tuberculosis IR was higher among those who did not complete TPT than in those who did (2.9 [95% CI, 1.3-5.6] vs 1.1 [.4-2.3] per 1000 PY; IR ratio, 2.7 [1.0-7.2]). The tuberculosis IR was higher within 28 months after randomization (IR, 3.5 [95% CI, 1.6-6.6] vs 1.1 [.5-2.1] per 1000 PY between 28 and 143 months; IR ratio, 3.1 [1.2-8.2]). Treatment noncompletion was the only variable associated with incident tuberculosis (aHR, 3.2 [95% CI, 1.1-9.7]). CONCLUSIONS: In a mostly HIV-noninfected population, a complete course of TPT conferred long-term protection against tuberculosis.

The Effectiveness of a Self-Directed e-Learning Module on Trainee Knowledge and Confidence during Plastic Surgery Clinical Rotations.

Background: Exposure to plastic surgery is limited during medical school. This makes rotations for clinical clerks and off-service residents challenging. Available resources are often too detailed and overwhelming. Having an accessible, concise, and interactive plastic surgery e-learning module reviewing core plastic surgery topics could help prepare incoming trainees for their rotations. Methods: An e-learning module was created using text, images, and in-house recorded video recordings. Two cohorts were recruited: control cohort (n = 9), who completed their plastic surgery rotation without use of the module, and an interventional cohort (n = 18), who completed the rotation with use of the module. A demographic survey, a 20-question multiple-choice knowledge test, and self-reported confidence score were completed by both cohorts at the end of their plastic surgery rotations. The intervention cohort also completed the knowledge test at the beginning of their rotation to establish baseline. Knowledge and confidence scores were compared using two-tailed, unpaired, nonparametric analyses (Mann-Whitney test). Results: Learners from the intervention cohort reported a 95% module completion rate and found the resource "extremely helpful" (average Likert of 4.8/5). Learners indicated that they were very likely to recommend the resource to others (average Likert 4.9/5). The intervention cohort scored significantly higher on the knowledge test compared with the control cohort (P = 0.008), and on average reported higher confidence levels; however, this was not statistically significant (P = 0.057). Conclusion: An accessible and concise module on core plastic surgery concepts enhances learner knowledge and confidence during plastic surgery clinical rotations.

Gender Equality in Plastic Surgery Training: A Canadian Nationwide Cross-sectional Analysis.

Introduction: One of the important factors in achieving gender equity is ensuring equitable surgical training for all. Previous studies have shown that females get significantly lower surgical exposure than males in certain surgical specialties. Gender gap in surgical exposure has never been assessed in plastic surgery. To that end, the goal of this study was to assess if there are any differences in plastic surgery training between male and female residents. Methods: A survey was sent to all plastic surgery residency programs in Canada to assess the No. of surgeries residents operated on as a co-surgeon or primary assistant during their training. The survey also assessed career goals, level of interest in the specialty, and subjective perception of gender bias. Results: A total of 89 plastic surgery residents (59.3% participation rate) completed the survey and were included in the study. The average No. of reconstructive cases residents operated on as a co-surgeon or primary assistant was 245 ± 312 cases. There was no difference in either reconstructive or aesthetic surgery case logs between male and female residents (p > .05). However, a significantly larger proportion of females (39%) compared to males (4%) felt that their gender limited their exposure to surgical cases and led to a worsening of their overall surgical training (p < .001). Finally, a larger proportion of male residents were interested in academic careers while a larger proportion of female residents were interested in a community practice (p = .024). Conclusion: While there is no evidence of differences in the volume of logged cases between genders, female surgical residents still feel that their respective gender limits their overall surgical training. Gender inequalities in training should be addressed by residency programs.

Introduction: L'un des facteurs importants pour atteindre l'égalité des genres est d'assurer une formation chirurgicale équitable pour tous. Des études antérieures ont montré que les femmes ont une exposition significativement moindre à la chirurgie que les hommes dans certaines spécialités chirurgicales. L'écart entre genres pour l'exposition à la chirurgie n'a jamais été évalué en chirurgie plastique. À cette fin, la présente étude a eu pour objectif d'évaluer s'il y avait des différences dans la formation à la chirurgie plastique entre les résidents masculins et féminins. Méthodes: Une enquête a été envoyée à tous les programmes canadiens de résidence en chirurgie plastique pour évaluer le nombre d'interventions auxquelles les résidents ont participé en tant que co-chirurgien ou assistant principal au cours de leur formation. L'enquête a également évalué les objectifs de carrière, le niveau d'intérêt dans la spécialité et la perception subjective d'un biais lié au genre. Résultats: En tout, 89 résidents en chirurgie plastique (taux de participation de 59,3 %) ont répondu à l'enquête et ont été inclus dans l'étude. Le nombre moyen de cas de chirurgie reconstructrice au cours desquelles les résidents sont intervenus en tant que co-chirurgien ou principal assistant était de 245 ± 312 cas. Il n'y a pas eu de différence entre les journaux de cas, qu'il s'agisse de chirurgie reconstructrice ou de chirurgie esthétique entre résidents masculins et féminins (P > 0,05). Cependant, un nettement plus grand pourcentage de femmes (39 %) que d'hommes (4 %) estimait que leur genre limitait leur exposition à des cas chirurgicaux et résultait dans une aggravation de leur formation globale à la chirurgie (P < 0,001). Enfin, un plus grand pourcentage de résidents masculins était intéressé par une carrière universitaire alors qu'un plus grand pourcentage de résidentes était intéressé par une pratique dans la communauté (P = 0,024). Conclusion: Bien qu'il n'y ait pas de données probantes étayant des différences de volume des cas consignés entre les genres, les résidentes féminines en chirurgie pensent encore que leur genre limite leur formation chirurgicale. Les inégalités entre genres devraient être abordées par les programmes de résidence.

GeneXpert or chest-X-ray or tuberculin skin testing for household contact assessment (GXT): protocol for a cluster-randomized trial.

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.

Improving Equity, Diversity, and Inclusion in Plastic, Reconstructive, and Aesthetic Surgery in Canada: A Call to Action.

The global COVID-19 pandemic has brought to light the significant inequities in the delivery of healthcare, vaccine inequity, and differential access to life-saving treatments, which have disproportionately impacted marginalized and racialized populations. In this article, we acknowledge and recognize the centuries-old legacies perpetuating inequity, injustice, and oppression, we discuss the principles of Equity, Diversity, and Inclusion (EDI) and we call our Canadian plastic surgery colleagues and trainees to action. We propose a plan for (1) Education, (2) Mitigating Disparities in the Clinical Setting, and (3) Policy, Societies, and Leadership Education.

La pandémie mondiale de COVID-19 a mis en lumière des iniquités importantes dans la prestation des soins, l'iniquité vaccinale et l'accès différentiel à des traitements salvateurs, qui ont touché démesurément les populations marginalisées et racisées. Dans le présent article, les auteurs reconnaissent les héritages séculaires qui perpétuent l'iniquité, l'injustice et l'oppression, ils abordent les principes d'équité, de diversité et d'inclusion et ils appellent à l'action leurs collègues et leurs stagiaires canadiens en chirurgie plastique. Ils proposent un plan en matière (1) d'éducation, (2) d'atténuation des disparités en milieu clinique et (3) de politique, de société et d'éducation au leadership.

Can We Reach a Consensus on the Appropriate Use of Before and After Photos in Breast Surgery?

Breast surgery is an area of practice where patients value before and after photographs (BAPs). Consensus is needed to develop guidelines to address the deficit in the literature regarding appropriate use of BAPs, as these may ultimately play a significant role in the breast surgery consent process. METHODS: Expert breast reconstructive surgeons participated in a modified nominal group technique (NGT) to establish expert consensus on categories and criteria to be used when evaluating appropriate use of BAPs as part of informed consent. Endorsement rate of 75% and coefficients of variance within and between rounds were conducted to determine validity of each criteria item's rank order. RESULTS: Eight experts participated in the NGT in-person meeting and subsequent online survey. five of seven categories were endorsed for discussion: purpose, image type, anatomy, results, and photographic integrity. Overall consensus was obtained for six of 11 criteria. Criteria items found to have consensus were: patients considering surgery being the intended photograph audience (100% endorsement, CV1 - CV2 = 0.01), use of photographic images (75% endorsement, CV1 - CV2 = 0.04), defining the standard clinical photograph by having patients in the same body position (100% endorsement, CV1 - CV2 = 0.14), anonymizing images by removing all digital tags (88% endorsement, CV1 - CV2 = 0.03) and patient identifiers (75% endorsement, CV1 - CV2 = 0.00), not limiting the number of photograph sets needed for sufficient representation (100% endorsement, CV1 - CV2 = 0.07), and representing average outcomes (100%, CV1 - CV2 = 0.06). CONCLUSIONS: Early use of this validated and effective technique helps identify potential consensus categories and criteria that surgeons recommend for the use of BAPs in the informed consent process. Further study is required.

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

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

Effects of programmatic interventions to improve the management of latent tuberculosis: a follow up study up to five months after implementation.

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.

Solutions to improve the latent tuberculosis Cascade of Care in Ghana: a longitudinal impact assessment.

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.

Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials.

BACKGROUND: An important problem limiting treatment of latent tuberculosis infection is the occurrence of adverse events with isoniazid. We combined populations from phase 2 and phase 3 open-label, randomised controlled trials, to establish risk factors for adverse events during latent tuberculosis infection treatment. METHODS: We did a post-hoc safety analysis based on data from two open-label, randomised controlled trials done in health-care facilities in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea. Participants were consenting adults (aged ≥18 years) with a positive latent tuberculosis infection diagnostic test, indication for treatment, and without contraindications to rifampicin or isoniazid. Patients were centrally randomly assigned 1:1 to 4 months of daily 10 mg/kg rifampicin or 9 months of daily 5 mg/kg isoniazid. The primary outcome evaluated was adverse events (including grade 1-2 rash and all events of grade 3-5) resulting in permanent discontinuation of study medication and judged possibly or probably related to study drug by a masked, independent, three-member adjudication panel (trial registration: NCT00170209; NCT00931736). FINDINGS: Participants were recruited from April 27, 2004, up until Jan 31, 2007 (phase 2), and Oct 1, 2009, up until Dec 31, 2014 (phase 3). The safety populations for each group comprised 3205 individuals receiving isoniazid and 3280 receiving rifampicin. Among those receiving isoniazid, 86 (2·7%) of 3205 had grade 1-2 rash or any grade 3-5 adverse events, more than the 50 (1·5%) of 3280 who had these events with rifampicin (risk difference -1·2%, 95% CI -1·9 to -0·5). Age was associated with adverse events in adults receiving isoniazid. Compared with individuals aged 18-34 years, the adjusted odds ratio (OR) for adverse events was 1·8 (95% CI 1·1-3·0) for individuals aged 35-64 years and 3·0 (1·2-6·8) for individuals aged 65-90 years. With rifampicin, adverse events were associated with inconsistent medication adherence (adjusted OR 2·0, 1·1-3·6) and concomitant medication use (2·8, 1·5-5·2), but not age, with an adjusted OR of 1·1 (0·6-2·1) for individuals aged 35-64 years and 1·7 (0·5-4·7) for individuals aged 65-90 years. One treatment-related death occurred in the isoniazid group. INTERPRETATION: In patients without a contraindication, rifampicin is likely to be the safest latent tuberculosis infection treatment option. With more widespread use of rifampicin, rare, but serious adverse events might be seen. However, within these randomised trials, rifampicin was safer than isoniazid and adverse events were not associated with older age. Therefore, rifampicin should become a primary treatment option for latent tuberculosis infection based on its safety. FUNDING: Canadian Institutes of Health Research.

The mTST - An mHealth approach for training and quality assurance of tuberculin skin test administration and reading.

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.

Enhancing the public health impact of latent tuberculosis infection diagnosis and treatment (ACT4): protocol for a cluster randomised trial.

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.

Safety and Side Effects of Rifampin versus Isoniazid in Children.

BACKGROUND: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid. METHODS: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis. RESULTS: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14). CONCLUSIONS: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis.

Major adverse reactions to antituberculosis drugs can cause significant morbidity, and compromise treatment regimens for tuberculosis (TB). Among patients treated for active TB we estimated the incidence, and risk factors, of major side effects from first-line anti-TB drugs. Side effects, resulting in modification or discontinuation of therapy, or hospitalization, were attributed on the basis of resolution after withdrawal, and/or recurrence with rechallenge. Among 430 patients treated between 1990 and 1999, the incidence of all major adverse effects was 1.48 per 100 person-months of exposure (95% confidence interval [95% CI], 1.31 to 1.61) for pyrazinamide, compared with 0.49 (95% CI, 0.42 to 0.55) for isoniazid, 0.43 (95% CI, 0.37 to 0.49) for rifampin, and 0.07 (95% CI, 0.04 to 0.10) for ethambutol. Occurrence of any major side effect was associated with female sex (adjusted hazard ratio, 2.5; 95% CI, 1.3 to 4.7), age over 60 years (adjusted hazard ratio, 2.9; 95% CI, 1.3 to 6.3), birthplace in Asia (adjusted hazard ratio, 2.5; 95% CI, 1.3 to 5.0), and human immunodeficiency virus-positive status (adjusted hazard ratio, 3.8; 95% CI, 1.05 to 13.4). Pyrazinamide-associated adverse events were associated with age over 60 years (adjusted hazard ratio, 2.6; 95% CI, 1.01 to 6.6) and birthplace in Asia (adjusted hazard ratio, 3.4; 95% CI, 1.4 to 8.3), whereas rifampin-associated adverse events were associated with age over 60 years (adjusted hazard ratio, 3.9; 95% CI, 1.02 to 14.9) and human immunodeficiency virus-positive status (adjusted hazard ratio, 8.0; 95% CI, 1.5 to 43). The incidence of pyrazinamide-induced hepatotoxicity and rash during treatment for active TB was substantially higher than with the other first-line anti-TB drugs, and higher than previously recognized.