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Background: Tuberculosis (TB) imposes a substantial health and economic burden on many populations and countries, but lack of funding has significantly contributed to several countries falling short of global TB reduction targets. Furthermore, existing assessments of the economic impact of TB do not capture the impacts on productivity and economic growth or the pathways by which epidemiology, demography, and the economy interact. Evidence is needed to answer how investment in treatment and control measures may help to mitigate the twin Indian health and macroeconomic burdens of TB over the coming decades., Methods and Findings: We develop a fully integrated dynamic macroeconomic-health-demographic simulation model for India, the country with the largest national TB burden, and use it to estimate the macroeconomic return to investment in TB treatment. Our estimated results indicate that, over 2021 to 2040, the health and macroeconomic burdens of TB in India will include over 62.4m incident cases, 8.1m TB-related deaths and a cumulative gross domestic product (GDP) loss of US$146.4bn. Low-income households will bear larger health and relative economic burdens while larger absolute economic burdens will fall on high-income households. Achieving the World Health Organisation's End TB target of 90% case detection could reduce clinical and demographic disease burdens by 75% to 89% and reduce the macroeconomic burden by US$120.2bn. Developing a 95% effective pan-TB treatment regimen would reduce the same burdens by 25% to 31% and US$35.3bn, respectively, while less effective but immediately achievable scaling-up of existing treatment regimens would reduce burdens by 20% to 25% and US$28.4bn, respectively. If an increase in case detection to 90% could be combined with 95% effective pan-TB treatment, it could reduce clinical and demographic disease burdens by 78% to 91% and reduce the macroeconomic burden by US$124.2bn. In order to develop this complex integrated model framework, some aspects of the epidemiological model were simplified such that the model does not capture, for example, separate modelling of drug susceptible and multidrug-resistant (MDR) cases or separate public/private healthcare provision. However, future iterations of the model could address these limitations., Conclusions: In this study, we find that even our least effective, but most accessible, revised TB treatment regimen has the potential to generate US$28bn in GDP gains. Clearly, the economic gains of increasing case detection rates and implementing improved TB treatment regimens hinges on both the feasibility and timeframe over which they can be achieved in practice. Nevertheless, the revised TB treatment regimen is readily accessible, and our results therefore demonstrate that there is room for undertaking substantial additional investment in control and treatment of TB in India, in order to reduce the suffering of TB patients while maintaining acceptable provision of resourcing elsewhere in the Indian economy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Keogh-Brown et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tuberculosis infection prevention and control (TB IPC) measures are a cornerstone of policy, but measures are diverse and variably implemented. Limited attention has been paid to the health system environment, which influences successful implementation of these measures. We used qualitative system dynamics and group-model-building methods to (1) develop a qualitative causal map of the interlinked drivers of Mycobacterium tuberculosis (Mtb) transmission in South African primary healthcare facilities, which in turn helped us to (2) identify plausible IPC interventions to reduce risk of transmission. Two 1-day participatory workshops were held in 2019 with policymakers and decision makers at national and provincial levels and patient advocates and health professionals at clinic and district levels. Causal loop diagrams were generated by participants and combined by investigators. The research team reviewed diagrams to identify the drivers of nosocomial transmission of Mtb in primary healthcare facilities. Interventions proposed by participants were mapped onto diagrams to identify anticipated mechanisms of action and effect. Three systemic drivers were identified: (1) Mtb nosocomial transmission is driven by bottlenecks in patient flow at given times; (2) IPC implementation and clinic processes are anchored within a staff 'culture of nominal compliance'; and (3) limited systems learning at the policy level inhibits effective clinic management and IPC implementation. Interventions prioritized by workshop participants included infrastructural, organizational and behavioural strategies that target three areas: (1) improve air quality, (2) improve use of personal protective equipment and (3) reduce the number of individuals in the clinic. In addition to core mechanisms, participants elaborated specific additional enablers who would help sustain implementation. Qualitative system dynamics modelling methods allowed us to capture stakeholder views and potential solutions to address the problem of sub-optimal TB IPC implementation. The participatory elements of system dynamics modelling facilitated problem-solving and inclusion of multiple factors frequently neglected when considering implementation., (© The Author(s) 2024. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Providing social support to tuberculosis (TB) patients is a recommended strategy as households having TB patients find themselves in a spiral of poverty because of high cost, huge income loss and several other economic consequences associated with TB treatment. However, there are few examples of social support globally. The Indian government introduced the 'Nikshay Poshan Yojana' scheme in 2018 to provide nutritional support for all registered TB patients. A financial incentive of 500 Indian Rupee (6 United States Dollars) per month was proposed to be transferred directly to the registered beneficiaries' validated bank accounts. We examined the reach, timing, amount of benefit receipt and the extent to which the benefit alleviated catastrophic costs (used as a proxy to measure the impact on permanent economic welfare as catastrophic cost is the level of cost that is likely to result in a permanent negative economic impact on households) by interviewing 1482 adult drug-susceptible TB patients from 16 districts of four states during 2019 to 2023, using the methods recommended by the World Health Organization for estimating household costs of TB nationally. We also estimated the potential amount of social support required to achieve a zero catastrophic cost target. At the end of treatment, 31-54% of study participants received the benefit. In all, 34-60% of TB patients experienced catastrophic costs using different estimation methods and the benefit helped 2% of study participants to remain below the catastrophic cost threshold. A uniform benefit amount of Indian Rupee 10 000 (127 United States Dollars) for 6 months of treatment could reduce the incidence of catastrophic costs by 43%. To improve the economic welfare of TB patients, levels of benefit need to be substantially increased, which will have considerable budgetary impact on the TB programme. Hence, a targeted rather than universal approach may be considered. To maximize impact, at least half of the revised amount should be given immediately after treatment registration., (© The Author(s) 2024. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

We read with great interest the recent paper by Lo et al., who argue that there is an urgent need to ensure the quality of modelling evidence used to support international and national guideline development. Here we outline efforts by the Tuberculosis Modelling and Analysis Consortium, together with the World Health Organization Global Task Force on Tuberculosis Impact Measurement, to develop material to improve the quality and transparency of country-level tuberculosis modelling to inform decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There has been an increasing interest in assessing disease-specific catastrophic costs incurred by affected households as part of economic evaluations and to inform joint social/health policies for vulnerable groups. Although the longitudinal study design is the gold standard for estimating disease-specific household costs, many assessments are implemented with a cross-sectional design for pragmatic reasons. We aimed at identifying the potential biases of a cross-sectional design for estimating household cost, using the example of tuberculosis (TB), and exploring optimal approaches for sampling and interpolating cross-sectional cost data to estimate household costs., Methods: Data on patient incurred costs, household income and coping strategies were collected from TB patients in Negros Occidental and Cebu in the Philippines between November 2018 and October 2020. The data collection tools were developed by adapting WHO Tuberculosis Patient Cost Surveys: A Handbook into a longitudinal study design. TB-specific catastrophic cost estimates were compared between longitudinal and simulated cross-sectional designs using different random samples from different times points in treatment (intensive and continuation phases)., Results: A total of 530 adult TB patients were enrolled upon TB diagnosis in this study. Using the longitudinal design, the catastrophic cost estimate for TB-affected households was 69 % using the output approach. The catastrophic cost estimates with the simulated cross-sectional design were affected by the reduction and recovery in household income during the episode of TB care and ranged from 40 to 55 %., Conclusion: Using longitudinally collected costs incurred by TB-affected households, we illustrated the potential limitations and implications of estimating household costs using a cross-sectional design. Not capturing changes in household income at multiple time points during the episode of the disease and estimating from inappropriate samples may result in biases that underestimates catastrophic cost., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Diabetes is a risk factor for TB mortality and relapse. The Philippines has a high TB incidence with co-morbid diabetes. This study assessed the pre- and post-TB diagnosis costs incurred by people with TB and diabetes (TB-DM) and their households in the Philippines., Methods: Longitudinal data was collected for costs, income, and coping mechanisms of TB-affected households in Negros Occidental and Cebu, the Philippines. Data collection was conducted four times during TB treatment. The data collection tools were developed by adapting WHO's cross-sectional questionnaire in the Tuberculosis Patient Cost Surveys: A Handbook into a longitudinal study design. Demographic and clinical characteristics, self-reported household income, number of facility visits, patient costs, the proportion of TB-affected households facing catastrophic costs due to TB (>20% of annual household income before TB), coping mechanisms, and social support received were compared by diabetes status at the time of TB diagnosis., Results: 530 people with TB were enrolled in this study, and 144 (27.2%) had TB-DM based on diabetes testing at the time of TB diagnosis. 75.4% of people with TB-DM were more than 45 years old compared to 50.3% of people with TB-only (p<0.001). People with TB-DM had more frequent visits for TB treatment (120 vs 87 visits, p = 0.054) as well as for total visits for TB-DM treatment (129 vs 88 visits, p = 0.010) compared to those with TB-only. There was no significant difference in the proportion of TB-affected households facing catastrophic costs between those with TB-DM (76.3%) and those with TB-only (68.7%, p = 0.691)., Conclusion: People with TB-DM in the Philippines face extensive health service use. However, this does not translate into substantial differences in the incidence of catastrophic cost. Further study is required to understand the incidence of catastrophic costs due to diabetes-only in the Philippines., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yamanaka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Declaration of interests ABe reports a grant through the University of California San Francisco (UCSF) from the US Agency for International Development (USAID) for the SMART4TB Initiative. RC reports a grant from USAID. HC is a member of the Data Safety Monitoring Board for the TRIAD study. CMD reports grants from the US National Institutes of Health (NIH), WHO, German Ministry of Education and Research, German Alliance for Global Health Research, USAID, FIND, German Center for Infection Research, UNAIDS, and Roche Diagnostics; is an academic editor for PLOS Medicine; and is a member of the WHO technical advisory group for tuberculosis diagnostics. EG is a board member for the TB Alliance and reports a grant from USAID for the SMART4TB Initiative. JH reports a grant from the Stop TB Partnership Private Sector Constituency. NH is a member of the British Parliament and co-chair of the Global TB Caucus. PHo reports a grant from USAID for the SMART4TB Initiative. AKi reports personal fees and a contract through UCSF (which also provides travel support) from USAID for the SMART4TB Initiative. IK holds a leadership position at the Save the Children Federation. EL reports personal fees from USAID for the SMART4TB initiative and held a leadership position with Treatment Action Group. PN reports a grant from USAID for the SMART4TB Initiative. MRe reports a grant from USAID for the SMART4TB Initiative. MO reports grants from the Global Fund, Johnson & Johnson, and Cepheid. MP serves as an advisor for the Bill & Melinda Gates Foundation, Foundation for Innovative New Diagnostics, WHO, and Stop TB Partnership. PS reports stock in Hyfe AI. AV reports a grant from Johnson & Johnson. GEV reports grants from the NIH/National Institute of Allergy and Infectious Diseases, Harvard Medical School, Harvard Global Health Institute, Unitaid/Partners in Health, and USAID; and is a protocol co-vice chair for a study with the TB Alliance and for a study with Janssen. GY reports grants from the Gates Foundation and WHO. AZ reports personal fees from Open Consultants. AC reports grants from the US NIH, Global Health Labs, and USAID; and is a member of the Centers for Disease Control and Prevention Advisory Council on Elimination of TB. PHe reports a grant from the Gates Foundation. The remaining authors declare no competing interests.

Background: Drug-sensitive tuberculosis treatment requires 6 months of therapy, so adherence problems are common. Digital adherence technologies might improve tuberculosis treatment outcomes. We aimed to evaluate the effect of a daily reminder medication monitor, monthly review of adherence data by the health-care provider, and differentiated care for patients with adherence issues, on tuberculosis treatment adherence and outcomes., Methods: We did a cluster-randomised superiority trial across four prefectures in China. 24 counties or districts (clusters) were randomly assigned (1:1) to intervention or control groups. We enrolled patients aged 18 years or older with GeneXpert-positive, rifampicin-sensitive pulmonary tuberculosis, who were receiving daily fixed-dose combination treatment. Patients in the intervention group received a medication monitor for daily drug-dosing reminders, monthly review of adherence data by health-care provider, and management of poor adherence; and patients in the control group received routine care (silent-mode monitor-measured adherence). Only the independent endpoints review committee who assessed endpoint data for some participants were masked to study group assignment. Patients were followed up (with sputum solid culture) at 12 and 18 months. The primary outcome was a composite of death, loss to follow-up, treatment failure, switch to multidrug-resistant tuberculosis treatment, or tuberculosis recurrence by 18 months from treatment start, analysed in the intention-to-treat population. Analysis accounted for study design with multiple imputation for the primary outcome. This trial is now complete and is registered with ISRCTN, 35812455., Findings: Between Jan 26, 2017, and April 3, 2019, 15 257 patients were assessed for eligibility and 3074 were enrolled, 2686 (87%) of whom were included in the intention-to-treat population. 1909 (71%) of 2686 patients were male, 777 (29%) were female, and the median age was 44 years (IQR 29-58). By 18 months from treatment start, using multiple imputation for missing outcomes, 239 (16% [geometric mean of cluster-level proportion]) of 1388 patients in the control group and 224 (16%) of 1298 in the intervention group had a primary composite outcome event (289 [62%] of 463 events were loss to follow-up during treatment and 42 [9%] were tuberculosis recurrence). The intervention had no effect on risk of the primary composite outcome (adjusted risk ratio 1·01, 95% CI 0·73-1·40)., Interpretation: Our digital medication monitor intervention had no effect on unfavourable outcomes, which included loss to follow-up during treatment, tuberculosis recurrence, death, and treatment failure. There was a failure to change patient management following identification of treatment non-adherence at monthly reviews. A better understanding of adherence patterns and how they relate to poor outcomes, coupled with a more timely review of adherence data and improved implementation of differentiated care, may be required., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Nosocomial Mycobacterium tuberculosis ( Mtb ) transmission substantially impacts health workers, patients and communities. Guidelines for tuberculosis infection prevention and control (TB IPC) exist but implementation in many settings remains suboptimal. Evidence is needed on cost-effective investments to prevent Mtb transmission that are feasible in routine clinic environments., Methods: A set of TB IPC interventions was codesigned with local stakeholders using system dynamics modelling techniques that addressed both core activities and enabling actions to support implementation. An economic evaluation of these interventions was conducted at two clinics in KwaZulu-Natal, employing agent-based models of Mtb transmission within the clinics and in their catchment populations. Intervention costs included the costs of the enablers (eg, strengthened supervision, community sensitisation) identified by stakeholders to ensure uptake and adherence., Results: All intervention scenarios modelled, inclusive of the relevant enablers, cost less than US$200 per disability-adjusted life-year (DALY) averted and were very cost-effective in comparison to South Africa's opportunity cost-based threshold (US$3200 per DALY averted). Two interventions, building modifications to improve ventilation and maximising use of the existing Central Chronic Medicines Dispensing and Distribution system to reduce the number of clinic attendees, were found to be cost saving over the 10-year model time horizon. Incremental cost-effectiveness ratios were sensitive to assumptions on baseline clinic ventilation rates, the prevalence of infectious TB in clinic attendees and future HIV incidence but remained highly cost-effective under all uncertainty analysis scenarios., Conclusion: TB IPC interventions in clinics, including the enabling actions to ensure their feasibility, afford very good value for money and should be prioritised for implementation within the South African health system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

BACKGROUND: The Ethiopian Government has identified efficiency of TB services as a key priority in planning and budgeting. Understanding the magnitude and sources of inefficiencies is key to ensuring value for money and improved service provision, and a requirement from donors to justify resource needs. This study identifies the cost of providing a wide range of TB services in public and private facilities in Ethiopia. METHODS: Financial and economic unit costs were estimated from a health provider´s perspective, and collected retrospectively in 26 health facilities using both top-down (TD) and bottom-up (BU) costing approaches for each TB service output. Capacity inefficiency was assessed by investigating the variation between TD and BU unit costs where the factor was 2.0 or more. RESULTS: Overall, TD unit costs were two times higher than BU unit costs. There was some variation across facility ownership and level of care. Unit costs in urban facilities were on average 3.8 times higher than in rural facilities. CONCLUSION: We identified some substantial inefficiencies in staff, consumable and capital inputs. Addressing these inefficiencies and rearranging the TB service delivery modality would be important in ensuring the achievement of the country´s End TB strategy.

BACKGROUND: There are currently large gaps in unit cost data for TB, and substantial variation in the quality and methods of unit cost estimates. Uncertainties remain about sample size, range and comprehensiveness of cost data collection for different purposes. We present the methods and results of a project implemented in Kenya, Ethiopia, India, The Philippines and Georgia to estimate unit costs of TB services, focusing on findings most relevant to these remaining methodological challenges. METHODS: We estimated financial and economic unit costs, in close collaboration with national TB programmes. Gold standard methods included both top-down and bottom-up approaches to resource use measurement. Costs are presented in 2018 USD and local currency unit. RESULTS: Cost drivers of outputs varied by service and across countries, as did levels of capacity inefficiency. There was substantial variation in unit cost estimates for some interventions and high overhead costs were observed. Estimates were subject to sampling uncertainty, and some data gaps remain. CONCLUSION: This paper describes detailed methods for the largest TB costing effort to date, to inform prioritisation and planning for TB services. This study provides a strong baseline and some cost estimates may be extrapolated from this data; however, regular further studies of similar quality are needed to add estimates for remaining gaps, or to add new or changing services and interventions. Further research is needed on the best approach to extrapolation of cost data. Costing studies are best implemented as partnerships with policy makers to generate a community of mutual learning and capacity development.

To better understand and plan health systems featuring multiple levels and complex causal elements, there have been increasing attempts to incorporate tools arising from complexity science to inform decisions. The utilization of new planning approaches can have important implications for the types of evidence that inform health policymaking and the mechanisms through which they do so. This paper presents an empirical analysis of the application of one such tool-system dynamics modelling (SDM)-within a tuberculosis control programme in South Africa in order to explore how SDM was utilized, and to reflect on the implications for evidence-informed health policymaking. We observed group model building workshops that served to develop the SDM process and undertook 19 qualitative interviews with policymakers and practitioners who partook in these workshops. We analysed the relationship between the SDM process and the use of evidence for policymaking through four conceptual perspectives: (1) a rationalist knowledge-translation view that considers how previously-generated research can be taken up into policy; (2) a programmatic approach that considers existing goals and tasks of decision-makers, and how evidence might address them; (3) a social constructivist lens exploring how the process of using an evidentiary planning tool like SDM can shape the understanding of problems and their solutions; and (4) a normative perspective that recognizes that stakeholders may have different priorities, and thus considers which groups are included and represented in the process. Each perspective can provide useful insights into the SDM process and the political nature of evidence use. In particular, SDM can provide technical information to solve problems, potentially leave out other concerns and influence how problems are conceptualized by formalizing the boundaries of the policy problem and delineating particular solution sets. Undertaking the process further involves choices on stakeholder inclusion affecting whose interests may be served as evidence to inform decisions., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Background: The nationwide lockdown (March 25 to June 8, 2020) to curb the spread of coronavirus infection had significant health and economic impacts on the Indian economy. There is limited empirical evidence on how COVID-19 restrictive measures may impact the economic welfare of specific groups of patients, e.g., tuberculosis patients. We provide the first such evidence for India., Methods: A total of 291 tuberculosis patients from the general population and from a high-risk group, patients from tea garden areas, were interviewed at different time points to understand household income loss during the complete lockdown, three and eight months after the complete lockdown was lifted. Income loss was estimated by comparing net monthly household income during and after lockdown with prelockdown income. Tuberculosis service utilization patterns before and during the lockdown period also were examined. Household income loss, travel and other expenses related to tuberculosis drug pickup were presented in 2020 US dollars (1 US$ = INR 74.132)., Results: 26% of households with tuberculosis patients in tea garden areas and 51% of households in the general population had zero monthly income during the complete lockdown months (April-May 2020). Overall income loss slowly recovered during July-August compared to April-May 2020. Approximately 7% of patients in the general population and 4% in tea garden areas discontinued their tuberculosis medicines because of the complete lockdown., Conclusion: Discontinuation of medicine will have an additional burden on the tuberculosis elimination program in terms of additional cases, including multidrug resistant tuberculosis cases. Income loss for households and poor restoration of income after the lockdown will likely have an impact on the nutrition of tuberculosis patients and families. Tuberculosis patients working in the informal sector were the worst affected group during the nationwide lockdown. This emphasizes that a policy priority must continue to protect those working in informal sectors from the economic consequences of such restrictive measures, including paid sick leave, additional food support, and direct benefit transfers. Alongside ensuring widespread access to COVID-19 vaccines, these policy actions remain pivotal in ensuring the well-being of those who are unfortunate enough to be living with tuberculosis., (© 2022. The Author(s).)

Health system constraints are increasingly recognized as an important addition to model-based analyses of disease control interventions, as they affect achievable impact and scale. Enabling activities implemented alongside interventions to relax constraints and reach the intended coverage may incur additional costs, which should be considered in priority setting decisions. We explore the use of group model building, a participatory system dynamics modelling technique, for eliciting information from key stakeholders on the constraints that apply to tuberculosis infection prevention and control processes within primary healthcare clinics in South Africa. This information was used to design feasible interventions, including the necessary enablers to relax existing constraints. Intervention and enabler costs were then calculated at two clinics in KwaZulu-Natal using input prices and quantities from the published literature and local suppliers. Among the proposed interventions, the most inexpensive was retrofitting buildings to improve ventilation (US$1644 per year), followed by maximizing the use of community sites for medication collection among stable patients on antiretroviral therapy (ART; US$3753) and introducing appointments systems to reduce crowding (US$9302). Enablers identified included enhanced staff training, supervision and patient engagement activities to support behaviour change and local ownership. Several of the enablers identified by the stakeholders, such as obtaining building permissions or improving information flow between levels of the health systems, were not amenable to costing. Despite this limitation, an approach to costing rooted in system dynamics modelling can be successfully applied in economic evaluations to more accurately estimate the 'real world' opportunity cost of intervention options. Further empirical research applying this approach to different intervention types (e.g. new preventive technologies or diagnostics) may identify interventions that are not cost-effective in specific contexts based on the size of the required investment in enablers., (© The Author(s) 2021. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

BACKGROUND: Patient-centred care along with optimal financing of inpatient and outpatient services are the main priorities of the Georgia National TB Programme (NTP). This paper presents TB diagnostics and treatment unit cost, their comparison with NTP tariffs and how the study findings informed TB financing policy. METHODS: Top-down (TD) and bottom-up (BU) mean unit costs for TB interventions by episode of care were calculated. TD costs were compared with NTP tariffs, and variations in these and the unit costs cost composition between public and private facilities was assessed. RESULTS: Outpatient interventions costs exceeded NTP tariffs. Unit costs in private facilities were higher compared with public providers. There was very little difference between per-day costs for drug-susceptible treatment and NTP tariffs in case of inpatient services. Treatment day financing exceeded actual costs in the capital (public facility) for drug-resistant TB, and this was lower in the regions. CONCLUSION: Use of reliable unit costs for TB services at policy discussions led to a shift from per-day payment to a diagnosis-related group model in TB inpatient financing in 2020. A next step will be informing policy decisions on outpatient TB care financing to reduce the existing gap between funding and costs.

BACKGROUND: The reduction of Kenya´s TB burden requires improving resource allocation both to and within the National TB, Leprosy and Lung Disease Program (NTLD-P). We aimed to estimate the unit costs of TB services for budgeting by NTLD-P, and allocative efficiency analyses for future National Strategic Plan (NSP) costing. METHODS: We estimated costs of all TB interventions in a sample of 20 public and private health facilities from eight counties. We calculated national-level unit costs from a health provider´s perspective using bottom-up (BU) and top-down (TD) approaches for the financial year 2017-2018 using Microsoft Excel and STATA v16. RESULTS: The mean unit cost for passive case-finding (PCF) was respectively US$38 and US$60 using the BU and TD approaches. The unit BU and TD costs of a 6-month first-line treatment (FLT) course, including monitoring tests, was respectively US$135 and US$160, while those for adult drug-resistant TB (DR-TB) treatment was respectively US$3,230.28 and US$3,926.52 for the 9-month short regimen. Intervention costs highlighted variations between BU and TD approaches. Overall, TD costs were higher than BU, as these are able to capture more costs due to inefficiency (breaks/downtime/leave). CONCLUSION: The activity-based TB unit costs form a comprehensive cost database, and the costing process has built-in capacity within the NTLD-P and international TB research networks, which will inform future TB budgeting processes.

BACKGROUND: There is a dearth of economic analysis required to support increased investment in TB in India. This study estimates the costs of TB services from a health systems´ perspective to facilitate the efficient allocation of resources by India´s National Tuberculosis Elimination Programme. METHODS: Data were collected from a multi-stage, stratified random sample of 20 facilities delivering TB services in two purposively selected states in India as per Global Health Cost Consortium standards and using Value TB Data Collection Tool. Unit costs were estimated using the top-down (TD) and bottom-up (BU) methodology and are reported in 2018 US dollars. RESULTS: Cost of delivering 50 types of TB services and four interventions varied according to costing method. Key services included sputum smear microscopy, Xpert ® MTB/RIF and X-ray with an average BU costs of respectively US$2.45, US$17.36 and US$2.85. Average BU cost for bacille Calmette-Guérin vaccination, passive case-finding, TB prevention in children under 5 years using isoniazid and first-line drug treatment in new pulmonary and extrapulmonary TB cases was respectively US$0.76, US$1.62, US$2.41, US$103 and US$98. CONCLUSION: The unit cost of TB services and outputs are now available to support investment decisions, as diagnosis algorithms are reviewed and prevention or treatment for TB are expanded or updated in India.

Objectives: This paper presents the iterative process of participatory multistakeholder engagement that informed the development of a new national tuberculosis (TB) policy in Georgia, and the lessons learnt., Methods: Guided by realist evaluation methods, a multistakeholder dialogue was organised to elicit stakeholders' assumptions on challenges and possible solutions for better TB control. Two participatory workshops were conducted with key actors, interspersed by reflection meetings within the research team and discussions with policymakers. Using concept mapping and causal mapping techniques, and drawing causal loop diagrams, we visualised how actors understood TB service provision challenges and the potential means by which a results-based financing (RBF) policy could address these., Setting: The study was conducted in Tbilisi, Georgia., Participants: A total of 64 key actors from the Ministry of Labour, Health and Social Affairs, staff of the Global Fund to Fight AIDS, TB and Malaria Georgia Project, the National Centre for Disease Control and Public Health, the National TB programme, TB service providers and members of the research team were involved in the workshops., Results: Findings showed that beyond provider incentives, additional policy components were necessary. These included broadening the incentive package to include institutional and organisational incentives, retraining service providers, clear redistribution of roles to support an integrated care model, and refinement of monitoring tools. Health system elements, such as effective referral systems and health information systems were highlighted as necessary for service improvement., Conclusions: Developing policies that address complex issues requires methods that facilitate linkages between multiple stakeholders and between theory and practice. Such participatory approaches can be informed by realist evaluation principles and visually facilitated by causal loop diagrams. This approach allowed us leverage stakeholders' knowledge and expertise on TB service delivery and RBF to codesign a new policy., Competing Interests: Competing interests: AZ being the project PI, is both a member of the Results4TB research team and a member of parliament in Georgia., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Early in the COVID-19 pandemic, models predicted hundreds of thousands of additional TB deaths as a result of health service disruption. To date, empirical evidence on the effects of COVID-19 on TB outcomes has been limited. Here we summarise the evidence available at a country level, identifying broad mechanisms by which COVID-19 may modify TB burden and mitigation efforts. From the data, it is clear that there have been substantial disruptions to TB health services and an increase in vulnerability to TB. Evidence for changes in Mycobacterium tuberculosis transmission is limited, and it remains unclear how the resources required and available for the TB response have changed. To advocate for additional funding to mitigate the impact of COVID-19 on the global TB burden, and to efficiently allocate resources for the TB response, requires a significant improvement in the TB data available.

Objectives: Health systems face nonfinancial constraints that can influence the opportunity cost of interventions. Empirical methods to explore their impact, however, are underdeveloped. We develop a conceptual framework for defining health system constraints and empirical estimation methods that rely on routine data. We then present an empirical approach for incorporating nonfinancial constraints in cost-effectiveness models of health benefit packages for the health sector., Methods: We illustrate the application of this approach through a case study of defining a package of services for tuberculosis case-finding in South Africa. An economic model combining transmission model outputs with unit costs was developed to examine the cost-effectiveness of alternative screening and diagnostic algorithms. Constraints were operationalized as restrictions on achievable coverage based on: (1) financial resources; (2) human resources; and (3) policy constraints around diagnostics purchasing. Cost-effectiveness of the interventions was assessed under one "unconstrained" and several "constrained" scenarios. For the unconstrained scenario, incremental cost-effectiveness ratios were estimated with and without the costs of "relaxing" constraints., Results: We find substantial differences in incremental cost-effectiveness ratios across scenarios, leading to variations in the decision rules for prioritizing interventions. In constrained scenarios, the limiting factor for most interventions was not financial, but rather the availability of human resources., Conclusions: We find that optimal prioritization among different tuberculosis control strategies in South Africa is influenced by whether and how constraints are taken into consideration. We thus demonstrate both the importance and feasibility of considering nonfinancial constraints in health sector resource allocation models., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

BACKGROUND: Despite a scarcity of tuberculosis (TB) cost data, a substantial body of evidence has been accumulating for drug-susceptible TB (DS-TB) treatment. In this study, we review unit costs for DS-TB treatment from a provider´s perspective. We also examine factors driving cost variations and extrapolate unit costs across low- and middle-income countries (LMICs). METHODS: We searched published and grey literature for any empirically collected TB cost estimates. We selected a subgroup of estimates looking at DS-TB treatment. We extracted information on activities and inputs included. We standardised costs into an average per person-month, fitted a multi-level regression model and cross-validated country-level predictions. We then extrapolated estimates for facility-based, directly observed DS-TB treatment across countries. RESULTS: We included 95 cost estimates from 28 studies across 17 countries. Costs predictions were sensitive to characteristics such as delivery mode, whether hospitalisation was included, and inputs accounted for, as well as gross domestic product per capita. Extrapolation results are presented with uncertainty intervals (UIs) for LMICs. Predicted median costs per 6 months of treatment were US$315.30 (95% CI US$222.60-US$417.20) for low-income, US$527.10 (95% CI US$395.70-US$743.70) for lower middle-income and US$896.40 (95% CI US$654.00-US$1214.40) for upper middle-income countries. CONCLUSIONS: Our study provides country-level DS-TB treatment cost estimates suitable for priority setting. These estimates, while not standing as a substitute for local high-quality primary data, can inform global, regional and national exercises.

Background: There is a need for easily accessible tuberculosis unit cost data, as well as an understanding of the variability of methods used and reporting standards of that data., Objective: The aim of this systematic review was to descriptively review papers reporting tuberculosis unit costs from a healthcare provider perspective looking at methodological variation; to assess quality using a study quality rating system and machine learning to investigate the indicators of reporting quality; and to identify the data gaps to inform standardised tuberculosis unit cost collection and consistent principles for reporting going forward., Methods: We searched grey and published literature in five sources and eight databases, respectively, using search terms linked to cost, tuberculosis and tuberculosis health services including tuberculosis treatment and prevention. For inclusion, the papers needed to contain empirical unit cost estimates for tuberculosis interventions from low- and middle-income countries, with reference years between 1990 and 2018. A total of 21,691 papers were found and screened in a phased manner. Data were extracted from the eligible papers into a detailed Microsoft Excel tool, extensively cleaned and analysed with R software (R Project, Vienna, Austria) using the user interface of RStudio. A study quality rating was applied to the reviewed papers based on the inclusion or omission of a selection of variables and their relative importance. Following this, machine learning using a recursive partitioning method was utilised to construct a classification tree to assess the reporting quality., Results: This systematic review included 103 provider perspective papers with 627 unit costs (costs not presented here) for tuberculosis interventions among a total of 140 variables. The interventions covered were active, passive and intensified case finding; tuberculosis treatment; above-service costs; and tuberculosis prevention. Passive case finding is the detection of tuberculosis cases where individuals self-identify at health facilities; active case finding is detection of cases of those not in health facilities, such as through outreach; and intensified case finding is detection of cases in high-risk populations. There was heterogeneity in some of the reported methods used such cost allocation, amortisation and the use of top-down, bottom-up or mixed approaches to the costing. Uncertainty checking through sensitivity analysis was only reported on by half of the papers (54%), while purposive and convenience sampling was reported by 72% of papers. Machine learning indicated that reporting on 'Intervention' (in particular), 'Urbanicity' and 'Site Sampling', were the most likely indicators of quality of reporting. The largest data gap identified was for tuberculosis vaccination cost data, the Bacillus Calmette-Guérin (BCG) vaccine in particular. There is a gap in available unit costs for 12 of 30 high tuberculosis burden countries, as well as for the interventions of above-service costs, tuberculosis prevention, and active and intensified case finding., Conclusion: Variability in the methods and reporting used makes comparison difficult and makes it hard for decision makers to know which unit costs they can trust. The study quality rating system used in this review as well as the classification tree enable focus on specific reporting aspects that should improve variability and increase confidence in unit costs. Researchers should endeavour to be explicit and transparent in how they cost interventions following the principles as laid out in the Global Health Cost Consortium's Reference Case for Estimating the Costs of Global Health Services and Interventions, which in turn will lead to repeatability, comparability and enhanced learning from others.

Background and Objective: In context of the End TB goal of zero tuberculosis (TB)-affected households encountering catastrophic costs due to TB by 2020, the estimation of national prevalence of catastrophic costs due to TB is a priority to inform programme design. We explore approaches to estimate the national prevalence of catastrophic costs due to TB from existing datasets as an alternative to nationally representative surveys., Methods: We obtained, standardized and merged three patient-level datasets from existing studies on patient-incurred costs due to TB in South Africa. A deterministic cohort model was developed with the aim of estimating the national prevalence of catastrophic costs, using national data on the prevalence of TB and likelihood of loss to follow-up by income quintile and HIV status. Two approaches were tested to parameterize the model with existing cost data. First, a meta-analysis summarized study-level data by HIV status and income quintile. Second, a regression analysis of patient-level data also included employment status, education level and urbanicity. We summarized findings by type of cost and examined uncertainty around resulting estimates., Results: Overall, the median prevalence of catastrophic costs for the meta-analysis and regression approaches were 11% (interquartile range [IQR] 9-13%) and 6% (IQR 5-8%), respectively. Both approaches indicated that the main burden of catastrophic costs falls on the poorest households. An individual-level regression analysis produced lower uncertainty around estimates than a study-level meta-analysis., Conclusions: This paper presents a novel application of existing data to estimate the national prevalence of catastrophic costs due to TB. This type of model could be useful for researchers and policy makers looking to inform certain policy decisions; however, some uncertainties remain due to limitations in data availability. There is an urgent need for standardized reporting of cost data and improved guidance on methods to collect income data to improve these estimates going forward.

Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an on-going project entitled Umoya omuhle ("good air"), conducted in two provinces of South Africa, that adopts an interdisciplinary, 'whole systems' approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A 'whole systems' approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission.

Background: Tuberculosis, which is often undiagnosed, is the major cause of death among HIV-positive people. We aimed to test whether the use of a clinical algorithm enabling the initiation of empirical tuberculosis treatment by nurses in primary health-care clinics would reduce mortality compared with standard of care for adults with advanced HIV disease., Methods: In this open-label cluster-randomised controlled trial, we recruited individuals from 24 primary health-care clinics in South Africa. The clinics were randomly assigned (1:1) to either deliver an intervention or routine care (control) using computer-generated random numbers. Eligible participants were HIV-positive adults (aged ≥18 years) with CD4 counts of 150 cells per μL or less, who had not had antiretroviral therapy (ART) in the past 6 months or tuberculosis treatment in the past 3 months, and did not require urgent hospital referral. In intervention clinics, study nurses assessed participants on the basis of tuberculosis symptoms, body-mass index, point-of-care haemoglobin concentrations, and urine lipoarabinomannan assay results. Participants classified by a study algorithm as having high probability of tuberculosis (positive urine lipoarabinomannan assay, body-mass index <18·5 kg/m 2 , or haemoglobin concentration <100 g/L) were recommended to start tuberculosis treatment immediately followed by ART 2 weeks later; participants classified as medium probability (tuberculosis symptoms, no high probability criteria) were recommended to have symptom-guided investigation; and participants classified as low probability (no tuberculosis symptoms or high probability criteria) were recommended to start ART immediately. In standard-of-care clinics, participants received treatment in accordance with South African guidelines. Investigators and participants were aware of treatment allocation. The primary outcome was all-cause mortality at 6 months, assessed in the intention-to-treat population. Safety was also analysed in the intention-to treat population. This trial is registered with the ISRCTN registry, ISRCTN35344604, and the South African National Clinical Trials Register, DOH-27-0812-3902., Findings: Between Dec 19, 2012, and Dec 18, 2014, 3091 individuals were screened for eligibility, of whom 3053 were recruited, and 3022 (1507 participants in the intervention group and 1515 participants in the control group) were analysed for the primary outcome. 930 (61·7%) of 1507 participants in the intervention group versus 172 (11·4%) of 1515 participants in the control group had started tuberculosis treatment by 2 months. At 6 months, the mortality rate was 19·0 deaths per 100 person-years for the intervention group versus 21·6 deaths per 100 person-years in the control group (unadjusted hazard ratio [HR] 0·92, 95% CI 0·67-1·26, p=0·58; adjusted HR 0·87, 0·61-1·24, p=0·41). 28 (1·9%) of 1507 participants in the intervention group and ten (0·7%) of 1515 participants in the control group reported serious or severe adverse events. Grade 3 or 4 nausea and vomiting was the most common adverse event (ten participants in the intervention group and four participants in the control group). Among participants with adverse events, eight participants (six participants in the intervention group and two participants in the control group) died; none of the six deaths in the intervention group were attributed to the study intervention., Interpretation: Our intervention substantially increased coverage of tuberculosis treatment in this high-risk population, but did not reduce mortality., Funding: Joint Global Health Trials (Medical Research Council, Department for International Development, Wellcome Trust)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Consistently defined, accurate, and easily accessible cost data are a valuable resource to inform efficiency analyses, budget preparation, and sustainability planning in global health. The Global Health Cost Consortium (GHCC) designed the Unit Cost Study Repository (UCSR) to be a resource for standardised HIV and TB intervention cost data displayed by key characteristics such as intervention type, country, and target population. To develop the UCSR, the GHCC defined a typology of interventions for each disease; aligned interventions according to the standardised principles, methods, and cost and activity categories from the GHCC Reference Case for Estimating the Costs of Global Health Services and Interventions; completed a systematic literature review; conducted extensive data extraction; performed quality assurance; grappled with complex methodological issues such as the proper approach to the inflation and conversion of costs; developed and implemented a study quality rating system; and designed a web-based user interface that flexibly displays large amounts of data in a user-friendly way. Key lessons learned from the extraction process include the importance of assessing the multiple uses of extracted data; the critical role of standardising definitions (particularly units of measurement); using appropriate classifications of interventions and components of costs; the efficiency derived from programming data checks; and the necessity of extraction quality monitoring by senior analysts. For the web interface, lessons were: understanding the target audiences, including consulting them regarding critical characteristics; designing the display of data in "levels"; and incorporating alert and unique trait descriptions to further clarify differences in the data.

Background: India and many other high-burden countries have committed to providing universal access to high-quality diagnosis and drug susceptibility testing (DST) for tuberculosis (TB), but the most cost-effective approach to achieve this goal remains uncertain. Centralized testing at district-level hub facilities with a supporting sample transport network can generate economies of scale, but decentralization to the peripheral level may provide faster diagnosis and reduce losses to follow-up (LTFU)., Methods: We generated functions to evaluate the costs of centralized and decentralized molecular testing for tuberculosis with Xpert MTB/RIF (Xpert), a WHO-endorsed test which can be performed at centralized and decentralized levels. We merged the cost estimates with an agent-based simulation of TB transmission in a hypothetical representative region in India to assess the impact and cost-effectiveness of each strategy., Results: Compared against centralized Xpert testing, decentralization was most favorable when testing volume at decentralized facilities and pre-treatment LTFU were high, and specimen transport network was exclusively established for TB. Assuming equal quality of centralized and decentralized testing, decentralization was cost-saving, saving a median $338,000 (interquartile simulation range [IQR] - $222,000; $889,000) per 20 million people over 10 years, in the most cost-favorable scenario. In the most cost-unfavorable scenario, decentralized testing would cost a median $3161 [IQR $2412; $4731] per disability-adjusted life year averted relative to centralized testing., Conclusions: Decentralization of Xpert testing is likely to be cost-saving or cost-effective in most settings to which these simulation results might generalize. More decentralized testing is more cost-effective in settings with moderate-to-high peripheral testing volumes, high existing clinical LTFU, inability to share specimen transport costs with other disease entities, and ability to ensure high-quality peripheral Xpert testing. Decision-makers should assess these factors when deciding whether to decentralize molecular testing for tuberculosis.

Mathematical models are increasingly being used to compare strategies for tuberculosis (TB) control and inform policy decisions. Models often do not consider financial and other constraints on implementation and may overestimate the impact that can be achieved. We developed a pragmatic approach for incorporating resource constraints into mathematical models of TB. Using a TB transmission model calibrated for South Africa, we estimated the epidemiologic impact and resource requirements (financial, human resource (HR), and diagnostic) of 9 case-finding interventions. We compared the model-estimated resources with scenarios of future resource availability and estimated the impact of interventions under these constraints. Without constraints, symptom screening in public health clinics and among persons receiving care for human immunodeficiency virus infection was predicted to lead to larger reductions in TB incidence (9.5% (2.5th-97.5th percentile range (PR), 8.6-12.2) and 14.5% (2.5th-97.5th PR, 12.2-16.3), respectively) than improved adherence to diagnostic guidelines (2.7%; 2.5th-97.5th PR, 1.6-4.1). However, symptom screening required large increases in resources, exceeding future HR capacity. Even under our most optimistic HR scenario, the reduction in TB incidence from clinic symptom screening was 0.2%-0.9%-less than that of improved adherence to diagnostic guidelines. Ignoring resource constraints may result in incorrect conclusions about an intervention's impact and may lead to suboptimal policy decisions. Models used for decision-making should consider resource constraints., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. "TIME Impact" is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To evaluate the effect of an intervention to optimize TB/HIV integration on patient outcomes., Methods: Cluster randomised control trial at 18 primary care clinics in South Africa. The intervention was placement of a nurse (TB/HIV integration officer) to facilitate provision of integrated TB/HIV services, and a lay health worker (TB screening officer) to facilitate TB screening for 24 months. Primary outcomes were i) incidence of hospitalisation/death among individuals newly diagnosed with HIV, ii) incidence of hospitalisation/death among individuals newly diagnosed with TB and iii) proportion of HIV-positive individuals newly diagnosed with TB who were retained in HIV care 12 months after enrolment., Results: Of 3328 individuals enrolled, 3024 were in the HIV cohort, 731 in TB cohort and 427 in TB-HIV cohort. For the HIV cohort, the hospitalisation/death rate was 12.5 per 100 person-years (py) (182/1459py) in the intervention arm vs. 10.4/100py (147/1408 py) in the control arms respectively (Relative Risk (RR) 1.17 [95% CI 0.92-1.49]).For the TB cohort, hospitalisation/ death rate was 17.1/100 py (67/ 392py) vs. 11.1 /100py (32/289py) in intervention and control arms respectively (RR 1.37 [95% CI 0.78-2.43]). For the TB-HIV cohort, retention in care at 12 months was 63.0% (213/338) and 55.9% (143/256) in intervention and control arms (RR 1.11 [95% 0.89-1.38])., Conclusions: The intervention as implemented failed to improve patient outcomes beyond levels at control clinics. Effective strategies are needed to achieve better TB/HIV service integration and improve TB and HIV outcomes in primary care clinics., Trial Registration: South African Register of Clinical Trials (registration number DOH-27-1011-3846)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The World Health Organization recommends point-of-care (POC) lateral flow urine lipoarabinomannan (LF-LAM) for tuberculosis (TB) diagnosis in selected human immunodeficiency virus (HIV) positive people. South Africa had 438 000 new TB episodes in 2016, 58.9% of which were contributed by HIV-positive people. LF-LAM is being considered for scale-up in South Africa., Methods: We estimated the costs of using LF-LAM in HIV-positive adults with CD4 counts  150 cells/μl enrolled in the TB Fast Track Trial in South Africa. We also estimated costs of POC haemoglobin (Hb), as this was used in the study algorithm. Data on clinic-level (10 intervention clinics) and above-clinic-level costs were collected., Results: A total of 1307 LF-LAM tests were performed at 10 clinics over 24 months. The mean clinic-level costs were US$12.80 per patient for LF-LAM and POC Hb; LF-LAM costs were US$11.49 per patient. The mean above-clinic-level unit costs for LF-LAM were US$12.06 for clinic preparation, training, coordination and mentoring. The mean total cost of LF-LAM was US$23.55 per patient., Conclusion: At clinic level, the cost of LF-LAM was comparable to other TB diagnostics in South Africa. It is important to consider above-clinic-level costs for POC tests, as these may be required to support roll-out and ensure successful implementation.

Background: National Tuberculosis Programmes (NTPs) require specialist input to support the development of policy and practice informed by evidence, typically against tight deadlines., Objective: To describe lessons learned from establishing a dedicated tuberculosis (TB) think tank to advise the South African NTP on TB policy., Intervention and Evaluation Methods: A national TB think tank was established to advise the NTP in support of evidence-informed policy. Support was provided for activities, including meetings, modelling and regular telephone calls, with a wider network of unpaid expert advisers under an executive committee and working groups. Intervention evaluation used desktop analysis of documentary evidence, interviews and direct observation., Results: The TB Think Tank evolved over time to acquire three key roles: an 'institution', a 'policy dialogue forum' and an 'interface'. Although enthusiasm was high, motivating participation among the NTP and external experts proved challenging. Motivation of working groups was most successful when aligned to a specific need for NTP decision making. Despite challenges, the TB Think Tank contributed to South Africa's first ever TB and human immunodeficiency virus (HIV) investment case, and the decision to create South Africa's first ever ring-fenced grant for TB. The TB Think Tank also assisted the NTP in formulating strategy to accelerate progress towards reaching World Health Organization targets., Discussion: With partners, the TB Think Tank achieved major successes in supporting evidence-informed decision making, and garnered increased funding for TB in South Africa. Identifying ways to increase the involvement of NTP staff and other experts, and keeping the scope of the Think Tank well defined, could facilitate greater impact. Think tank initiatives could be replicated in other settings to support evidence-informed policy making.

Background: The economic burden on households affected by tuberculosis through costs to patients can be catastrophic. WHO's End TB Strategy recognises and aims to eliminate these potentially devastating economic effects. We assessed whether aggressive expansion of tuberculosis services might reduce catastrophic costs., Methods: We estimated the reduction in tuberculosis-related catastrophic costs with an aggressive expansion of tuberculosis services in India and South Africa from 2016 to 2035, in line with the End TB Strategy. Using modelled incidence and mortality for tuberculosis and patient-incurred cost estimates, we investigated three intervention scenarios: improved treatment of drug-sensitive tuberculosis; improved treatment of multidrug-resistant tuberculosis; and expansion of access to tuberculosis care through intensified case finding (South Africa only). We defined tuberculosis-related catastrophic costs as the sum of direct medical, direct non-medical, and indirect costs to patients exceeding 20% of total annual household income. Intervention effects were quantified as changes in the number of households incurring catastrophic costs and were assessed by quintiles of household income., Findings: In India and South Africa, improvements in treatment for drug-sensitive and multidrug-resistant tuberculosis could reduce the number of households incurring tuberculosis-related catastrophic costs by 6-19%. The benefits would be greatest for the poorest households. In South Africa, expanded access to care could decrease household tuberculosis-related catastrophic costs by 5-20%, but gains would be seen largely after 5-10 years., Interpretation: Aggressive expansion of tuberculosis services in India and South Africa could lessen, although not eliminate, the catastrophic financial burden on affected households., Funding: Bill & Melinda Gates Foundation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: This study describes the post-diagnosis care-seeking costs incurred by people living with TB and/or HIV and their households, in order to identify the potential benefits of integrated care., Methods: We conducted a cross-sectional study with 454 participants with TB or HIV or both in public primary health care clinics in Ekurhuleni North Sub-District, South Africa. We collected information on visits to health facilities, direct and indirect costs for participants and for their guardians and caregivers. We define 'integration' as receipt of both TB and HIV services at the same facility, on the same day. Costs were presented and compared across participants with TB/HIV, TB-only and HIV-only. Costs exceeding 10% of participant income were considered catastrophic., Results: Participants with both TB and HIV faced a greater economic burden (US$74/month) than those with TB-only (US$68/month) or HIV-only (US$40/month). On average, people with TB/HIV made 18.4 visits to health facilities, more than TB-only participants or HIV-only participants who made 16 and 5.1 visits, respectively. However, people with TB/HIV had fewer standalone TB (10.9) and HIV (2.2) visits than those with TB-only (14.5) or HIV-only (4.4). Although people with TB/HIV had access to 'integrated' services, their time loss was substantially higher than for other participants. Overall, 55% of participants encountered catastrophic costs. Access to official social protection schemes was minimal., Conclusions: People with TB/HIV in South Africa are at high risk of catastrophic costs. To some extent, integration of services reduces the number of standalone TB and HIV of visits to the health facility. It is however unlikely that catastrophic costs can be averted by service integration alone. Our results point to the need for timely social protection, particularly for HIV-positive people starting TB treatment., (© The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India., Methods: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients., Results: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US$ 1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099)., Conclusions: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.

Background: The World Health Organization (WHO) recommendation for regular tuberculosis (TB) screening of HIV-positive individuals with Xpert MTB/RIF as the first diagnostic test has major resource implications., Objective: To develop a diagnostic prediction model for TB, for symptomatic adults attending for routine HIV care, to prioritise TB investigation., Design: Cohort study exploring a TB testing algorithm., Setting: HIV clinics, South Africa., Participants: Representative sample of adult HIV clinic attendees; data from participants reporting ≥1 symptom on the WHO screening tool were split 50:50 to derive, then internally validate, a prediction model., Outcome: TB, defined as "confirmed" if Xpert MTB/RIF, line probe assay or M. tuberculosis culture were positive; and "clinical" if TB treatment started without microbiological confirmation, within six months of enrolment., Results: Overall, 79/2602 (3.0%) participants on ART fulfilled TB case definitions, compared to 65/906 (7.2%) pre-ART. Among 1133/3508 (32.3%) participants screening positive on the WHO tool, 1048 met inclusion criteria for this analysis: 52/515 (10.1%) in the derivation and 58/533 (10.9%) in the validation dataset had TB. Our final model comprised ART status (on ART > 3 months vs. pre-ART or ART < 3 months); body mass index (continuous); CD4 (continuous); number of WHO symptoms (1 vs. >1 symptom). We converted this to a clinical score, using clinically-relevant CD4 and BMI categories. A cut-off score of ≥3 identified those with TB with sensitivity and specificity of 91.8% and 34.3% respectively. If investigation was prioritised for individuals with score of ≥3, 68% (717/1048) symptomatic individuals would be tested, among whom the prevalence of TB would be 14.1% (101/717); 32% (331/1048) of tests would be avoided, but 3% (9/331) with TB would be missed amongst those not tested., Conclusion: Our clinical score may help prioritise TB investigation among symptomatic individuals.

Background: In 2010 a new diagnostic test for tuberculosis, Xpert MTB/RIF, received a conditional programmatic recommendation from WHO. Several model-based economic evaluations predicted that Xpert would be cost-effective across sub-Saharan Africa. We investigated the cost-effectiveness of Xpert in the real world during national roll-out in South Africa., Methods: For this real-world cost analysis and economic evaluation, we applied extensive primary cost and patient event data from the XTEND study, a pragmatic trial examining Xpert introduction for people investigated for tuberculosis in 40 primary health facilities (20 clusters) in South Africa enrolled between June 8, and Nov 16, 2012, to estimate the costs and cost per disability-adjusted life-year averted of introducing Xpert as the initial diagnostic test for tuberculosis, compared with sputum smear microscopy (the standard of care)., Findings: The mean total cost per study participant for tuberculosis investigation and treatment was US$312·58 (95% CI 252·46-372·70) in the Xpert group and $298·58 (246·35-350·82) in the microscopy group. The mean health service (provider) cost per study participant was $168·79 (149·16-188·42) for the Xpert group and $160·46 (143·24-177·68) for the microscopy group of the study. Considering uncertainty in both cost and effect using a wide range of willingness to pay thresholds, we found less than 3% probability that Xpert introduction improved the cost-effectiveness of tuberculosis diagnostics., Interpretation: After analysing extensive primary data collection during roll-out, we found that Xpert introduction in South Africa was cost-neutral, but found no evidence that Xpert improved the cost-effectiveness of tuberculosis diagnosis. Our study highlights the importance of considering implementation constraints, when predicting and evaluating the cost-effectiveness of new tuberculosis diagnostics in South Africa., Funding: Bill & Melinda Gates Foundation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Setting: Of 18 sites that participated in an implementation study of the Xpert® MTB/RIF assay in India, we selected five microscopy centres and two reference laboratories., Objective: To obtain unit costs of diagnostic tests for tuberculosis (TB) and drug-resistant TB., Design: Laboratories were purposely selected to capture regional variations and different laboratory types. Both bottom-up and the top-down methods were used to estimate unit costs., Results: At the microscopy centres, mean bottom-up unit costs were respectively US$0.83 (range US$0.60-US$1.10) and US$12.29 (US$11.61-US$12.89) for sputum smear microscopy and Xpert. At the reference laboratories, mean unit costs were US$1.69 for the decontamination procedure, US$9.83 for a solid culture, US$11.06 for a liquid culture, US$29.88 for a drug susceptibility test, and US$18.18 for a line-probe assay. Top-down mean unit cost estimates were higher for all tests, and for sputum smear microscopy and Xpert these increased to respectively US$1.51 and US$13.58. The difference between bottom-up and top-down estimates was greatest for tests performed at the reference laboratories., Conclusion: These unit costs for TB diagnostics can be used to estimate resource requirements and cost-effectiveness in India, taking into account geographical location, laboratory type and capacity utilisation.

Background: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials., Methods: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence., Results: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh., Conclusion: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

Background: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements., Methods: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy., Findings: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis., Interpretation: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level., Funding: Bill and Melinda Gates Foundation., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa., Methods: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice., Findings: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective., Interpretation: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary., Funding: Bill & Melinda Gates Foundation., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

User-friendly models (UFMs) allow local decision makers to explore relationships and apply results from more detailed models of such outcomes as cost-effectiveness. When developing UFMs, modelers must decide which simplifications may be appropriate, enabling the UFM to retain accuracy while reducing complexity. We use the example of cost-effectiveness analysis (CEA) for novel shortened anti-tuberculosis treatment regimens across four settings to demonstrate how UFMs can allow decision makers to adapt published results to their local context. We simplified a complex model to produce a UFM that provides similar results, the ability to modify key parameter values, and receive customized results in seconds.

Background: Shortened treatment regimens for tuberculosis are under development to improve treatment outcomes and reduce costs. We estimated potential savings from a societal perspective in Brazil following the introduction of a hypothetical four-month regimen for tuberculosis treatment., Methods: Data were gathered in ten randomly selected health facilities in Rio de Janeiro. Health service costs were estimated using an ingredient approach. Patient costs were estimated from a questionnaire administered to 126 patients. Costs per visits and per case treated were analysed according to the type of therapy: self-administered treatment (SAT), community- and facility-directly observed treatment (community-DOT, facility-DOT)., Results: During the last 2 months of treatment, the largest savings could be expected for community-DOT; on average USD 17,351-18,203 and USD 43,660-45,856 (bottom-up and top-down estimates) per clinic. Savings to patients could also be expected as the median (interquartile range) patient-related costs during the two last months were USD 108 (13-291), USD 93 (36-239) and USD 11 (7-126), respectively for SAT, facility-DOT and community-DOT., Conclusion: Introducing a four-month regimen may result in significant cost savings for both the health service and patients, especially the poorest. In particular, a community-DOT strategy, including treatment at home, could maximise health services savings while limiting patient costs. Our cost estimates are likely to be conservative because a 4-month regimen could hypothetically increase the proportion of patients cured by reducing the number of patients defaulting and we did not include the possible cost benefits from the subsequent prevention of costs due to downstream transmission averted and rapid clinical improvement with less side effects in the last two months.

Background: A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa., Method: An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015-2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds., Results: It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618)., Conclusion: The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa.

Social protection against the cost of illness is a central policy objective of Universal Health Coverage and the post-2015 Global strategy for Tuberculosis (TB). Understanding the economic burden associated with TB illness and care is key to identifying appropriate interventions towards achieving this target. The aims of this study were to identify points in patient pathways from start of TB symptoms to treatment completion where interventions could be targeted to reduce the economic impact on patients and households, and to identify those most vulnerable to these costs. Two cohorts of patients accessing TB services from ten clinics in four provinces in South Africa were surveyed between July 2012 and June 2013. One cohort of 351 people with suspected TB were interviewed at the point of receiving a TB diagnostic and followed up six months later. Another cohort of 168 patients on TB treatment, at the same ten facilities, was interviewed at two-months and five-months on treatment. Patients were asked about their health-seeking behaviour, associated costs, income loss, and coping strategies used. Patients incurred the greatest share of TB episode costs (41%) prior to starting treatment, with the largest portion of these costs being due to income loss. Poorer patients incurred higher direct costs during treatment than those who were less poor but only 5% of those interviewed were accessing cash-transfers during treatment. Indirect costs accounted for 52% of total episode cost. Despite free TB diagnosis and care in South Africa, patients incur substantial direct and indirect costs particularly prior to starting treatment. The poorest group of patients were incurring higher costs, with fewer resources to pay for it. Both the direct and indirect cost of illness should be taken into account when setting levels of financial protection and social support, to prevent TB illness from pushing the poor further into poverty., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Early mortality for HIV-positive people starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis the most important cause. Existing rapid diagnostic tests for tuberculosis lack sensitivity among HIV-positive people, and consequently, tuberculosis treatment is either delayed or started empirically (without bacteriological confirmation). We developed a management algorithm for ambulatory HIV-positive people, based on body mass index and point-of-care tests for haemoglobin and urine lipoarabinomannan (LAM), to identify those at high risk of tuberculosis and mortality. We designed a clinical trial to test whether implementation of this algorithm reduces six-month mortality among HIV-positive people with advanced immunosuppression., Methods/design: The TB Fast Track study is an open, pragmatic, cluster randomised superiority trial, with 24 primary health clinics randomised to implement the intervention or standard of care. Adults (aged ≥18 years) with a CD4 count of 150 cells/μL or less, who have not received any tuberculosis treatment in the last three months, or ART in the last six months, are eligible. In intervention clinics, the study algorithm is used to classify individuals as at high, medium or low probability of tuberculosis. Those classified as high probability start tuberculosis treatment immediately, followed by ART after two weeks. Medium-probability patients follow the South African guidelines for test-negative tuberculosis and are reviewed within a week, to be re-categorised as low or high probability. Low-probability patients start ART as soon as possible. The primary outcome is all-cause mortality at six months. Secondary outcomes include severe morbidity, time to ART start and cost-effectiveness., Discussion: This trial will test whether a primary care-friendly management algorithm will enable nurses to identify HIV-positive patients at the highest risk of tuberculosis, to facilitate prompt treatment and reduce early mortality. There remains an urgent need for better diagnostic tests for tuberculosis, especially for people with advanced HIV disease, which may render empirical treatment unnecessary., Trial Registration: This trial was registered with Current Controlled Trials (identifier: ISRCTN35344604 ) on 12 September 2012.