Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Determinants of Bacillus Calmette-Guérin (BCG) vaccination among Québec children.

OBJECTIVES: To identify determinants of Bacillus Calmette-Guérin (BCG) vaccination among children born in Québec, Canada, in 1974, the last year of the systematic vaccination campaign. METHOD: A retrospective birth cohort was assembled in 2011 through probabilistic linkage of administrative databases (n=81,496). Potential determinants were documented from administrative databases and by interviewing a subset of subjects (n=1643) in 2012. Analyses were conducted among subjects with complete data, 71,658 (88%) birth cohort subjects and 1154 (70%) interviewed subjects, then redone using multiple imputation. Determinants of BCG vaccination during the organized vaccination program (in 1974), and after the program (1975 onwards) were assessed separately. Logistic regression with backward elimination was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Overall, 46% of subjects were BCG vaccinated, 43% during the program and 4% after it ended. BCG vaccination during the program was associated with parents' birthplace and urban or rural residence. BCG vaccination after the organized program was only related to ethnocultural origin of the child's grandparents. CONCLUSION: Different factors were related to vaccination within and after the organized program. Determinants of BCG vaccination in Québec, Canada, have never been studied and will be useful for future research and vaccination campaigns.

Molecular confirmation of nine cases of Cornelia de Lange syndrome diagnosed prenatally.

OBJECTIVES: Cornelia de Lange syndrome (CdLS) is characterized by distinct facial features, growth retardation, upper limb reduction defects, hirsutism, and intellectual disability. NIPBL mutations have been identified in approximately 60% of patients with CdLS diagnosed postnatally. Prenatal ultrasound findings include upper limb reduction defects, intrauterine growth restriction, and micrognathia. CdLS has also been associated with decreased PAPP-A and increased nuchal translucency (NT). We reviewed NIPBL sequence analysis results for 12 prenatal samples in our laboratory to determine the frequency of mutations in our cohort. METHODS: This retrospective study analyzed data from all 12 prenatal cases with suspected CdLS, which were received by The University of Chicago Genetic Services Laboratories. Diagnostic NIPBL sequencing was performed for all samples. Clinical information was collected from referring physicians. RESULTS: NIPBL mutations were identified in 9 out of the 12 cases prenatally (75%). Amongst the NIPBL mutation-positive cases with clinical information available, the most common findings were upper limb malformations and micrognathia. Five patients had NT measurements in the first trimester, of which four were noted to be increased. CONCLUSION: We demonstrate that prenatally-detected phenotypes of CdLS, particularly severe micrognathia and bilateral upper limb defects, are associated with an increased frequency of NIPBL mutations.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Epidemiology of tuberculosis immunology.

Immunological impairment plays a major role in the epidemiology of TB. Globally, the most common causes of immunological impairment are malnutrition, diabetes, HIV/AIDS, aging, and smoking. With the notable exception of HIV, each factor leads to relatively mild immunological impairment in individuals. However, as these conditions affect a significant proportion of the population, they contribute substantially to the incidence of TB at a global scale. Understanding immunological impairment is central to understanding the global TB pandemic, and vital to the development of effective disease control strategies.

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

The impact and cost-effectiveness of strategies to detect drug-resistant tuberculosis.

Drug-resistant tuberculosis (TB) is a serious emerging problem in many low-resource countries. TB control programmes are uncertain of which drug susceptibility tests (DSTs) to use and when to test patients. We predicted the potential cost-effectiveness of different DST strategies, in settings with varying prevalence of drug resistance. Using decision analysis, we assessed the cost-effectiveness of conventional and rapid DSTs for previously diagnosed smear-positive TB cases. Five different time-points were considered for administering DSTs. Different initial drug resistance and HIV scenarios were also considered. All DST scenarios in the wide range of settings considered were found to be cost-effective. The strategy of performing a rapid DST that detects any form of isoniazid (INH) and rifampicin (RIF) resistance for all patients before the initiation of treatment was predicted to be the most cost-effective strategy. In a setting with moderate drug resistance, the cost per disability-adjusted life year gained was as low as US$744. Our findings support the roll-out of rapid drug susceptibility testing at the moment of diagnosis to detect any form of INH and RIF resistance in all countries with moderate or greater burdens of drug-resistant TB.

Development and evaluation of an objective laparoscopic assessment tool: LapPass®.

INTRODUCTION: Laparoscopic surgery is technically challenging and assessment of competency is necessary to ensure patient safety and guide training. We report on the development of LapPass®, an accessible objective simulation assessment tool with credentialing potential. We provide a preliminary evaluation of its usability and aspects of validity. METHODS: The domains of LapPass® were defined through a consensus process by the executive council of the Association of Laparoscopic Surgeons of Great Britain and Ireland (ALSGBI). A survey of both assessors and trainees was used to test for usability, face and content validity of LapPass®. Internal consistency was tested with Cronbach's alpha, and a composite marker of validity and usability was obtained. RESULTS: LapPass® was developed to consist of four tasks: (1) grasping and manipulation, (2) simulated appendicectomy, (3) cutting a disk and (4) intracorporeal suturing. A total of 76 participants contributed to the evaluation of LapPass®: 13 assessors and 63 trainees. For assessors, Cronbach's alpha for usability of tasks 1-4 was 0.84, 0.84, 0.76 and 0.86, whereas validity was 0.80, 0.85, 0.88, 0.95, respectively. For trainees, Cronbach's alpha was 0.75, 0.77, 0.80 and 0.85 for usability, and 0.79, 093, 0.87 and 0.91 for validity. Consensus was that each task was usable and had face and content validity, with median scores of 4.0 or higher (interquartile range 0.0-1.0). CONCLUSION: LapPass® has potential for the objective assessment of basic laparoscopic skills but further research is required to explore its predictive capabilities in a clinical setting.

Patterns and characteristics of TB among key risk groups in Canada, 1993-2018.

BACKGROUND: Canada has a low incidence of TB, although certain groups are disproportionately affected.OBJECTIVE: To describe and compare the epidemiology, trends and characteristics of TB in Quebec, Canada, among all patients reported during 1993-2018.METHODS: Demographics and risk factors were compared for the three groups accounting for most TB diagnoses reported in Quebec (foreign-born, Canadian-born non-Indigenous and Inuit). Average annual incidence and incidence rate ratios (IRRs) were estimated and compared using Poisson regression.RESULTS: Of 6,941 persons with a first episode of TB, 4,077 (59%) were foreign-born, 2,314 (33%) were Canadian-born non-Indigenous and 389 (6%) were Inuit. The average annual incidence for foreign-born, Canadian-born non-Indigenous and Inuit was respectively 17.0, 1.4 and 137.1 per 100,000 population. Compared to Canadian-born non-Indigenous, the IRR for foreign-born and Inuit was respectively 12.3 (95% CI 11.6-12.9) and 98.7 (95% CI 88.6-109.9). There was evidence of community transmission among the Inuit, with more than 80% of patients having a TB contact (2012-2018 data) and 65% (251/389) of diagnoses in those aged <25 years.CONCLUSION: Although TB rates among the Canadian-born non-Indigenous are extremely low, there are persistent and distinct TB epidemics among the foreign-born and Inuit. Tailored approaches to TB prevention and care are needed to address TB among high-risk populations in low TB incidence settings.

Implementing the 4R and 9H regimens for TB preventive treatment in Indonesia.

BACKGROUND: The implementation of tuberculosis preventive treatment (TPT) is challenging especially in resource-limited settings. As part of a Phase 3 trial on TPT, we described our experience with the use of rifampicin for 4 months (4R) and isoniazid for 9 months (9H) in Indonesia.METHODS: In 2011-2017, children and adults with latent TB infection were randomised to either 4R or 9H and followed until 16 months after randomisation for children and 28 months for adults. The primary outcome was the treatment completion rate. Secondary outcomes were Grade 3-5 adverse events (AEs), active TB occurrence, and health costs.RESULTS: A total of 157 children and 860 adults were enrolled. The 4R treatment completion rate was significantly higher than that of 9H (78.7% vs. 65.5%), for a rate difference of 13.2% (95% CI 7.1-19.2). No Grade 3-5 AEs were reported in children; in adults, it was lower in 4R (0.4%) compared to 9H (2.8%). The incidence of active TB was lower with 4R than with 9H (0.09/100 person-year vs. 0.36/100 person-year) (rate difference: -0.36/100 person-year). The total cost per patient was lower for the 4R regimen than for the 9H regimen (USD151.9 vs. USD179.4 in adults and USD152.9 vs. USD206.5 in children)CONCLUSIONS: Completion and efficacy rates for 4R were better than for 9H. Compared to 9H, 4R was cheaper in all age groups, safer in adults and equally safe in children. The Indonesian TB program could benefit from these benefits of the 4R regimen.

WHO target product profiles for TB preventive treatment.

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.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis.

Lipoarabinomannan (LAM) is a potential marker of active tuberculosis (TB). We performed a systematic review and meta-analysis regarding use of urinary LAM assays for diagnosing active TB. We systematically searched for published and unpublished studies that evaluated urinary LAM for active TB diagnosis. Extracted data were pooled using bivariate random effects models and hierarchical summary receiver operating characteristic curves. Heterogeneity was explored through subgroup analysis and meta-regression. Quality was assessed according to standardised QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. In seven studies that assessed test accuracy in microbiologically confirmed cases only, estimates of sensitivity ranged from 13% to 93%, while specificity ranged from 87% to 99%. In five studies that assessed accuracy in clinical and confirmed TB cases, sensitivity ranged from 8% to 80%, while specificity ranged from 88% to 99%. In five studies with results stratified by HIV status, sensitivity was 3-53% higher in HIV-positive than HIV-negative subgroups; sensitivity was highest with advanced immunosuppression. The LAM urinary assay has several characteristics that make it attractive for diagnosing active TB, but has suboptimal sensitivity for routine clinical use. Further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV or for diagnosis of paediatric TB.

Aspergillus sensitization is associated with airflow limitation and bronchiectasis in severe asthma.

BACKGROUND: Abnormalities, including bronchiectasis, that are detectable on high-resolution computed tomography (HRCT) have been associated with severe asthma. Bronchiectasis is associated with the diagnosis of allergic bronchopulmonary aspergillosis (ABPA), which also occurs in patients with severe asthma. We sought to determine the frequency and pattern of HRCT abnormality and the relationship with Aspergillus fumigatus sensitization in one severe asthma population. METHODS: We examined our database of patients attending a supraregional severe asthma service (Manchester, UK). Clinical, physiological and immunological characteristics were compared between those with HRCT evidence of airway disease (specifically bronchiectasis) and those with no radiological abnormality. RESULTS: Of 133 patients analysed, 111 (83.4%) had an abnormal HRCT with bronchial wall thickening (41.3%), bronchiectasis (35.3%), air trapping (20.3%) and bronchial dilatation (16.5%) occurring most frequently. Radiological evidence of airway disease was associated with more obstructive spirometry (postbronchodilator FEV1/FVC ratio 73.2%vs 64.8% [difference -8.5%, 95% CI -16.9 to -0.1, P = 0.048]). A. fumigatus sensitization was associated with a 2.01 increased hazard ratio of bronchiectasis (95% CI 1.26 to 3.22, P = 0.005), and more obstructive spirometry (postbronchodilator FEV1/FVC ratio 57.6 vs 70.3 [difference -12.8, 95% CI -19.8 to -5.7, P = 0.001]). Patients with A. fumigatus sensitization had variable clinical and radiological characteristics that frequently did not conform to the conventional diagnostic criteria for ABPA. CONCLUSION: Patients with severe asthma frequently have radiological abnormalities on HRCT. Sensitization to A. fumigatus is associated with bronchiectasis and greater airflow obstruction, even when diagnostic criteria for ABPA are not met.

Experiences with latent TB cascade of care strengthening for household contacts in Calgary, Canada.

SETTING: Identification, assessment, and treatment of latent TB infection (LTBI), collectively known as the LTBI cascade of care, is critical for TB prevention. OBJECTIVE: The objective of this research, conducted within the ACT4 trial, was to assess and strengthen the LTBI cascade of care for household contacts at Calgary TB Services, a clinic serving a predominately foreign-born population in Western Canada. DESIGN: Baseline assessment consisted of a retrospective LTBI cascade analysis of 32 contact investigations, and questionnaires administered to patients and health care workers. Four solutions were implemented in response to identified gaps. Solution impact was measured for 6 months using descriptive statistics. RESULTS: Pre-implementation, 56% of household contacts initiated treatment. Most contacts were lost to care because the tuberculin skin test (TST) was not initiated, or physicians did not recommend treatment. Evening clinics, a patient education pamphlet, a nursing workshop, and treatment recommendation guidelines were implemented. Post-implementation, losses due to LTBI treatment non-recommendation were reduced; however, the overall proportion of household contacts initiating treatment did not increase. CONCLUSION: Close engagement between researchers and TB programmes can reduce losses in the LTBI cascade. To see sustained improvement in overall outcomes, long-term engagement and data collection for ongoing problem-solving are required.

CONTEXTE: L'identification, l'évaluation et le traitement de l'infection tuberculeuse latente (LTBI) ­ collectivement connus sous le nom de « cascade de soins de la LTBI ¼ ­ sont essentiels à la prévention de la TB. OBJECTIF: L'objectif de cette étude, réalisée dans le cadre de l'essai ACT4, était d'évaluer et de renforcer la cascade de soins de la LTBI pour les contacts domestiques au Calgary TB Services, une clinique traitant principalement une population née à l'étranger dans l'ouest du Canada. PLAN: Il s'agissait d'une évaluation initiale comprenant une analyse rétrospective de la cascade de soins de la LTBI de 32 recherches de contacts et des questionnaires administrés aux patients et aux professionnels de santé. Quatre solutions ont été mises en place en réponse aux lacunes identifiées. L'impact des solutions a été mesuré pendant 6 mois à l'aide de statistiques descriptives. RÉSULTATS: Avant la mise en place des solutions, 56% des contacts domestiques avaient démarré un traitement. La plupart des contacts ont été perdus de vue car l'intradermoréaction à la tuberculine (TST) n'avait pas été effectuée ou car les médecins ne recommandaient pas de traitement. Des solutions ont été mises en place, telles que l'ouverture des cliniques en soirée, un dépliant informatif pour les patients, un atelier de travail à destination des infirmiers et des directives thérapeutiques. Après la mise en place des solutions, les pertes dues à l'absence de recommandation de traitement contre la LTBI ont été réduites, mais la proportion globale de contacts domestiques démarrant un traitement n'a pas augmenté. CONCLUSION: Une collaboration étroite entre chercheurs et programmes de lutte contre la TB peut réduire les pertes observées au cours de la cascade de soins de la LTBI. Afin d'obtenir une amélioration durable des résultats globaux, un engagement de long terme et un recueil des données sont requis pour résoudre les problèmes actuels.

TB preventive treatment in high- and intermediate-incidence countries: research needs for scale-up.

BACKGROUND: In 2018, the WHO Member States committed to providing TB preventive treatment (TPT) to at least 30 million people by 2022. However, only 6.3 million people had initiated TPT by the end of 2019. Major knowledge gaps and research needs in diagnosis, treatment and the programmatic management of TPT (PMTPT) require to be addressed urgently.METHODS: In September 2019, a group of stakeholders involved in PMTPT in high TB burden countries met to develop an action agenda to support the global expansion of PMTPT.RESULTS: Barriers at the health system level, and priorities for research to overcome these, were identified for each step of the PMTPT cascade. The need for data on TPT financing, gaps and coverage under national health insurance schemes, as well as the need for mathematical and cost-effectiveness modelling of the impact of TPT on TB incidence and mortality were highlighted. Specific research needs were identified for high-risk populations such as household contacts of any age and people living with HIV, as well as other people at risk.CONCLUSIONS: The meeting facilitated agreement on a set of actions needed to ensure that PMTPT continues to expand to achieve the End TB Strategy targets.

Predicting outcomes and drug resistance with standardised treatment of active tuberculosis.

New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment. A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance. Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48-86 fewer persons will require retreatment, and 3-12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50-94% of failures and 3-56% of relapses will have multidrug-resistant TB. We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.

Interventions to reduce losses in the cascade of care for latent tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Losses can occur throughout the latent tuberculosis infection (LTBI) cascade of care. This can result in suboptimal rates of effective treatment for LTBI. We conducted a systematic review and meta-analysis to estimate the effect of different interventions to reduce losses in the LTBI cascade before treatment completion.METHODS: We searched several databases for articles reporting outcomes for interventions designed to strengthen the LTBI cascade. We included papers published in English from January 1990 until February 2018. Where possible, estimates were pooled using random-effects meta-analysis.RESULTS: We identified 30 studies that evaluated 32 different interventions aimed at reducing losses in the LTBI cascade. In pooled analysis, interventions that improved completion of cascade steps included patient incentives (respectively 42 [95% CI 34-51] and 48 [95% CI 15-81] additional patients completing initial assessment and medical evaluation per 100 starting); health care worker education (28 [95% CI 4-52] additional patients initiating initial assessment per 100 identified; home visits (additional 13 [95% CI 4-21] patients completing initial assessment per 100 starting); digital solutions (additional 11 [95% CI 4-21] patients initiating initial assessment per 100 identified); and patient reminders (additional 7 [95% CI 0.3-13] patients completing initial assessment per 100 starting). Several other interventions reduced losses at specific cascade steps, but evidence for these interventions came from single studies and could not be pooled.CONCLUSIONS: Although there is limited evidence that any single intervention significantly improves the LTBI cascade, many studies provide information about effective ways to strengthen it.

A public health approach to increase treatment of latent TB among household contacts in Brazil.

SETTING: Two consecutive trials were conducted to evaluate the effectiveness of a public health approach to identify and correct problems in the care cascade for household contacts (HHCs) of TB patients in three Brazilian high TB incidence cities.METHODS: In the first trial, 12 clinics underwent standardised evaluation using questionnaires administered to TB patients, HHCs and healthcare workers, and analysis of the cascade of latent TB care among HHCs. Six clinics were then randomised to receive interventions to strengthen management of latent TB infection (LTBI), including in-service training provided by nurses, work process organisation and additional clinic-specific solutions. In the second trial, a similar but streamlined evaluation was conducted in two clinics, who then received initial and subsequent intensive in-service training provided by a physician.RESULTS: In the evaluation phase of both trials, many HHCs were identified, but few started LTBI treatment. After the intervention, the number of HHCs initiating treatment per 100 active TB patients increased by 10 (95%CI - 11 to 30) in the first trial, and by 44 (95%CI 26 to 61) in the second trial.DISCUSSION: A public health approach with standardised evaluation, local decisions for improvements, followed by intensive initial and in-service training appears promising for improved LTBI management.