Determining cost and placement decisions for moderate complexity NAATs for tuberculosis drug susceptibility testing.

BACKGROUND: Access to drug resistant testing for tuberculosis (TB) remains a challenge in high burden countries. Recently, the World Health Organization approved the use of several moderate complexity automated nucleic acid amplification tests (MC-NAAT) that have performance profiles suitable for placement in a range of TB laboratory tiers to improve drug susceptibility tests (DST) coverage. METHODS: We conducted cost analysis of two MC-NAATs with different testing throughput: Lower Throughput (LT, < 24 tests per run) and Higher Throughput (HT, upto 90+ tests per run) for placement in a hypothetical laboratory in a resource limited setting. We used per-test cost as the main indicator to assess 1) drivers of cost by resource types and 2) optimized levels of annual testing volumes for the respective MC-NAATs. RESULTS: The base-case per test cost of $18.52 (range: $13.79 - $40.70) for LT test and $15.37 (range: $9.61 - $37.40) for HT test. Per test cost estimates were most sensitive to the number of testing days per week, followed by equipment costs and TB-specific workloads. In general, HT NAATs were cheaper at all testing volume levels, but at lower testing volumes (less than 2,000 per year) LT tests can be cheaper if the durability of the testing system is markedly better and/or procured equipment costs are lower than that of HT NAAT. CONCLUSION: Assuming equivalent performance and infrastructural needs, placement strategies for MC-NAATs need to be prioritized by laboratory system's operational factors, testing demands, and costs.

Human resource time commitments and associated costs of Community Caregiver outreach team operations in South Africa.

INTRODUCTION: In South Africa, Community Caregivers (CCGs) visit households to provide basic healthcare services including those for tuberculosis and HIV. However, CCG workloads, costs, and time burden are largely unknown. Our objective was to assess the workloads and operational costs for CCG teams operating in different settings in South Africa. METHODS: Between March and October 2018, we collected standardized self-reported activity time forms from 11 CCG pairs working at two public health clinics in Ekurhuleni district, South Africa. CCG workloads were assessed based on activity unit times, per-household visit time, and mean daily number of successful household visits. Using activity-based times and CCG operating cost data, we assessed CCG annual and per-household visit costs (USD 2019) from the health system perspective. RESULTS: CCGs in clinic 1 (peri-urban, 7 CCG pairs) and 2 (urban, informal settlement; 4 CCG pairs) served an area of 3.1 km2 and 0.6 km2 with 8,035 and 5,200 registered households, respectively. CCG pairs spent a median 236 minutes per day conducting field activities at clinic 1 versus 235 minutes at clinic 2. CCG pairs at clinic 1 spent 49.5% of this time at households (versus traveling), compared to 35.0% at clinic 2. On average, CCG pairs successfully visited 9.5 vs 6.7 households per day for clinics 1 and 2, respectively. At clinic 1, 2.7% of household visits were unsuccessful, versus 28.5% at clinic 2. Total annual operating costs were higher in clinic 1 ($71,780 vs $49,097) but cost per successful visit was lower ($3.58) than clinic 2 ($5.85). CONCLUSIONS: CCG home visits were more frequent, successful, and less costly in clinic 1, which served a larger and more formalized settlement. The variability in workload and cost observed across pairs and clinics suggests that circumstantial factors and CCG needs must be carefully assessed for optimized CCG outreach operations.

Healthcare use and medical cost before and after diagnosis of nontuberculous mycobacterial infection in Korea: the National Health Insurance Service-National Sample Cohort Study.

BACKGROUND AND OBJECTIVE: The global prevalence and incidence of nontuberculous mycobacterial (NTM) infections are increasing; however, population-level data on healthcare use and medical costs for people with NTM infections are limited. Thus, we investigated the rates of healthcare use and medical costs of people with NTM infections in South Korea using the National Health Insurance Service-National Sample Cohort from 2002 to 2015. METHODS: In this cohort study, people with and without NTM infection aged 20-89 years were matched 1 to 4 by sex, age, Charlson comorbidity index, and year of diagnosis. The overall and annual average healthcare use and medical costs were calculated. In addition, trends in healthcare use and medical costs for each of the 3 years before and after NTM diagnosis were investigated for people diagnosed with NTM infection. RESULTS: A total of 798 individuals (336 men and 462 women) diagnosed with NTM infection and 3192 controls were included in the study. NTM-infected patients had significantly higher rates of healthcare use and medical costs than those in the control group (p < 0.05). NTM-infected patients showed 1.5 times the medical cost and 4.5 times the respiratory disease cost of the control group. People diagnosed with NTM infection incurred the highest medical costs in the 6 months before diagnosis. CONCLUSION: NTM infection increases the economic burden on Korean adults. Appropriate diagnostic tests and treatment plans for NTM infections are needed to reduce the burden of the disease caused by such infection.

Multicomponent strategy with decentralised molecular testing for tuberculosis in Uganda: a cost and cost-effectiveness analysis.

BACKGROUND: Decentralised molecular testing for tuberculosis could reduce missed diagnoses and losses to follow-up in high-burden settings. The aim of this study was to evaluate the cost and cost-effectiveness of the Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) study strategy, a multicomponent strategy including decentralised molecular testing for tuberculosis, in Uganda. METHODS: We conducted a costing and cost-effectiveness analysis nested in a pragmatic cluster-randomised trial of onsite (decentralised) versus hub-and-spoke (centralised) testing for tuberculosis with Xpert MTB/RIF Ultra (Xpert) in 20 community health centres in Uganda. We collected empirical data on the cost of the XPEL-TB strategy (decentralised Xpert testing, workflow redesign, and performance feedback) and routine tuberculosis testing (onsite smear microscopy with specimen transport for centralised Xpert testing) from the health system perspective. Time-and-motion studies were performed to estimate activity-based service costs. Cost-effectiveness was assessed as the incremental cost (2019 US$) per tuberculosis diagnosis and per 14-day treatment initiation. FINDINGS: The XPEL-TB study ran from Oct 22, 2018, to March 1, 2020. Effectiveness and cost-effectiveness outcomes were assessed from Dec 1, 2018, to Nov 30, 2019 and included 4867 women and 3139 men. On a per-test basis, the cost of decentralised ($20·46, range $17·85-25·72) and centralised ($18·20, range $16·58-24·25) Xpert testing was similar. However, decentralised testing resulted in more patients receiving appropriate Xpert testing, so the per-patient cost of decentralised testing was higher: $20·28 (range $17·68-25·48) versus $9·59 (range $7·62-14·34). The XPEL-TB strategy was estimated to cost $1332 (95% uncertainty range $763-5558) per incremental tuberculosis diagnosis and $687 ($501-1207) per incremental patient initiating tuberculosis treatment within 14 days. Cost-effectiveness was reduced in sites performing fewer than 150-250 tests annually. INTERPRETATION: The XPEL-TB strategy facilitated higher rates of Xpert testing for tuberculosis at a similar per-test cost and modest incremental cost per tuberculosis diagnosis and treatment initiation. Decentralised Xpert testing, with appropriate implementation supports, should be scaled up to clinics with sufficient testing volume to support a single-module device. FUNDING: The National Heart, Lung, and Blood Institute.

Economic evaluation of implementation science outcomes in low- and middle-income countries: a scoping review.

BACKGROUND: Historically, the focus of cost-effectiveness analyses has been on the costs to operate and deliver interventions after their initial design and launch. The costs related to design and implementation of interventions have often been omitted. Ignoring these costs leads to an underestimation of the true price of interventions and biases economic analyses toward favoring new interventions. This is especially true in low- and middle-income countries (LMICs), where implementation may require substantial up-front investment. This scoping review was conducted to explore the topics, depth, and availability of scientific literature on integrating implementation science into economic evaluations of health interventions in LMICs. METHODS: We searched Web of Science and PubMed for papers published between January 1, 2010, and December 31, 2021, that included components of both implementation science and economic evaluation. Studies from LMICs were prioritized for review, but papers from high-income countries were included if their methodology/findings were relevant to LMIC settings. RESULTS: Six thousand nine hundred eighty-six studies were screened, of which 55 were included in full-text review and 23 selected for inclusion and data extraction. Most papers were theoretical, though some focused on a single disease or disease subset, including: mental health (n = 5), HIV (n = 3), tuberculosis (n = 3), and diabetes (n = 2). Manuscripts included a mix of methodology papers, empirical studies, and other (e.g., narrative) reviews. Authorship of the included literature was skewed toward high-income settings, with 22 of the 23 papers featuring first and senior authors from high-income countries. Of nine empirical studies included, no consistent implementation cost outcomes were measured, and only four could be mapped to an existing costing or implementation framework. There was also substantial heterogeneity across studies in how implementation costs were defined, and the methods used to collect them. CONCLUSION: A sparse but growing literature explores the intersection of implementation science and economic evaluation. Key needs include more research in LMICs, greater consensus on the definition of implementation costs, standardized methods to collect such costs, and identifying outcomes of greatest relevance. Addressing these gaps will result in stronger links between implementation science and economic evaluation and will create more robust and accurate estimates of intervention costs. TRIAL REGISTRATION: The protocol for this manuscript was published on the Open Science Framework. It is available at: https://osf.io/ms5fa/ (DOI: 10.17605/OSF.IO/32EPJ).

Comparative assessment of the cost-effectiveness of Tuberculosis (TB) active case-finding interventions: A systematic analysis of TB REACH wave 5 projects.

PURPOSE: Interventions that can help streamline and reduce gaps in the tuberculosis (TB) care cascade can play crucial roles in TB prevention and care, but are often operationally complex and resource intensive, given the heterogenous settings in which they are implemented. In this study, we present a comparative analysis on cost-effectiveness of TB REACH Wave 5 projects with diverse programmatic objectives to inform future decisions regarding funding, strategic adoption, and scale-up. METHODS: We comprehensively reviewed project reports and financial statements from TB REACH Wave 5, a funding mechanism for interventions that aimed to strengthen the TB care cascade in diverse settings. Two independent reviewers abstracted cost (in 2017 US dollars) and key programmatic data, including project type (case-finding only; case-finding and linkage-to-care; or case-finding, linkage-to-care and patient support), operational setting (urban or rural), and project outputs (numbers of people with TB diagnosed, started on treatment, and successfully completing treatment). Cost-effectiveness ratios for each project were calculated as ratios of apportioned programmatic expenditures to corresponding project outputs. RESULTS: Of 32 case finding and patient support projects funded through TB REACH Wave 5, 29 were included for analysis (11 case-finding only; 9 case-finding and linkage-to-care; and 9 case-finding, linkage-to-care and patient support). 21 projects (72%) were implemented in either Africa or Southeast Asia, and 19 (66%) focused on serving urban areas. Average cost-effectiveness was $184 per case diagnosed (range: $30-$10,497), $332 per diagnosis and treatment initiation ($123-$10,608), and $40 per patient treatment supported ($8-$160). Cost per case diagnosed was lower for case-finding-only projects ($132) than projects including linkage-to-care ($342) or linkage-to-care and patient support ($254), and generally increased with the corresponding country's per-capita GDP ($543 per $1000 increase, 95% confidence interval: -$53, $1138). CONCLUSION: The costs and cost-effectiveness of interventions to strengthen the TB care cascade were heterogenous, reflecting differences in context and programmatic objective. Nevertheless, many such interventions are likely to offer good value for money. Systematic collection and analysis of cost-effectiveness data can help improve comparability, monitoring, and evaluation.

Tuberculosis (TB) Aftermath: study protocol for a hybrid type I effectiveness-implementation non-inferiority randomized trial in India comparing two active case finding (ACF) strategies among individuals treated for TB and their household contacts.

BACKGROUND: Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). METHODS: We will enroll 1076 adults (≥ 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month "mop-up" visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs (n = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. DISCUSSION: This novel trial will guide India's scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings. TRIAL REGISTRATION: NCT04333485 , registered April 3, 2020. CTRI/2020/05/025059 [Clinical Trials Registry of India], registered May 6 2020.

Cost and Cost-Effectiveness of a Digital Adherence Technology for Tuberculosis Treatment Support in Uganda.

OBJECTIVES: Digital adherence technologies like 99DOTS are increasingly considered as an alternative to directly observed therapy for tuberculosis (TB) treatment supervision. We evaluated the cost and cost-effectiveness of 99DOTS in a high-TB-burden setting. METHODS: We assessed the costs of implementing 99DOTS in Uganda through a pragmatic, stepped-wedge randomized trial. We measured costs from the health system perspective at 5 of 18 study facilities. Self-reported service activity time data were used to assess activity-based service costs; other costs were captured from budgets and key informant discussions using standardized forms. We estimated costs and effectiveness considering the 8-month study period ("trial specific") and using a 5-year time horizon ("extended activities"), the latter including a "marginal clinic" expansion scenario that ignored above-site implementation costs. Cost-effectiveness was assessed as cost per patient successfully completing treatment, using Monte Carlo simulation, cost-effectiveness acceptability curves, and sensitivity analyses to evaluate uncertainty and robustness of results. RESULTS: The total cost of implementing 99DOTS in the "trial-specific" scenario was $99 554 across 18 clinics (range $3771-$6238 per clinic). The cost per treatment success in the "trial-specific" scenario was $355 (range $229-$394), falling to $59 (range $50-$70) assuming "extended activities," and $49 (range $42-$57) in the "marginal clinic" scenario. The incremental cost-effectiveness of 99DOTS in the "extended-activity" scenario was $355 per incremental treatment success. CONCLUSIONS: Costs and cost-effectiveness of 99DOTS were influenced by the degree to which infrastructure is scaled over time. If sustained and scaled up, 99DOTS can be a cost-effective option for TB treatment adherence support in high-TB-burden settings like Uganda.

A cost analysis of implementing mobile health facilitated tuberculosis contact investigation in a low-income setting.

INTRODUCTION: Mobile health (mHealth) applications may improve timely access to health services and improve patient-provider communication, but the upfront costs of implementation may be prohibitive, especially in resource-limited settings. METHODS: We measured the costs of developing and implementing an mHealth-facilitated, home-based strategy for tuberculosis (TB) contact investigation in Kampala, Uganda, between February 2014 and July 2017. We compared routine implementation involving community health workers (CHWs) screening and referring household contacts to clinics for TB evaluation to home-based HIV testing and sputum collection and transport with test results delivered by automated short messaging services (SMS). We carried out key informant interviews with CHWs and asked them to complete time-and-motion surveys. We estimated program costs from the perspective of the Ugandan health system, using top-down and bottom-up (components-based) approaches. We estimated total costs per contact investigated and per TB-positive contact identified in 2018 US dollars, one and five years after program implementation. RESULTS: The total top-down cost was $472,327, including $358,504 (76%) for program development and $108,584 (24%) for program implementation. This corresponded to $320-$348 per household contact investigated and $8,873-$9,652 per contact diagnosed with active TB over a 5-year period. CHW time was spent primarily evaluating household contacts who returned to the clinic for evaluation (median 30 minutes per contact investigated, interquartile range [IQR]: 30-70), collecting sputum samples (median 29 minutes, IQR: 25-30) and offering HIV testing services (median 28 minutes, IQR: 17-43). Cost estimates were sensitive to infrastructural capacity needs, program reach, and the epidemiological yield of contact investigation. CONCLUSION: Over 75% of all costs of the mHealth-facilitated TB contact investigation strategy were dedicated to establishing mHealth infrastructure and capacity. Implementing the mHealth strategy at scale and maintaining it over a longer time horizon could help decrease development costs as a proportion of total costs.

Budgetary impact of using BPaL for treating extensively drug-resistant tuberculosis.

INTRODUCTION: Bedaquiline, pretomanid and linezolid (BPaL) is a new all oral, 6-month regimen comprised of bedaquiline, the new drug pretomanid and linezolid, endorsed by the WHO for use under operational research conditions in patients with extensively drug-resistant tuberculosis (XDR-TB). We quantified per-patient treatment costs and the 5-year budgetary impact of introducing BPaL in Indonesia, Kyrgyzstan and Nigeria. METHODS: Per-patient treatment cost of BPaL regimen was compared head-to-head with the conventional XDR-TB treatment regimen for respective countries based on cost estimates primarily assessed using microcosting method and expected frequency of each TB service. The 5-year budget impact of gradual introduction of BPaL against the status quo was assessed using a Markov model that represented patient's treatment management and outcome pathways. RESULTS: The cost per patient completing treatment with BPaL was US$7142 in Indonesia, US$4782 in Kyrgyzstan and US$7152 in Nigeria - 57%, 78% and 68% lower than the conventional regimens in the respective countries. A gradual adoption of the BPaL regimen over 5 years would result in an 5-year average national TB service budget reduction of 17% (US$128 780) in XDR-TB treatment-related expenditure in Indonesia, 15% (US$700 247) in Kyrgyzstan and 32% (US$1 543 047) in Nigeria. CONCLUSION: Our study demonstrates that the BPaL regimen can be highly cost-saving compared with the conventional regimens to treat patients with XDR-TB in high drug-resistant TB burden settings. This supports the rapid adoption of the BPaL regimen to address the significant programmatic and clinical challenges in managing patients with XDR-TB in high DR-TB burden countries.

Costs and cost-effectiveness of a comprehensive tuberculosis case finding strategy in Zambia.

INTRODUCTION: Active-case finding (ACF) programs have an important role in addressing case detection gaps and halting tuberculosis (TB) transmission. Evidence is limited on the cost-effectiveness of ACF interventions, particularly on how their value is impacted by different operational, epidemiological and patient care-seeking patterns. METHODS: We evaluated the costs and cost-effectiveness of a combined facility and community-based ACF intervention in Zambia that utilized mobile chest X-ray with computer-aided reading/interpretation software and laboratory-based Xpert MTB/RIF testing. Programmatic costs (in 2018 US dollars) were assessed from the health system perspective using prospectively collected cost and operational data. Cost-effectiveness of the ACF intervention was assessed as the incremental cost per TB death averted over a five-year time horizon using a multi-stage Markov state-transition model reflecting patient symptom-associated care-seeking and TB care under ACF compared to passive care. RESULTS: Over 18 months of field operations, the ACF intervention costed $435 to diagnose and initiate treatment for one person with TB. After accounting for patient symptom-associated care-seeking patterns in Zambia, we estimate that this one-time ACF intervention would incrementally diagnose 407 (7,207 versus 6,800) TB patients and avert 502 (611 versus 1,113) TB-associated deaths compared to the status quo (passive case finding), at an incremental cost of $2,284 per death averted over the next five-year period. HIV/TB mortality rate, patient symptom-associated care-seeking probabilities in the absence of ACF, and the costs of ACF patient screening were key drivers of cost-effectiveness. CONCLUSIONS: A one-time comprehensive ACF intervention simultaneously operating in public health clinics and corresponding catchment communities can have important medium-term impact on case-finding and be cost-effective in Zambia. The value of such interventions increases if targeted to populations with high HIV/TB mortality, substantial barriers (both behavioral and physical) to care-seeking exist, and when ACF interventions can optimize screening by achieving operational efficiency.

Costing the implementation of public health interventions in resource-limited settings: a conceptual framework.

BACKGROUND: Failing to account for the resources required to successfully implement public health interventions can lead to an underestimation of costs and budget impact, optimistic cost-effectiveness estimates, and ultimately a disconnect between published evidence and public health decision-making. METHODS: We developed a conceptual framework for assessing implementation costs. We illustrate the use of this framework with case studies involving interventions for tuberculosis and HIV/AIDS in resource-limited settings. RESULTS: Costs of implementing public health interventions may be conceptualized as occurring across three phases: design, initiation, and maintenance. In the design phase, activities include developing intervention components and establishing necessary infrastructure (e.g., technology, standard operating procedures). Initiation phase activities include training, initiation of supply chains and quality assurance procedures, and installation of equipment. Implementation costs in the maintenance phase include ongoing technical support, monitoring and evaluation, and troubleshooting unexpected obstacles. Within each phase, implementation costs can be incurred at the site of delivery ("site-specific" costs) or more centrally ("above-service" or "central" costs). For interventions evaluated in the context of research studies, implementation costs should be classified as programmatic, research-related, or shared research/program costs. Purely research-related costs are often excluded from analysis of programmatic implementation. CONCLUSIONS: In evaluating public health interventions in resource-limited settings, accounting for implementation costs enables more realistic estimates of budget impact and cost-effectiveness and provides important insights into program feasibility, scale-up, and sustainability. Assessment of implementation costs should be planned prospectively and performed in a standardized manner to ensure generalizability.

Redefining and revisiting cost estimates of routine ART care in Zambia: an analysis of ten clinics.

INTRODUCTION: Accurate costing is key for programme planning and policy implementation. Since 2011, there have been major changes in eligibility criteria and treatment regimens with price reductions in ART drugs, programmatic changes resulting in clinical task-shifting and decentralization of ART delivery to peripheral health centres making existing evidence on ART care costs in Zambia out-of-date. As decision makers consider further changes in ART service delivery, it is important to understand the current drivers of costs for ART care. This study provides updates on costs of ART services for HIV-positive patients in Zambia. METHODS: We evaluated costs, assessed from the health systems perspective and expressed in 2016 USD, based on an activity-based costing framework using both top-down and bottom-up methods with an assessment of process and capacity. We collected primary site-level costs and resource utilization data from government documents, patient chart reviews and time-and-motion studies conducted in 10 purposively selected ART clinics. RESULTS: The cost of providing ART varied considerably among the ten clinics. The average per-patient annual cost of ART service was $116.69 (range: $59.38 to $145.62) using a bottom-up method and $130.32 (range: $94.02 to $162.64) using a top-down method. ART drug costs were the main cost driver (67% to 7% of all costs) and are highly sensitive to the types of patient included in the analysis (long-term vs. all ART patients, including those recently initiated) and the data sources used (facility vs. patient level). Missing capacity costs made up 57% of the total difference between the top-down and bottom-up estimates. Variability in cost across the ten clinics was associated with operational characteristics. CONCLUSIONS: Real-world costs of current routine ART services in Zambia are considerably lower than previously reported estimates and sensitive to operational factors and methods used. We recommend collection and monitoring of resource use and capacity data to periodically update cost estimates.

Standardized framework for evaluating costs of active case-finding programs: An analysis of two programs in Cambodia and Tajikistan.

INTRODUCTION: Over the years, technological and process innovations enabled active case finding (ACF) programs to expand their capacities and scope to have evolved to close gaps in missing TB patients globally. However, with increased ACF program's operational complexity and a need for significant resource commitments, a comprehensive, transparent, and standardized approach in evaluating costs of ACF programs is needed to properly determine costs and value of ACF programs. METHODS: Based on reviews of program activity and financial reports, multiple interviews with program managers of two TB REACH funded ACF programs deployed in Cambodia and Tajikistan, we first identified common program components, which formed the basis of the cost data collection, analysis, reporting framework. Within each program component and sub-activity group, cost data were collected and organized by relevant resource types (human resource, capital, recurrent, and overhead costs). Total shared, indirect and overhead costs were apportioned into each activity category based on direct human resource contribution (e.g. a number of staff and their relative level of effort dedicated to each program component). Capital assets were assessed specific to program components and were annualized based on their expected useful life and a 3% discount rate. All costs were assessed based on the service provider perspective and expressed in 2015 USD. RESULTS: Over the two program years (April 2013 to December 2015), the Cambodia and Tajikistan ACF programs cumulated a total cost of $336,951 and $771,429 to screen 68,846 and 1,980,516 target population, bacteriologically test 4,589 and 19,764 presumptive TB, diagnose 731 and 2,246 TB patients in the respective programs. Recurrent costs were the largest cost components (54% and 34%) of the total costs for the respective programs and Xpert MTB/RIF (Xpert) testing incurred largest program component/activity cost for both programs. Cost per screening was $0.63 and $0.10 and cost per Xpert test was $25 and $18; Cost per TB case detected (Xpert) was $373 and $343 in Cambodia and Tajikistan. CONCLUSIONS: Results from two contextually and programmatically different multi-component ACF programs demonstrate that our tool is fully capable of comprehensively and transparently evaluating and comparing costs of various ACF programs.

Informing decision-making for universal access to quality tuberculosis diagnosis in India: an economic-epidemiological model.

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.

Point of care Xpert MTB/RIF versus smear microscopy for tuberculosis diagnosis in southern African primary care clinics: a multicentre economic evaluation.

BACKGROUND: Rapid on-site diagnosis facilitates tuberculosis control. Performing Xpert MTB/RIF (Xpert) at point of care is feasible, even when performed by minimally trained health-care workers, and when compared with point-of-care smear microscopy, reduces time to diagnosis and pretreatment loss to follow-up. However, whether Xpert is cost-effective at point of care remains unclear. METHODS: We empirically collected cost (US$, 2014) and clinical outcome data from participants presenting to primary health-care facilities in four African countries (South Africa, Zambia, Zimbabwe, and Tanzania) during the TB-NEAT trial. Costs were determined using an bottom-up ingredients approach. Effectiveness measures from the trial included number of cases diagnosed, initiated on treatment, and completing treatment. The primary outcome was the incremental cost-effectiveness of point-of-care Xpert relative to smear microscopy. The study was performed from the perspective of the health-care provider. FINDINGS: Using data from 1502 patients, we calculated that the mean Xpert unit cost was lower when performed at a centralised laboratory (Lab Xpert) rather than at point of care ($23·00 [95% CI 22·12-23·88] vs $28·03 [26·19-29·87]). Per 1000 patients screened, and relative to smear microscopy, point-of-care Xpert cost an additional $35 529 (27 054-40 025) and was associated with an additional 24·3 treatment initiations ([-20·0 to 68·5]; $1464 per treatment), 63·4 same-day treatment initiations ([27·3-99·4]; $511 per same-day treatment), and 29·4 treatment completions ([-6·9 to 65·6]; $1211 per completion). Xpert costs were most sensitive to test volume, whereas incremental outcomes were most sensitive to the number of patients initiating and completing treatment. The probability of point-of-care Xpert being cost-effective was 90% at a willingness to pay of $3820 per treatment completion. INTERPRETATION: In southern Africa, although point-of-care Xpert unit cost is higher than Lab Xpert, it is likely to offer good value for money relative to smear microscopy. With the current availability of point-of-care nucleic acid amplification platforms (eg, Xpert Edge), these data inform much needed investment and resource allocation strategies in tuberculosis endemic settings. FUNDING: European Union European and Developing Countries Clinical Trials Partnership.

Cost and operational impact of promoting upfront GeneXpert MTB/RIF test referrals for presumptive pediatric tuberculosis patients in India.

BACKGROUND: Outreach and promotion programs are essential to ensuring uptake of new public health interventions and guidelines. We assessed the costs and operation dynamics of outreach and promotion efforts for up front Xpert MTB/RIF (Xpert) testing for pediatric presumptive tuberculosis (TB) patients in four major Indian cities. METHODS: Xpert test costs were assessed as weighted average per-test costs based on the daily workload dynamics matched by test volume specific Xpert unit cost at each study site. Costs of outreach programs to recruit health providers to refer pediatric patients for Xpert testing were assessed as cost per referral for each quarter based on total program costs and referral data. All costs were assessed in the health service provider's perspective and expressed in 2015 USD. RESULTS: Weighted average per-test costs ranged from $14.71 to $17.81 at the four laboratories assessed. Differences between laboratories were associated with unused testing capacity and/or frequencies of overtime work to cope with increasing demand and same-day testing requirements. Outreach activities generated between 825 and 2,065 Xpert testing referrals on average each quarter across the four study sites, translating into $0.63 to $2.55 per patient referred. Overall outreach costs per referral decreased with time, stabilizing at an average cost of $1.10, and demonstrated a clear association with increased referrals. CONCLUSIONS: Xpert test and outreach program costs within and across study sites were mainly driven by the dynamics of Xpert testing demand resulting from the combined outreach activities. However, these increases in demand required considerable overtime work resulting in additional costs and operational challenges at the study laboratories. Therefore, careful laboratory operational adjustment should be evaluated at target areas in parallel to the anticipated demand from the Xpert referral outreach program scale-up in other Indian regions.

Cost-effectiveness of Preventive Therapy for Tuberculosis With Isoniazid and Rifapentine Versus Isoniazid Alone in High-Burden Settings.

Background: A short-course regimen of 3 months of weekly rifapentine and isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily isoniazid (isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown. Methods: We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT. Results: Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved. Conclusions: 3HP may be a cost-effective alternative to IPT in high-burden settings, but cost-effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay.

The Sensitivity and Specificity of Loop-Mediated Isothermal Amplification (LAMP) Assay for Tuberculosis Diagnosis in Adults with Chronic Cough in Malawi.

BACKGROUND: Current tuberculosis diagnostics lack sensitivity, and are expensive. Highly accurate, rapid and cheaper diagnostic tests are required for point of care use in low resource settings with high HIV prevalence. OBJECTIVE: To investigate the sensitivity and specificity, and cost of loop-mediated isothermal amplification (LAMP) assay for tuberculosis diagnosis in adults with chronic cough compared to Xpert® MTB/RIF, fluorescence smear microscopy. METHODS: Between October 2013 and March 2014, consecutive adults at a primary care clinic were screened for cough, offered HIV testing and assessed for tuberculosis using LAMP, Xpert® MTB/RIF and fluorescence smear microscopy. Sensitivity and specificity (with culture as reference standard), and costs were estimated. RESULTS: Of 273 adults recruited, 44.3% (121/273) were HIV-positive and 19.4% (53/273) had bacteriogically confirmed tuberculosis. The sensitivity of LAMP compared to culture was 65.0% (95% CI: 48.3% to 79.4%) with 100% (95% CI: 98.0% to 100%) specificity. The sensitivity of Xpert® MTB/RIF (77.5%, 95% CI: 61.5% to 89.2%) was similar to that of LAMP, p = 0.132. The sensitivity of concentrated fluorescence smear microscopy with routine double reading (87.5%, 95% CI: 73.2% to 95.8%) was higher than that of LAMP, p = 0.020. All three tests had high specificity. The lowest cost per test of LAMP was at batch size of 14 samples (US$ 9.98); this was lower than Xpert® MTB/RIF (US$ 13.38) but higher than fluorescence smear microscopy (US$ 0.65). CONCLUSION: The sensitivity of LAMP was similar to Xpert® MTB/RIF but lower than fluorescence smear microscopy; all three tests had high specificity. These findings support the Malawi policy that recommends a combination of fluorescence smear microscopy and Xpert® MTB/RIF prioritised for people living with HIV, already found to be smear-negative, or being considered for retreatment of tuberculosis.