Marc D'Elbee

Background: The World Health Organization (WHO) recommends 4-month treatment for children with non-severe pulmonary tuberculosis, outlining eligibility criteria for settings with and without chest X-ray (CXR). We evaluated the diagnostic accuracy of the WHO eligibility criteria in settings without CXR (WHO-criteria) and developed clinical scores to support disease classification. Methods: Using data from an individual participant dataset (IPD; Decide TB) of children with confirmed/unconfirmed tuberculosis from four diagnostic studies (RaPaed-TB, Umoya, TB-Speed HIV, TB-Speed Decentralisation), we assessed the diagnostic accuracy of the WHO-criteria (with/without bacteriological testing) using expert CXR interpretation as a reference. We developed two multivariable logistic regression models with (Score 1) and without (Score 2) bacteriological testing, converted coefficients into integer scores with a threshold of >10 corresponding to a sensitivity ≥70%. Results: Of 2,383 children in the Decide TB IPD, 633 (26.6%) met the eligibility criteria for a 4-month regimen, of whom 116 (18.3%) had radiologically severe disease. With and without bacteriological testing, the WHO-criteria had sensitivities of 30.1% (95%CI: 20.3%-40.2%) and 21.7% (95%CI: 10.4%-34.5%), and specificities of 83.4% (95%CI: 80.2%-86.4%) and 81.9% (95%CI: 78.8%-84.9%), respectively. Score 1 and Score 2 had sensitivities of 41.1% (95%CI: 32.4%-49.5%) and 30.9% (95%CI: 22.6%-40.4%), and specificities of 77.3% (95%CI: 73.6%-80.8%) and 83.0% (95%CI: 79.5%-86.3%), respectively. Using WHO-criteria, 91/116 (78.4%) and 105/116 (90.5%) of children were at risk of undertreatment, compared to 68/116 (58.6%) and 80/116 (68.9%) when using developed scores. Conclusions: Developed scores demonstrated better sensitivity than WHO-criteria, however, performance remained suboptimal. Implementing shorter antituberculosis regimens without CXR remains challenging in children.

Introduction: Of 1.2 million children and young adolescents (<15 years) developing tuberculosis (TB) yearly, more than 50% are undiagnosed and unreported to national TB programmes (NTPs) and the World Health Organization (WHO). This is mainly due to poor performance of microbiological tests, limited clinical skills and structural barriers for childhood TB diagnosis at decentralised levels of care. Treatment decision algorithms (TDAs) could improve child TB outcomes but require external validation. We aim to evaluate a comprehensive TDA-based approach for childhood TB screening, diagnosis and treatment decision-making at district hospital (DH) and primary health centre (PHC) levels in Mozambique and Zambia. Methods and analysis: Decide TB is a pragmatic, hybrid effectiveness-implementation type 2 cluster-randomised trial with a stepped wedge design. The comprehensive TDA-based approach (intervention) will be implemented under programmatic conditions in four districts in each country (each comprising one DH and six PHCs), randomly selected to switch sequentially from the standard of care to the intervention. Evaluations will assess epidemiological, clinical, economic, social sciences, implementation and health policy endpoints. Aggregated and individual data from children with presumptive TB will be extracted from facility registers and individual data will be collected using an electronic medical record (EMR), both data sources will be entered in national Demographic Health Information System 2 databases. Questionnaires and individual/group interviews (among healthcare workers (HCWs), parents/caregivers and key informants), supervision and mentoring reports and quantitative cost tools will be used. Ethics and dissemination: Ethics approval was obtained from national ethics committees in Mozambique (Instituto Nacional de Saúde review board and National Committee for Bioethics in Health) and Zambia (University of Zambia ethical review board and National Health Research Authority); this includes a waiver for analysing data collected by NTPs (no identifiable information reported, intervention with minimal risk) without individual consent from children’s parents/caregivers. Informed consent will be obtained from HCWs, parents/caregivers and key informants. Results will be openly shared with the scientific community, WHO and national and international stakeholders for translation into policy and practice. Procedures for requesting further use of Decide TB data will be publicly available. Trial registration number: NCT06593080 ; PACTR202407866544155.

Tuberculosis predominates in communities with multiple health and socioeconomic vulnerabilities. Tuberculosis diagnosis presents an opportunity for expanded health services to tuberculosis-affected households. We conducted a modified Delphi process to ascertain if and how expanded services should be offered to people with tuberculosis and their households. Purposively invited panellists were identified through professional networks and included researchers, service providers, policymakers and members of tuberculosis-affected communities. Panellists completed two online survey rounds. Round one sought to establish consensus on the perceived value of integration and capture diverse views on service integration priorities through free-text responses. Round two explored broad consensus statements (consensus defined as ≥75% agreement) developed from round one responses using Likert scales and country-specific priorities. Free-text responses were analysed using inductive thematic analysis. The percentage of panellists agreeing with each statement was calculated as a proportion of all responses, overall and by pre-specified subgroups of professional categories and WHO region. In round one, 223 panellists from 44 countries indicated strong support for expanded and better integrated services for people with tuberculosis (98% agreement), and their household contacts (84%). In round two, 324 people from 68 countries reached consensus on key motivations for service integration. These included improved tuberculosis treatment and other health outcomes among people with tuberculosis, and increased tuberculosis screening and preventive treatment uptake among contacts. Almost all (>99%) panellists agreed that people with tuberculosis should be routinely screened for relevant non-tuberculosis conditions, but only 69% thought this was appropriate among household contacts. There was consensus (93%) that population-wide tuberculosis screening should be integrated with other disease screening. Multiple, often context-specific, considerations for implementation were highlighted. Integrated tuberculosis screening and care is highly valued by global tuberculosis experts. This international consensus provides a strong mandate for research evaluating the feasibility and effectiveness of integrated tuberculosis service delivery and further policy and guideline development.

Background: Children with severe acute malnutrition (SAM) are an important risk group for underdiagnosis and death from tuberculosis. In 2022, the World Health Organization (WHO) recommended use of treatment decision algorithms (TDAs) for tuberculosis diagnosis in children. There is currently no cost-effectiveness evidence for TDA-based approaches compared to routine practice. Methods: The TB-Speed SAM study developed i) a one-step TDA including Xpert, clinical, radiological and echography features, and ii) a two-step TDA, which also included a screening phase, for children under 5 years hospitalised with SAM at tertiary hospitals in Uganda and Zambia. We assessed the diagnostic accuracy and cost-effectiveness of deploying TB-Speed and WHO TDA-based approaches compared to the standard of care (SOC). Estimated outcomes included children started on tuberculosis treatment, false positive rates, disability-adjusted life years (DALYs) and incremental cost-effectiveness ratios (ICERs). Findings: Per 100 children hospitalised with SAM, averaging 19 children with tuberculosis, the one-step TDA initiated 17 true positive children (95% uncertainty intervals [UI]: 12-23) on tuberculosis treatment, the two-step TDA 15 (95%UI: 10-22), the WHO TDA 14 (95%UI: 9-19), and SOC 4 (95%UI: 2-9). The WHO TDA generated the most false positives (35, 95%UI: 24-46), followed by the one-step TDA (18, 95%UI: 6-29), the two-step TDA (14, 95%UI: 1-25), and SOC (11, 95%UI: 3-17). All TDA-based approaches had ICERs below plausible country cost-effectiveness thresholds compared to SOC (one-step: $44-51/DALY averted, two-step: $34-39/DALY averted, WHO: $40-46/DALY averted). Interpretation: Our findings show that these TDA-based approaches are highly cost-effective for the vulnerable group of children hospitalised with SAM, compared to current practice. Funding: Unitaid Research in context: Evidence before this study: In 2022, the WHO conditionally recommended the use of treatment decision algorithms (TDAs) for tuberculosis diagnosis in children aged <10 with presumptive pulmonary tuberculosis. Two TDAs were suggested for use in settings with (TDA A) and without (TDA B) access to chest X-ray. These WHO-suggested TDAs propose a single approach to TB diagnosis in all children. The TB Speed SAM study developed specific algorithms for children <5 years hospitalised with severe acute malnutrition. Aiming to identify studies assessing the cost-effectiveness of using TDAs for childhood TB, we searched the PubMed database using (“Decision Support Systems, Clinical”[MeSH] OR “clinical decision support” OR “decision support” OR “clinical decision-making”) AND (“Algorithms”[MeSH] OR “algorithm” OR “decision-making” OR “decision model” OR “treatment decision algorithm”) AND (“Tuberculosis”[MeSH] OR “tuberculosis” OR “TB”) AND (“Costs and Cost Analysis”[MeSH] OR “cost-effectiveness” OR “cost analysis” OR “costs”) between 1st January 2004 and 18th October 2024, without language restrictions. Of 31 articles identified, 2 articles reported on the cost-effectiveness of interventions aiming to improve clinical decision making for tuberculosis diagnosis. Other articles were excluded because they were not an economic evaluation, not on tuberculosis, or only compared microbiological testing approaches related to tuberculosis care (microscopic observation drug susceptibility test versus Xpert MTB/RIF test, QuantiFERON-TB Gold In-Tube versus tuberculin skin test for tuberculosis diagnosis). Debes et al. assessed the cost-effectiveness of tuberculosis diagnosis using microscopic observation drug susceptibility, Xpert MTB/RIF and empiric treatment for all patients, in addition to current clinical diagnostic practices in Ugandan children. Van’t Hoog et al. explored combinations of sensitivity, specificity and cost at which a hypothetical triage test would improve affordability of the Xpert assay. We found no economic evaluations of a treatment decision algorithm (TDA)-based approach (screening, testing, treatment) for tuberculosis diagnosis. Added value of this study: This is the first study to assess the cost-effectiveness of using treatment decision algorithms in childhood tuberculosis diagnosis. It focuses on children <5 years hospitalised with severe acute malnutrition using the TB-Speed SAM one-step TDA and two-step TDA, which includes a screening step before the diagnostic step, and the WHO-suggested TDA A. We also evaluated the accuracy of the WHO-suggested TDA for paediatric tuberculosis in this patient group. This study found that for children hospitalised with SAM all three TDA-based approaches for paediatric tuberculosis diagnosis were cost-effective compared to the standard of care from a health systems perspective in Uganda and Zambia, including in lower tuberculosis prevalence settings. The TB-Speed two-step and WHO TDAs had lower costs than the TB-Speed one-step because their screening step resulted in fewer assessments overall, but also a smaller health impact due to a slightly lower sensitivity. The WHO TDA was less effective and more costly than the TB-Speed two-step TDA and involved substantial rates of overtreatment. The TB-Speed one-step TDA had the greatest health impact while remaining cost-effective, making it the preferred option. Implications of all the available evidence: The WHO has conditionally recommended incorporating TDAs, pending validation, into existing case detection strategies to support the decentralisation of clinical tools and improve the identification of tuberculosis in children. Our findings show that TDA-based approaches are cost-effective for the vulnerable group of children hospitalised with SAM, compared to current practices, and our sensitivity analysis suggests that these results are...

HIV self-testing (HIVST) empowers individuals to decide when and where to test and with whom to share their results. From 2019 to 2022, the ATLAS program distributed ∼ 400 000 HIVST kits in Côte d’Ivoire, Mali, and Senegal. It prioritised key populations, including female sex workers and men who have sex with men, and encouraged secondary distribution of HIVST to their partners, peers and clients. To preserve the confidential nature of HIVST, use of kits and their results were not systematically tracked. Instead, an anonymous phone survey was carried out in two phases during 2021 to estimate HIVST positivity rates (phase 1) and linkage to confirmatory testing (phase 2). Initially, participants were recruited via leaflets from March to June and completed a sociobehavioural questionnaire. In the second phase (September-October), participants who had reported two lines or who reported a reactive result were recontacted to complete another questionnaire. Of the 2 615 initial participants, 89.7% reported a consistent response between the number of lines on the HIVST and their interpretation of the result (i.e., ‘non-reactive’ for 1 line, ‘reactive’ for 2 lines). Overall positivity rate based on self-interpreted HIVST results was 2.5% considering complete responses, and could have ranged from 2.4% to 9.1% depending on the interpretation of incomplete responses. Using the reported number of lines, this rate was estimated at 4.5% (ranging from 4.4% to 7.2%). Positivity rates were significantly lower only among respondents with higher education. No significant difference was observed by age, key population profile, country or history of HIV testing. The second phase saw 78 out of 126 eligible participants complete the questionnaire. Of the 27 who reported a consistent reactive response in the first phase, 15 (56%, 95%CI: 36 to 74%) underwent confirmatory HIV testing, with 12 (80%) confirmed as HIV-positive, all of whom began antiretroviral treatment. The confirmation rate of HIVST results was fast, with 53% doing so within a week and 91% within three months of self-testing. Two-thirds (65%) went to a general public facility, and one-third to a facility dedicated to key populations. The ATLAS HIVST distribution strategy reached people living with HIV in West Africa. Linkage to confirmatory testing following a reactive HIVST remained relatively low in these first years of HIVST implementation. However, if confirmed HIV-positive, almost all initiated treatment. HIVST constitutes a relevant complementary tool to existing screening services.

Background: The burden of childhood tuberculosis remains high globally, largely due to under-diagnosis. Decentralising childhood tuberculosis diagnosis services to lower health system levels could improve case detection, but there is little empirically based evidence on cost-effectiveness or budget impact. Methods: We assessed the cost-effectiveness and budget impact of decentralising a comprehensive diagnosis package for childhood tuberculosis to district hospitals (DH-focused) or primary health centres (PHC-focused) compared to standard of care (SOC) in Cambodia, Cameroon, Côte d’Ivoire, Mozambique, Sierra Leone, and Uganda ( NCT04038632 ). A mathematical model was developed to assess the health and economic outcomes of the intervention from a health system perspective. Estimated outcomes were tuberculosis cases, deaths, disability- adjusted life years and incremental cost-effectiveness ratios (ICERs). We also calculated the budget impact of nationwide implementation. Findings: For the DH-focused strategy versus SOC, ICERs ranged between $263 (Cambodia) and $342 (Côte d’Ivoire) per disability-adjusted life-year (DALY) averted. For the PHC-focused strategy versus SOC, ICERs ranged between $477 (Cambodia) and $599 (Côte d’Ivoire) per DALY averted. Results were sensitive to TB prevalence and the discount rate used. The additional costs of implementing the DH-focused strategy ranged between $13M (Cambodia) and $50M (Mozambique), and between $14M (Sierra Leone) and $135M (Uganda) for the PHC-focused strategy. Interpretation: The DH-focused strategy may be cost-effective in some countries, depending on the cost- effectiveness threshold used for policy making. Either intervention would require substantial early investment. Funding: Unitaid

Appropriate costing and economic modeling are major factors for the successful scale‐up of health interventions. Various cost functions are currently being used to estimate costs of health interventions at scale in low‐ and middle‐income countries (LMICs) potentially resulting in disparate cost projections. The aim of this study is to gain understanding of current methods used and provide guidance to inform the use of cost functions that is fit for purpose. We reviewed seven databases covering the economic and global health literature to identify studies reporting a quantitative analysis of costs informing the projected scale‐up of a health intervention in LMICs between 2003 and 2019. Of the 8725 articles identified, 40 met the inclusion criteria. We classified studies according to the type of cost functions applied—accounting or econometric—and described the intended use of cost projections. Based on these findings, we developed new mathematical notations and cost function frameworks for the analysis of healthcare costs at scale in LMICs setting. These notations estimate variable returns to scale in cost projection methods, which is currently ignored in most studies. The frameworks help to balance simplicity versus accuracy and increase the overall transparency in reporting of methods.