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.

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.

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.

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.

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.

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.

Methodological considerations for economic modelling of latent tuberculous infection screening in migrants.

Tuberculosis (TB) in migrants from endemic to low-incidence countries results mainly from the reactivation of latent tuberculous infection (LTBI). LTBI screening policies for migrants vary greatly between countries, and the evidence on the cost-effectiveness of the different approaches is weak and heterogeneous. The aim of this review was to assess the methodology used in published economic evaluations of LTBI screening among migrants to identify critical methodological options that must be considered when using modelling to determine value for money from different economic perspectives. Three electronic databases were searched and 10 articles were included. There was considerable variation across this small number of studies with regard to economic perspective, main outcomes, modelling technique, screening options and target populations considered, as well as in parameterisation of the epidemiological situation, test accuracy, efficacy, safety and programme performance. Only one study adopted a societal perspective; others adopted a health care or wider government perspective. Parameters representing the cascade of screening and treating LTBI varied widely, with some studies using highly aspirational scenarios. This review emphasises the need for a more harmonised approach for economic analysis, and better transparency in how policy options and economic perspectives influence methodological choices. Variability is justifiable for some parameters. However, sufficient data are available to standardise others. A societal perspective is ideal, but can be challenging due to limited data. Assumptions about programme performance should be based on empirical data or at least realistic assumptions. Results should be interpreted within specific contexts and policy options, with cautious generalisations.

Sputum induction for tuberculosis diagnosis in an Arctic setting: a cost comparison.

SETTING: Tuberculosis (TB) incidence was 234 per 100 000 in Nunavut, Canada, in 2012. Until recently, some individuals seen in local clinics for presumed TB required costly air evacuation to Southern Canada (Ottawa) for investigation if they were unable to produce sputum spontaneously. OBJECTIVE: To estimate the cost per individual evaluated for TB, associated with the establishment of a sputum induction programme in Iqaluit, Nunavut, Canada. DESIGN: A decision analysis model compared the total cost per individual for two strategies: 1) initial investigation in Iqaluit, with transport to Ottawa for those requiring sputum induction; and 2) sputum induction at the hospital in Iqaluit, with further investigation in Ottawa only if needed. The model simulated diagnostic and treatment paths from the initial clinic visit to completion of TB investigation or treatment (when applicable). RESULTS: The estimated cost per person evaluated for TB with sputum induction in 1) Ottawa vs. 2) Iqaluit was CAD4798 (95% uncertainty range 2923-6650) vs. CAD2479 (1206-4256), respectively. Total costs were influenced by underlying TB prevalence, but local sputum induction consistently yielded cost savings. CONCLUSION: Providing sputum induction in a high-incidence Arctic community such as Iqaluit is projected to generate substantial cost savings in the investigation and management of individuals with presumed TB.

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.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Modeling social, environmental and biological determinants of tuberculosis.

Mathematical models have facilitated our understanding of infectious diseases dynamics and proved useful tools to compare control scenarios when interventional studies are not feasible or ethical. Here, we summarize evidence linking social, economic and biologic determinants to tuberculosis (TB) and review modeling approaches that have been used to understand their contribution to the epidemic dynamics of TB. Specifically, we find evidence for associations between smoking, indoor air pollution, diabetes mellitus, alcohol, nutritional status, crowding, migration, aging and economic trends, and the occurrence of TB infection and/or disease. We outline some methodological problems inherent to the study of these associations; these include study design issues, reverse causality and misclassification of both exposure and outcomes. We then go on to review two existing approaches to modeling the impact of determinants and the effect of interventions: the population attributable fraction model, which estimates the proportion of the TB burden that would be averted if exposure to a risk factor were eliminated from the population, and deterministic epidemic models that capture transmission dynamics and the indirect effects of interventions. We conclude by defining research priorities in both the study of specific determinants and the development of appropriate models to assess the impact of addressing these determinants.

Patient and family costs associated with tuberculosis, including multidrug-resistant tuberculosis, in Ecuador.

BACKGROUND: There is little published information on the costs of multidrug-resistant tuberculosis (MDR-TB) for patients and their families in low- or middle-income countries. METHODS: Between February and July 2007, patients with microbiologically confirmed active TB who had received 2 months of treatment completed an interviewer-administered questionnaire on direct out-of-pocket expenditures and indirect costs from lost wages. Clinical data were abstracted from their medical records. RESULTS: Among 104 non-MDR-TB patients, total TB-related patient costs averaged US$960 per patient, compared to an average total cost of US$6880 for 14 participating MDR-TB patients. This represents respectively 31% and 223% of the average Ecuadorian annual income. The high costs associated with MDR-TB were mainly due to the long duration of illness, which averaged 22 months up to the time of the interview. This resulted in very long periods of unemployment. Most patients experienced a significant drop in income, particularly the MDR-TB patients, all of whom were earning less than US$100/month at the time of the interview. CONCLUSION: Direct and indirect costs borne by patients with active TB and their families are very high in Ecuador, and are highest for patients with MDR-TB. These costs are important barriers to treatment completion.

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.

Global tuberculosis trends: a reflection of changes in tuberculosis control or in population health?

BACKGROUND: Many international organizations are advocating for new funds for tuberculosis (TB) specific interventions. Although this approach should help reduce TB incidence, improvements in population health may also be important. We have analyzed the association between changes in population health and health service indicators, and concomitant changes in TB incidence between 1990 and 2005. METHODS: Country level data on population health and health services, economic and epidemiologic indicators were obtained for 165 countries. Regression methods were used to estimate the association of changes in potential predictors with changes in TB incidence. RESULTS: Improvements in population health and health services are associated with improvements in TB outcomes. In adjusted analyses, each 1 year increase in life expectancy was associated with a 7.8/100,000 decline in TB incidence. A 1/1000 decrease in mortality rate in children aged <5 years and a 1% increase in measles vaccination coverage (serving as a general health services indicator) was associated with approximately a 1/100,000 decrease in TB incidence. In countries with a lower prevalence of human immunodeficiency virus (HIV) infection, a 1% increase in TB treatment success rate was also associated with a 1/100,000 decrease in incidence. CONCLUSION: Investment in improving population health and health services may be as important as targeted strategies for controlling TB.

Costs incurred by patients with pulmonary tuberculosis in rural India.

SETTING: Vellore District, Tamil Nadu, India. OBJECTIVE: To measure patient costs associated with diagnosis and the complete treatment of tuberculosis (TB). DESIGN: Prospective structured interview of 100 new smear-positive adult patients being treated for TB in Tamil Nadu, India, selected evenly from 10 representative health facilities in the state. Direct (out-of-pocket) and indirect (lost-time) costs were quantified by period of illness using a standardised questionnaire, and univariate regression investigated predictors of total cost. RESULTS: Seventy-four per cent of patients were male, with a mean age of 40.2 years. All were given a first-line regimen, and none had been previously treated. The mean direct cost was US$34.91 (SD $46.94), the mean indirect cost was $526.87 (SD $375.71), and the total mean cost per patient was $562.66 (SD $287.48). Twenty-five patients were admitted to hospital, at a mean cost of $279.43 (SD $142.88) per admission. Variation in costs was associated with admission. CONCLUSION: TB patients in India incur large costs associated with TB illness. The greatest single cost was time lost during admission. Total patient costs represent 193% of the estimated monthly income of a manual labourer.

Cost of tuberculosis diagnosis and treatment from the patient perspective in Lusaka, Zambia.

SETTING: Urban primary health centres in Lusaka, Zambia. OBJECTIVES: 1) To estimate patient costs for tuberculosis (TB) diagnosis and treatment and 2) to identify determinants of patient costs. METHODS: A cross-sectional survey of 103 adult TB patients who had been on treatment for 1-3 months was conducted using a standardised questionnaire. Direct and indirect costs were estimated, converted into US$ and categorised into two time periods: 'pre-diagnosis/care-seeking' and 'post-diagnosis/treatment'. Determinants of patient costs were analysed using multiple linear regression. RESULTS: The median total patient costs for diagnosis and 2 months of treatment was $24.78 (interquartile range 13.56-40.30) per patient--equivalent to 47.8% of patients' median monthly income. Sex, patient delays in seeking care and method of treatment supervision were significant predictors of total patient costs. The total direct costs as a proportion of income were higher for women than men (P < 0.001). Treatment costs incurred by patients on the clinic-based directly observed treatment strategy were more than three times greater than those incurred by patients on the self-administered treatment strategy (P < 0.001). CONCLUSION: Clinic-based treatment supervision posed a significant economic burden on patients. The creation or strengthening of community-based treatment supervision programmes would have the greatest potential impact on reducing patients' TB-related costs.

Interferon-gamma release assays and TB screening in high-income countries: a cost-effectiveness analysis.

OBJECTIVE: Interferon-gamma release assays (IGRA) are now available alternatives to tuberculin skin testing (TST) for detection of latent tuberculosis infection (LTBI). We compared the cost-effectiveness of TST and IGRA in different populations and clinical situations, and with variation of a number of parameters. METHODS: Markov modelling was used to compare expected TB cases and costs over 20 years following screening for TB with different strategies among hypothetical cohorts of foreign-born entrants to Canada, or contacts of TB cases. The less expensive commercial IGRA, Quanti-FERON-TB Gold (QFT), was examined. Model inputs were derived from published literature. RESULTS: For entering immigrants, screening with chest radiograph (CXR) would be the most and QFT the least cost-effective. Sequential screening with TST then QFT was more cost-effective than QFT alone in all scenarios, and more cost-effective than TST alone in selected subgroups. Among close and casual contacts, screening with TST or QFT would be cost saving; savings with TST would be greater than with QFT, except in contacts who were bacille Calmette-Guérin (BCG) vaccinated after infancy. CONCLUSIONS: Screening for LTBI, with TST or QFT, is cost-effective only if the risk of disease is high. The most cost-effective use of QFT is to test TST-positive persons.