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Three months of isoniazid-rifapentine (3HP) is being scaled up for tuberculosis (TB) preventive treatment (TPT) among people living with HIV (PLHIV) in high-burden settings. More evidence is needed to identify factors influencing successful 3HP delivery. We conducted a qualitative assessment of 3HP delivery nested within the 3HP Options Trial, which compared three optimized strategies for delivering 3HP: facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), and patient choice between facilitated DOT and facilitated SAT at the Mulago HIV/AIDS clinic in Kampala, Uganda. We conducted 72 in-depth interviews among PLHIV purposively selected to investigate factors influencing 3HP acceptance and completion. We conducted ten key informant interviews with healthcare providers (HCPs) involved in 3HP delivery to identify facilitators and barriers at the clinic level. We used post-trial 3HP delivery data to assess sustainability. We conducted an inductive thematic analysis and aligned the emergent themes with the RE-AIM framework dimensions to report implementation outcomes. Understanding the need for TPT, once-weekly dosing, shorter duration, and perceived 3HP safety enhanced acceptance overall. Treatment monitoring by HCPs and reduced risk of HIV status disclosure enabled DOT acceptance. Dosing autonomy enabled SAT acceptance. Switching between DOT and SAT as required enabled acceptance for patient choice. Dosing reminders, reimbursement for clinical visits, and social support enabled 3HP completion; pill burden, side effects, and COVID-19-related treatment restrictions hindered completion. All HCPs were trained and participated in 3HP delivery with high fidelity. Training, care integration, and collaboration among HCPs enabled, whereas initial concerns about 3HP safety among HCPs delayed 3HP adoption and implementation. SAT was maintained post-trial; DOT was discontinued due to inadequate ongoing financial support beyond the study period. Facilitated delivery strategies made 3HP treatment convenient for PLHIV and were feasible and implemented with high fidelity by HCPs. However, the costs of 3HP facilitation may limit wider scale-up.

Background: Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AE) could differ in routine settings. Real-world data on AE type, frequency, and timing is crucial for health systems considering 3HP programmatic scale-up., Methods: We reviewed AEs among people living with HIV (PLHIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including lab tests, diagnoses made, medications prescribed, and treatment interruptions., Results: Among 1655 PLHIV treated between July 2020-September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE., Conclusions: In a routine setting, 3HP was safe with 16% of PLHIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention.

The 2013-2016 Ebola virus disease epidemic and the coronavirus disease 2019 pandemic galvanized tremendous growth in models for emerging zoonotic and vector-borne viruses. Therefore, we have reviewed the main goals and methods of models to guide scientists and decision-makers. The elements of models for emerging viruses vary across spectrums: from understanding the past to forecasting the future, using data across space and time, and using statistical versus mechanistic methods. Hybrid/ensemble models and artificial intelligence offer new opportunities for modeling. Despite this progress, challenges remain in translating models into actionable decisions, particularly in areas at highest risk for viral disease outbreaks. To address this issue, we must identify gaps in models for specific viruses, strengthen validation, and involve policymakers in model development., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To provide accurate forecasts of the age distribution of people with HIV (PWH) in Kenya from 2025 to 2040., Design: Development of a compartmental model of HIV in Kenya, calibrated to historical estimates of HIV epidemiology., Methods: We forecasted changes in population size and age distribution of new HIV infections and PWH under the status quo and under scale-up of HIV services., Results: Without scale-up, new HIV infections were forecasted to fall from 34 000 (28 000-41 000) in 2,025 to 29 000 (15 000-57 000) in 2,040; the percentage of new infections occurring among persons over 30 increased from 33% (20-50%) to 40% (24-62%). The median age of PWH increased from 39 years (38-40) in 2025 to 43 years (39-46) in 2040, and the percentage of PWH over age 50 increased from 26% (23-29%) to 34% (26-43%). Under the full intervention scenario, new infections were forecasted to fall to 6,000 (3,000-12 000) in 2,040. The percentage of new infections occurring in people over age 30 increased to 52% (34-71%) in 2,040, and there was an additional shift in the age structure of PWH [forecasted median age of 46 (43-48) and 40% (33-47%) over age 50]., Conclusion: PWH in Kenya are forecasted to age over the next 15 years; improvements to the HIV care continuum are expected to contribute to the growing proportion of older PWH., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Conflicts of interest: none declared.

Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10·6 million people who developed tuberculosis globally in 2022, more than 3·1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures., Competing Interests: Declaration of interests TB reports patent applications in the field of tuberculosis detection and is a shareholder of Avelo. MP serves as an adviser for non-profits such as the Bill & Melinda Gates Foundation, FIND, WHO, and the Stop TB Partnership. All other authors declare no competing interests., (Copyright © 2024 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: Household contact investigation (HCI) is an effective and widely used approach to identify persons with tuberculosis (TB) disease and infection, globally. Despite widespread recommendations for the use of HCI, there remains poor understanding of the impact on and value of contact investigation for participants. Further, how HCI as a practice impacts psychosocial factors, including stigma and possible unintended disclosure of illness among persons with TB, their families, and communities, is largely unknown., Methods: This exploratory qualitative study nested within a randomized trial (ClinicalTrials.gov: NCT04520113, 17 August 2020) was conducted in South Africa to understand the impacts of HCI on index patients living with TB and their household contact persons in two rural districts in the Limpopo province (Vhembe and Capricorn) and Soshanguve, a peri-urban township in Gauteng province. People with TB and household members of people with TB were recruited to participate in in-depth interviews and focus group discussions using semi-structured guides. We explored individual, interpersonal, and community-level perceptions of potential impacts of household contact investigation to elucidate their perceptions of HCI. Thematic analysis identified key themes., Results: Twenty-four individual interviews and six focus group discussions (n=39 participants) were conducted. Participants viewed HCI as an effective approach to finding TB cases, helpful in educating households about TB symptoms and reducing barriers to health-related services. At the interpersonal level, HCI aided people with TB in safely disclosing their TB status to family members and facilitated family and social support for accountability. The introduction of HIV testing during HCI was reported by some participants as making household members slightly uncomfortable, decreasing interest in household members being tested for TB. HCI negatively impacted community-level TB and HIV-related stigma due to healthcare worker visibility at home., Conclusion: Our data suggests varying impacts of HCI on people with TB, their families and interpersonal relationships, and communities, highlighting the importance of considering approaches that address concerns about community stigma and HIV testing to enhance acceptance of HCI., Competing Interests: Competing interests The authors declare that they have no competing interests.

Background: With numerous trials investigating novel drug combinations to treat tuberculosis, we aimed to evaluate the extent to which future improvements in tuberculosis treatment regimens could offset potential increases in drug costs., Methods: In this modelling analysis, we used an ingredients-based approach to estimate prices at which novel regimens for rifampin-susceptible and rifampin-resistant tuberculosis treatment would be cost-neutral or cost-effective compared with standards of care in India, the Philippines, and South Africa. We modelled regimens meeting targets set in the WHO's 2023 Target Regimen Profiles (TRPs). Our decision-analytical model tracked cohorts of adults initiating rifampin-susceptible or rifampin-resistant tuberculosis treatment, simulating their health outcomes and costs accumulated during and following treatment under standard-of-care and novel regimen scenarios. Price thresholds included short-term cost-neutrality (considering only savings accrued during treatment), medium-term cost-neutrality (additionally considering savings from averted retreatments and secondary cases), and cost-effectiveness (incorporating willingness-to-pay for improved health outcomes)., Findings: Total medium-term costs per person treated using standard-of-care regimens were estimated at US$450 (95% uncertainty interval 310-630) in India, $560 (350-860) in the Philippines, and $730 (530-1090) in South Africa for rifampin-susceptible tuberculosis (current drug costs $46) and $2100 (1590-2810) in India, $2610 (2090-3280) in the Philippines, and $3790 (3090-4630) in South Africa for rifampin-resistant tuberculosis (current drug costs $432). A rifampin-susceptible tuberculosis regimen meeting the optimal targets defined in the TRPs could be cost-neutral in the short term at drug costs of $140 (90-210) per full course in India, $230 (130-380) in the Philippines, and $280 (180-460) in South Africa. For rifampin-resistant tuberculosis, short-term cost-neutral thresholds were higher with $930 (720-1230) in India, $1180 (980-1430) in the Philippines, and $1480 (1230-1780) in South Africa. Medium-term cost-neutral prices were approximately $50-100 higher than short-term cost-neutral prices for rifampin-susceptible tuberculosis and $250-550 higher for rifampin-resistant tuberculosis. Health system cost-neutral prices that excluded patient-borne costs were 45-70% lower (rifampin-susceptible regimens) and 15-50% lower (rifampin-resistant regimens) than the cost-neutral prices that included patient costs. Cost-effective prices were substantially higher. Shorter duration was the most important driver of medium-term savings with novel regimens, followed by ease of adherence., Interpretation: Improved tuberculosis regimens, particularly shorter regimens or those that facilitate better adherence, could reduce overall costs, potentially offsetting higher prices., Funding: WHO., Competing Interests: Declaration of interests TSR, CL, DWD, and EAK report funding from WHO. TSR and EAK report funding from the Bill & Melinda Gates Foundation. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Rationale: C-reactive protein (CRP) has demonstrated utility as a point-of-care triage test for tuberculosis (TB) in clinical settings, particularly among people with human immunodeficiency virus (HIV), but its performance for general-population TB screening is not well characterized. Objective: To assess the accuracy of CRP for detecting pulmonary TB disease among individuals undergoing community-based screening or presenting for evaluation of TB symptoms in Kampala, Uganda. Methods: We pooled data from two case-control studies conducted between May 2018 and December 2022 among adolescents and adults (⩾15 yr) in Kampala, Uganda. We conducted community-based screening for TB, regardless of symptoms. We enrolled people with Xpert MTB/RIF Ultra-positive (including trace) sputum results and a sample of people with Ultra-negative results. We also enrolled symptomatic patients diagnosed with TB and controls with negative TB evaluations from ambulatory care settings. Participants underwent further evaluation, including sputum culture, CRP, and HIV testing. We assessed the accuracy of CRP alone or with symptom screening against a bacteriologic reference standard. Our primary analysis evaluated the sensitivity and specificity of CRP at a cutoff of 5 mg/L. Diagnostic performance was summarized by calculating the area under the receiver operating curve (AUC). Results: In the community setting ( n  = 544), CRP ⩾ 5 mg/L had a sensitivity of 55.3% (95% confidence interval, 47.0-63.4%) and specificity of 84.7% (79.7-88.8%) for confirmed TB; AUC was 0.75 (0.70-0.79). Screening for CRP ⩾ 5 mg/L or positive symptoms increased sensitivity to 92.0% (86.4-95.8%) at the expense of specificity (57.1% [50.8-63.2%]). In the ambulatory care setting ( n  = 944), sensitivity of CRP ⩾ 5 mg/L was 86.7% (81.8-90.7%), specificity was 68.6% (64.8-72.2%), and AUC (0.84 [0.81-0.87]) did not differ significantly by HIV status. CRP ⩾ 5 mg/L was >90% sensitive among individuals with a medium or high semiquantitative Xpert result in both settings. Conclusions: Although CRP did not meet World Health Organization (WHO) TB screening benchmarks in the community, it demonstrated high specificity, and sensitivity was high among individuals with high sputum bacillary burden who are likely to be most infectious. In ambulatory care, estimated sensitivity and specificity were each within 4 percentage points of WHO benchmarks, with no meaningful difference in performance by HIV status.

Introduction: Antiretroviral therapy (ART) and tuberculosis preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase the uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men., Methods: We developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programmes during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e. ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for 10 years. We projected the number of TB cases, deaths and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated programme costs and incremental cost-effectiveness ratios from the provider perspective., Results: If community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3%-34.1%) and TB mortality by 34.6% (range 24.8%-42.2%) after 10 years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9%-36.0%) and TB mortality by 36.0% (range 26.9%-43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates, with a projected 54 more deaths annually among men than women (range 11-103) after 10 years of community-based care versus 109 (range 41-182) in standard care. Over 10 years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709-$1012)., Conclusions: By substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Laboratory networks provide services through onsite testing or through specimen transport to higher-tier laboratories. This decision is based on the interplay of testing characteristics, treatment characteristics, and epidemiological characteristics., Objectives: Our objective was to develop a generalizable model using the threshold approach to medical decision making to inform test placement decisions., Methods: We developed a decision model to compare the incremental utility of onsite versus send-out testing for clinical purposes. We then performed Monte Carlo simulations to identify the settings under which each strategy would be preferred. Tuberculosis was modeled as an exemplar., Results: The most important determinants of the decision to test onsite versus send-out were the clinical utility lost due to send-out testing delays and the accuracy decrement with onsite testing. When the sensitivity decrements of onsite testing were minimal, onsite testing tended to be preferred when send-out delays reduced clinical utility by >20%. By contrast, when onsite testing incurred large reductions in sensitivity, onsite testing tended to be preferred when utility lost due to delays was >50%. The relative cost of onsite versus send-out testing affected these thresholds, particularly when testing costs were >10% of treatment costs., Conclusions: Decision makers can select onsite versus send-out testing in an evidence-based fashion using estimates of the percentage of clinical utility lost due to send-out delays and the relative accuracy of onsite versus send-out testing. This model is designed to be generalizable to a wide variety of use cases., Highlights: The design of laboratory networks, including the decision to place diagnostic instruments at the point-of-care or at higher tiers as accessed through specimen transport, can be informed using the threshold approach to medical decision making.The most important determinants of the decision to test onsite versus send-out were the clinical utility lost due to send-out testing delays and the accuracy decrement with onsite testing.The threshold approach to medical decision making can be used to compare point-of-care testing accuracy decrements with the lost utility of treatment due to send-out testing delays.The relative cost of onsite versus send-out testing affected these thresholds, particularly when testing costs were >10% of treatment costs., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for this study was provided entirely by the National Institutes of Health (5R01AI136977, K01AI138853, and T32 MH 122357). The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.

Background: "Trace" results on Xpert MTB/RIF Ultra ("Ultra"; Cepheid) -a molecular diagnostic test for tuberculosis (TB)-are often interpreted as an indication for TB treatment, but may also represent detection of nonviable bacilli or analytical error. In community-screening settings where individual TB risk is low, there is limited guidance on how to interpret Ultra-trace results., Methods: We conducted systematic Ultra TB screening of adults and adolescents (≥15 years) in Kampala, Uganda, through door-to-door and event-based sputum collection. We enrolled individuals with trace-positive sputum for detailed clinical, radiographic, and microbiological (including 2 sputum cultures, repeat Ultra, and for people with HIV, urine lipoarabinomannan) evaluation, and compared those findings with similar evaluations in controls with Ultra-negative and Ultra-positive (non-trace) sputum., Results: Of 21 957 people screened with Ultra, 211 (1.0%) tested positive, including 96 (46% of positives) with trace results. Of 92 people enrolled with trace-positive sputum; 12% (11/92) were HIV-positive and 14% (13/92) had prior TB. The prevalence of TB among participants with trace-positive sputum results was 14% (13/92) by culture, 24% (22/92) using broader microbiological criteria, and 26% (24/92) after accounting for clinical diagnosis. The prevalence of cough and of abnormal chest computed tomography (CT) findings were 32% and 26%, respectively, if Ultra-negative; 34% and 54% if trace-positive/non-microbiologically confirmed; 72% and 95% if trace-positive/microbiologically confirmed; and 71% and 93% if Ultra-positive (more than trace)., Conclusions: Most individuals with trace-positive sputum in Ugandan communities did not have microbiologically confirmed TB but had more symptoms and chest CT abnormalities than people with Ultra-negative sputum., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies., Methods and Findings: In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings., Conclusions: Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers., Trial Registration: ClinicalTrials.gov NCT03934931., Competing Interests: A.S. and D.P. are human-centered design consultants for The Empathy Studio, LLC. D.P. is a human-centered design consultant for the Diversity Innovation Hub at Mt. Sinai. The other authors have declared that no competing interests exist., (Copyright: © 2024 Semitala 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.)

Background: In settings with large case detection gaps, active case-finding (ACF) may play a critical role in the uberculosis (TB) response. However, ACF is resource intensive, and its effectiveness depends on whether people detected with TB through ACF might otherwise spontaneously resolve or be diagnosed through routine care. We analysed the potential effectiveness of ACF for TB relative to the counterfactual scenario of routine care alone., Methods: We constructed a Markov simulation model of TB natural history, diagnosis, symptoms, ACF and treatment, using a hypothetical reference setting using data from South East Asian countries. We calibrated the model to empirical data using Bayesian methods, and simulated potential 5-year outcomes with an 'aspirational' ACF intervention (reflecting maximum possible effectiveness) compared with the standard-of-care outcomes., Results: Under the standard of care, 51% (95% credible interval, CrI: 31%, 75%) of people with prevalent TB at baseline were estimated to be diagnosed and linked to care over 5 years. With aspirational ACF, this increased to 88% (95% CrI: 84%, 94%). Most of this difference represented people who were diagnosed and treated through ACF but experienced spontaneous resolution under standard-of-care. Aspirational ACF was projected to reduce the average duration of TB disease by 12 months (95% CrI: 6%, 18%) and TB-associated disability-adjusted life-years by 71% (95% CrI: 67%, 76%)., Conclusion: These data illustrate the importance of considering outcomes in a counterfactual standard of care scenario, as well as trade-offs between overdiagnosis and averted morbidity through earlier diagnosis-not just for TB, but for any disease in which population-based screening is recommended., (© The Author(s) 2024; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Social events and stressful settings can be catalysts for alcohol consumption. Motivational enhancement therapy (MET) and cognitive behavioral therapy (CBT) are widely used in alcohol interventions. We assessed how alcohol consumption varied across three types of days (positive/social, negative/stressful, and neutral) among hazardous alcohol users living with HIV in Vietnam. We further evaluated how those consumption patterns changed after two MET/CBT alcohol reduction interventions versus the standard of care (SOC). The 'combined' intervention offered 6 individual sessions and 3 group sessions; the 'brief' intervention offered 2 individual sessions and 2 phone calls. A 30-day timeline follow-back was administered at study visits, detailing daily drinks and events. Days were categorized as neutral, positive/social, or negative/stressful; negative binomial models and generalized estimating equations were used to estimate drinks consumed by type of day at baseline and 12 months. Prior to intervention, more drinks were consumed on positive/social days (5.2 drinks; 95% Confidence Interval [CI]:4.8, 5.7) than negative/stressful (1.5; 95% CI:1.3, 1.9) and neutral days (2.2; 95% CI: 1.9, 2.5). After the brief intervention, drinks consumed decreased on neutral days (ratio: 0.5: 95% CI: 0.4, 0.7). After the combined intervention, drinks consumed decreased on neutral days (ratio: 0.4; 95% CI: 0.3, 0.6), positive/social days (ratio: 0.6; 95% CI: 0.5, 0.7) and negative/stressful days (ratio: 0.3; 95% CI: 0.2, 0.6). No reductions in consumption were observed in the SOC group. Social/positive days had the highest alcohol consumption prior to intervention, and the combined intervention showed the greatest decrease in consumption on those days. CLINICAL TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT02720237)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale & Objective: Vaccination for influenza is strongly recommended for people with chronic kidney disease (CKD) due to their immunocompromised state. Identifying risk factors for not receiving an influenza vaccine (non-vaccination) could inform strategies for improving vaccine uptake in this high-risk population., Study Design: Longitudinal observational study., Setting & Participants: 3,692 Chronic Renal Insufficiency Cohort Study (CRIC) participants., Exposure: Demographic factors, social determinants of health, clinical conditions, and health behaviors., Outcome: Influenza non-vaccination, which was assessed based on a receipt of influenza vaccine ascertained during annual clinic visits in a subset of participants who were under nephrology care., Analytical Approach: Mixed-effects Poisson models to estimate adjusted prevalence ratios (APRs)., Results: Between 2009 and 2020, the pooled mean vaccine uptake was 72% (mean age, 66 years; 44% female; 44% Black race). In multivariable models, factors significantly associated with influenza non-vaccination were younger age (APR, 2.16 [95% CI, 1.85-2.52] for<50 vs≥75 years), Black race (APR, 1.58 [95% CI, 1.43-1.75] vs White race), lower education (APR, 1.20 [95% CI, 1.04-1.39 for less than high school vs college graduate]), lower annual household income (APR, 1.26 [95% CI, 1.06-1.49] for <$20,000 vs >$100,000), formerly married status (APR, 1.22 [95% CI, 1.09-1.35] vs currently married), and nonemployed status (APR, 1.13 [95% CI, 1.02-1.24] vs employed). In contrast, participants with diabetes (APR, 0.80 [95% CI, 0.73-0.87] vs no diabetes), chronic obstructive pulmonary disease (COPD) (APR, 0.80 [95% CI, 0.70-0.92] vs no COPD), end-stage kidney disease (APR, 0.64 [0.56 to 0.76] vs estimated glomerular filtration rate≥60mL/min/1.73m 2 ), frailty (APR, 0.86 [95% CI, 0.74-0.99] vs no frailty), and ideal physical activity (APR, 0.90 [95% CI, 0.82-0.99] vs. physically inactive) were less likely to have non-vaccination status., Limitations: Possible residual confounding., Conclusions: Among adults with CKD receiving nephrology care, younger adults, Black individuals, and those with adverse social determinants of health were more likely to have the influenza non-vaccination status. Strategies are needed to address these disparities and reduce barriers to vaccination., Plain-Language Summary: Identifying risk factors for not receiving an influenza vaccine ("non-vaccination") in people living with kidney disease, who are at risk of influenza and its complications, could inform strategies for improving vaccine uptake. In this study, we examined whether demographic factors, social determinants of health, and clinical conditions were linked to the status of not receiving an influenza vaccine among people living with kidney disease and receiving nephrology care. We found that younger adults, Black individuals, and those with adverse social determinants of health were more likely to not receive the influenza vaccine. These findings suggest the need for strategies to address these disparities and reduce barriers to vaccination in people living with kidney disease., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Both 1 month of daily (1HP) and 3 months of weekly (3HP) isoniazid-rifapentine are recommended as short-course regimens for TB prevention among people living with HIV (PLHIV). We aimed to assess acceptability and preferences for 1HP vs. 3HP among PLHIV., Methods: In a cross-sectional survey among PLHIV at an HIV clinic in Kampala, Uganda, participants were randomly assigned to a hypothetical scenario of receiving 1HP or 3HP. Participants rated their level of perceived intention and confidence to complete treatment using a 0-10 Likert scale, and chose between 1HP and 3HP., Results: Among 429 respondents (median age: 43 years, 71% female, median time on ART: 10 years), intention and confidence were rated high for both regimens. Intention to complete treatment was rated at least 7/10 by 92% (189/206 randomized to 1HP) and 93% (207/223 randomized to 3HP). Respectively 86% (178/206) and 93% (208/223) expressed high confidence to complete treatment. Overall, 81% (348/429) preferred 3HP over 1HP., Conclusions: Both 1HP and 3HP were highly acceptable regimens, with 3HP preferred by most PLHIV. Weekly, rather than daily, dosing appears preferable to shorter duration of treatment, which should inform scale-up and further development of short-course regimens for TB prevention., (© 2024 The Authors.)

Introduction: In high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood., Methods: We developed a microsimulation model assessing 3 approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence 4 times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test, (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs., Results: Universal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3200 (2600 to 3900) TB-related disability-adjusted life years (DALYs) per 100 000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted., Conclusions: Screening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive., Competing Interests: Potential conflicts of interest. C.M. D. reports research grants from the US NIH, German Ministry of Education and Research, German Alliance for Global Health research, USAID, FIND, German Center for Infection Research, UNAIDS, World Health Organization (WHO), Roche. C. M. D. also declares a payment from Roche Diagnostics that she accepted as German law requires a manufacturer to pay for the use of data for regulatory purposes. Data were generated on a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test as part of an independent evaluation by C. M. D. and team. C. M. D. also reports a role as academic editor for PLoS Med and on technical advisory group Tuberculosis diagnostics for WHO. A. C. reports grants to institution from Global Health Labs, Stop TB Partnership, and Bill and Melinda Gates Foundation; unpaid participation on an Advisory Board for EDCTP-funded TB diagnostic trial; and stock options with Medaica. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Several clinical trials of tuberculosis preventive treatment (TPT) for household contacts of patients with multidrug- or rifampin-resistant tuberculosis (MDR/RR-TB) are nearing completion. The potential benefits of delivering TPT to MDR/RR-TB contacts extend beyond the outcomes that clinical trials can measure., Methods: We developed an agent-based, household-structured TB and MDR/RR-TB transmission model, calibrated to an illustrative setting in India. We simulated contact investigation in households of patients with MDR/RR-TB, comparing an MDR/RR-TPT regimen (assuming 6-month duration, 70% efficacy) and associated active case finding against alternatives of contact investigation without TPT or no household intervention. We simulated the TB and MDR/RR-TB incidence averted relative to placebo over 2 years, as measurable by a typical trial, as well as the incidence averted over a longer time horizon, in the broader population, and relative to no contact investigation., Results: Observing TPT and placebo recipients for 2 years as in a typical trial, MDR/RR-TPT was measured to prevent 72% (interquartile range, 45%-100%) of incident MDR/RR-TB among recipients; the median number needed to treat (NNT) to prevent 1 MDR/RR-TB case was 73, compared to placebo. This NNT decreased to 54 with 13-18 years of observation, to 27 when downstream transmission effects were also considered, and to 12 when the effects of active TB screening were included by comparing to a no-household-contact-intervention scenario., Conclusions: If forthcoming trial results demonstrate efficacy, the long-term population impact of TPT for MDR/RR-TB-including the large effect of increased active TB detection among MDR/RR-TB contacts-could be much greater than suggested by trial outcomes alone., Competing Interests: Potential conflicts of interest. D. W. D. reports institutional grants or contracts unrelated to this project from the NIH, Centers for Disease Control and Prevention, GiveWell.org, the US Agency for International Development, and the Foundation for Innovative New Diagnostics. E. A. K. reports a Catalyst Award for agent-based modeling of drug-resistant tuberculosis from Johns Hopkins University. A. G. reports payment or honoraria from Washington University for St Louis lectureship and from the Asia Pacific Congress of Clinical Microbiology and Infection plenary, and unpaid roles from the IndoUS Governing Board and the NIAID Council. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Geographical mobility, the movement of individuals or populations, may increase an individual's risk of acquiring or transmitting infectious diseases, including HIV, tuberculosis, malaria and COVID-19. Many studies have collected information on short-term mobility through self-reported travel histories or using GPS trackers, but there has been no consistent conceptualisation and operationalisation of such geographical mobility in global health research. This protocol aims to describe and synthesise different approaches to measuring short-term mobility., Methods and Analysis: We will search three databases (PubMed, Embase and Global Health) for peer-reviewed articles. After removing duplicates, two reviewers will first screen the titles and abstracts and then proceed to full-text screening. We will include studies that measure mobility at the individual level in the context of infectious diseases, including clinical trials, epidemiological studies and analyses of register data. Additional articles for inclusion may be identified through review of references in selected papers. We will summarise the method of data collection (GPS trackers, cellphones, retrospective self-report, travel journal, etc) and the specific measures used (overnight travel, having a secondary residence, travel outside of district, etc)., Ethics and Dissemination: This study consists of reviewing and abstracting existing data from publicly available materials, and therefore does not require ethical approval. The results of this study will be submitted for peer reviewed publication and may be presented at a relevant global health conference., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Our study aims to examine the factor structure, validity, and reliability of the combined scale Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) among people with HIV (PWH) in Vietnam., Methods: Baseline data from an alcohol-reduction intervention trial among ART clients in Thai Nguyen, Vietnam were used for this analysis ( n = 1547). A score ≥10 on the PHQ-9, GAD-7 and PHQ-ADS scale was considered having clinically meaningful depression, anxiety and distress symptoms. Factor structure of the combined PHQ-ADS scale was validated using confirmatory factor analysis, and three models were tested: a one-factor, a two-factor, and a bi-factor model. Reliability and construct validity were examined., Results: The prevalence of clinically meaningful depression and anxiety symptoms was 7% and 2%, respectively, while 19% had distress symptoms. A bi-factor model had the best fit to the data (RMSEA = 0.048; CFI = 0.99; TLI = 0.98). The Omega index of the bi-factor model was 0.97. The scale showed good construct validity through negative associations between depression, anxiety, distress symptoms and quality of life., Conclusions: Our study supports the use of a combined scale to measure general distress for PWH, which has good validity, reliability and is unidimensional enough to justify the use of a composite depression and anxiety score., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

BACKGROUND: TB-related stigma hampers access to diagnosis and treatment, making it important to understand the demographic and clinical characteristics associated with perceived TB stigma. TB stigma has not been studied in household contacts before, yet they comprise an important population for epidemic control, with high risk of infection. METHOD: A cross-sectional study was conducted among people with TB and household contacts in South Africa using a 12-item perceived TB stigma scale (score range: 0-36). Demographic and clinical characteristic data were collected using a close-ended questionnaire. A linear mixed-effects regression model was used to explore perceived TB stigma levels and its associated characteristics. RESULTS: The sample included 143 people with TB and 135 household contacts. The mean perceived TB stigma score among people with TB was 22.1 (95% CI 21.1-23.1) and 22.2 (95% CI 21.1-23.3) among household contacts. Being in the same household explained 24.3% variability in stigma perception. Residence in the urban study site (Soshanguve) and a positive HIV diagnosis were associated with higher perceived TB stigma score. CONCLUSIONS: People with TB and household contacts have similarly high prevalence of perceived TB stigma. Positive HIV status and urban location were associated with higher prevalence of perceived TB stigma.

Background: Tuberculosis(TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented., Methods: We are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including (1) a TB-education booklet, (2) a contact-identification algorithm, (3) an instructional sputum-collection video, and (4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including (1) collaborative improvement meetings, (2) regular audit-and-feedback reports, and (3) a digital group-chat application designed to develop a community of practice. Sites will cross-over from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB(#554), the Uganda National Council for Science and Technology(#HS1720ES), and the Yale Institutional Review Board(#2000023199) approved the study and waived informed consent for the main trial implementation-effectiveness outcomes. We will submit results for publication in peer-reviewed journals and disseminate findings to local policymakers and representatives of affected communities., Discussion: This pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden settings using contact investigation. It will also help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustaining evidence-based interventions in low-and-middle-income countries., Trial Registration: The trial was registered(ClinicalTrials.gov Identifier NCT05640648) on 16 November 2022, after the trial launch on 7 March 2022., (© 2023. BioMed Central Ltd., part of Springer Nature.)

People with tuberculosis (TB) are often lost to follow-up during treatment transition to another facility. These losses may result in substantial morbidity and mortality but are rarely recorded. We conducted a record review on adults diagnosed with TB at 11 hospitals in Limpopo, South Africa, who were subsequently transferred to a local clinic to initiate or continue treatment. We then performed in-depth record reviews at the primary care clinic to which they were referred and called participants who could not be identified as starting treatment. Between August 2017 and April 2018, we reviewed records of 778 individuals diagnosed with TB in-hospital and later referred to local clinics for treatment. Of the 778, 88 (11%) did not link to care, and an additional 43 (5.5%) died. Compared to people without cough, those with cough had higher odds of linking to care (aOR = 2.01, 95% CI: 1.26-3.25, p = 0.005) and were also linked more quickly [adjusted Time Ratio (aTR) = 0.53, 95% CI:0.36-0.79, p<0.001], as were those diagnosed microbiologically (aOR = 1.86, 95% CI: 1.16-3.06, p = 0.012; aTR = 0.58, 95% CI: 0.34-0.98, p = 0.04). People diagnosed with TB in hospitals often disengage following referral to local clinics. Interventions to identify and re-engage people who do not present to local clinics within days of referral might close an important gap in the TB treatment cascade., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Garg 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.)

Background: Guidelines and implementation of tuberculosis preventive treatment (TPT) vary by age and HIV status. Specifically, TPT is strongly recommended for people living with HIV/AIDS (PLWHA) and household contacts younger than 5 years but only conditionally recommended for older contacts. Cost remains a major barrier to implementation. The aim of this study was to evaluate the cost-effectiveness of TPT for household contacts and PLWHA., Methods: We developed a state-transition model to simulate short-course TPT for household contacts and PLWHA in 29 high-incidence countries based on data from previous studies and public databases. Our primary outcome was the incremental cost-effectiveness ratio, expressed as incremental discounted costs (2020 US$, including contact investigation costs) per incremental discounted disability-adjusted life year (DALY) averted, compared with a scenario without any TPT or contact investigation. We propagated uncertainty in all model parameters using probabilistic sensitivity analysis and also evaluated the sensitivity of results to the screening algorithm used to rule out active disease, the choice of TPT regimen, the modelling time horizon, assumptions about TPT coverage, antiretroviral therapy discontinuation, and secondary transmission., Findings: Between 2023 and 2035, scaling up TPT prevented 0·9 (95% uncertainty interval 0·4-1·6) people from developing tuberculosis and 0·13 (0·05-0·27) tuberculosis deaths per 100 PLWHA, at an incremental cost of $15 (9-21) per PLWHA. For household contacts, TPT (with contact investigation) averted 1·1 (0·5-2·0) cases and 0·7 (0·4-1·0) deaths per 100 contacts, at a cost of $21 (17-25) per contact. Cost-effectiveness was most favourable for household contacts younger than 5 years ($22 per DALY averted) and contacts aged 5-14 years ($104 per DALY averted) but also fell within conservative cost-effectiveness thresholds in many countries for PLWHA ($722 per DALY averted) and adult contacts ($309 per DALY averted). Costs per DALY averted tended to be lower when compared with a scenario with contact investigation but no TPT. The cost-effectiveness of TPT was not substantially altered in sensitivity analyses, except that TPT was more favourable in analysis that considered a longer time horizon or included secondary transmission benefits., Interpretation: In many high-incidence countries, short-course TPT is likely to be cost-effective for PLWHA and household contacts of all ages, regardless of whether contact investigation is already in place. Failing to implement tuberculosis contact investigation and TPT will incur a large burden of avertable illness and mortality in the next decade., Funding: Unitaid., Competing Interests: Declaration of interests REC reports funding from Unitaid through a grant subcontract to Johns Hopkins (2017-20-IMPAACT4TB). All other authors declare no competing interests., (Copyright © 2023 World Health Organization (acting as the host organization for Unitaid). Published by Elsevier Ltd. All rights reserved. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that Unitaid or WHO endorses any specific organisation, products or services. The use of the Unitaid or WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

99DOTS is a low-cost digital adherence technology that allows people with tuberculosis (TB) to self-report treatment adherence. There are limited data on its implementation, feasibility, and acceptability from sub-Saharan Africa. We conducted a longitudinal analysis and cross-sectional surveys nested within a stepped-wedge randomized trial at 18 health facilities in Uganda between December 2018 and January 2020. The longitudinal analysis assessed implementation of key components of a 99DOTS-based intervention, including self-reporting of TB medication adherence via toll-free phone calls, automated text message reminders and support actions by health workers monitoring adherence data. Cross-sectional surveys administered to a subset of people with TB and health workers assessed 99DOTS feasibility and acceptability. Composite scores for capability, opportunity, and motivation to use 99DOTS were estimated as mean Likert scale responses. Among 462 people with pulmonary TB enrolled on 99DOTS, median adherence was 58.4% (inter-quartile range [IQR] 38.7-75.6) as confirmed by self-reporting dosing via phone calls and 99.4% (IQR 96.4-100) when also including doses confirmed by health workers. Phone call-confirmed adherence declined over the treatment period and was lower among people with HIV (median 50.6% vs. 63.7%, p<0.001). People with TB received SMS dosing reminders on 90.5% of treatment days. Health worker support actions were documented for 261/409 (63.8%) people with TB who missed >3 consecutive doses. Surveys were completed by 83 people with TB and 22 health workers. Composite scores for capability, opportunity, and motivation were high; among people with TB, composite scores did not differ by gender or HIV status. Barriers to using 99DOTS included technical issues (phone access, charging, and network connection) and concerns regarding disclosure. 99DOTS was feasible to implement and highly acceptable to people with TB and their health workers. National TB Programs should offer 99DOTS as an option for TB treatment supervision., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kiwanuka 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.)

Background: Implementation science offers a systematic approach to adapting innovations and delivery strategies to new contexts but has yet to be widely applied in low- and middle-income countries. The Fogarty Center for Global Health Studies is sponsoring a special series, "Global Implementation Science Case Studies," to address this gap., Methods: We developed a case study for this series describing our approach and lessons learned while conducting a prospective, multi-modal study to design, implement, and evaluate an implementation strategy for TB contact investigation in Kampala, Uganda. The study included formative, evaluative, and summative phases that allowed us to develop and test an adapted contact investigation intervention involving home-based sample collection for TB and HIV testing. We concurrently developed a multi-component mHealth implementation strategy involving fingerprint scanning, electronic decision support, and automated reporting of test results via text message. We then conducted a household-randomized, hybrid implementation-effectiveness trial comparing the adapted intervention and implementation strategy to usual care. Our assessment included nested quantitative and qualitative studies to understand the strategy's acceptability, appropriateness, feasibility, fidelity, and costs. Reflecting on this process with a multi-disciplinary team of implementing researchers and local public health partners, we provide commentary on the previously published studies and how the results influenced the adaptation of international TB contact investigation guidelines to fit the local context., Results: While the trial did not show improvements in contact investigation delivery or public health outcomes, our multi-modal evaluation strategy helped us identify which elements of home-based, mHealth-facilitated contact investigation were feasible, acceptable, and appropriate and which elements reduced its fidelity and sustainability, including high costs. We identified a need for better tools for measuring implementation that are simple, quantitative, and repeatable and for greater attention to ethical issues in implementation science., Conclusions: Overall, a theory-informed, community-engaged approach to implementation offered many learnings and actionable insights for delivering TB contact investigation and using implementation science in low-income countries. Future implementation trials, especially those incorporating mHealth strategies, should apply the learnings from this case study to enhance the rigor, equity, and impact of implementation research in global health settings., (© 2023. The Author(s).)

BACKGROUND: Twelve weeks of weekly isoniazid and rifapentine (3HP) prevents TB disease among people with HIV (PWH), but the costs to people of taking TB preventive treatment is not well described. METHODS: We surveyed PWH who initiated 3HP at a large urban HIV/AIDS clinic in Kampala, Uganda, as part of a larger trial. We estimated the cost of one 3HP visit from the patient perspective, including both out-of-pocket costs and estimated lost wages. Costs were reported in 2021 Ugandan shillings (UGX) and US dollars (USD; USD1 = UGX3,587) RESULTS: The survey included 1,655 PWH. The median participant cost of one clinic visit was UGX19,200 (USD5.36), or 38.5% of the median weekly income. Per visit, the cost of transportation was the largest component (median: UGX10,000/USD2.79), followed by lost income (median: UGX4,200/USD1.16) and food (median: UGX2,000/USD0.56). Men reported greater income loss than women (median: UGX6,400/USD1.79 vs. UGX3,300/USD0.93), and participants who lived further than a 30-minute drive to the clinic had higher transportation costs than others (median: UGX14,000/USD3.90 vs. UGX8,000/USD2.23). CONCLUSION: Patient-level costs to receive 3HP accounted for over one-third of weekly income. Patient-centered approaches to averting or defraying these costs are needed.

Objective: We aimed to evaluate safety of 3 months weekly isoniazid-rifapentine (3HP) for tuberculosis (TB) prevention when co-administered with dolutegravir-based antiretroviral therapy (TLD), and compare viral suppression among those initiating TLD + 3HP vs. TLD alone., Design/methods: We analyzed data from an ongoing Phase 3 randomized trial comparing TB screening strategies among adults with CD4 + ≤350 cells/μl initiating routine antiretroviral therapy (ART) in Kampala, Uganda. TB screen-negative participants without contraindications are referred for self-administered 3HP. HIV viral load is routinely measured at 6 and 12 months. Here, we included TB-negative participants who initiated TLD with or without 3HP. We determined the number who discontinued 3HP due to drug toxicity. In addition, we assessed viral suppression at 6 and 12 months and used log-binomial regression to assess risk of viremia at 6 months for participants who initiated TLD + 3HP vs. TLD alone., Results: Of 453 participants initiating TLD (287 [63.4%] female, median age 30 years [interquartile range (IQR) 25-37], median pre-ART CD4 + cell count 188 cells/μl [IQR 86-271]), 163 (36.0%) initiated 3HP. Of these, 154 (94.5%) completed 3HP and one (0.6%) had treatment permanently discontinued due to a possible 3HP-related adverse event. At 6 months, for participants who received TLD + 3HP, risk of viremia >50 copies/ml was 1.51 [95% confidence interval (CI) 1.07-2.14] times that of participants who received TLD alone. There was no difference in viral suppression between those who received TLD + 3HP vs. TLD alone at 12 months., Conclusions: Co-administration of TLD + 3HP was well tolerated. However, those who received TLD + 3HP were less likely to achieve viral suppression within six-months compared to those who received TLD alone., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Phosphatidylethanol (PEth) is a biomarker for recent alcohol consumption that would ideally validate self-reported alcohol consumption behaviors. We assessed the relationship between PEth and several self-reported alcohol consumption metrics among hazardous alcohol users living with HIV in Vietnam., Methods: Participants in a three-arm randomized controlled trial assessing two alcohol interventions reported recent alcohol consumption on a 30-day timeline follow-back interview and had a PEth assessment at enrollment, 3 months, and 12 months of the study follow-up. We examined the relationship between self-reported alcohol consumption and quantitative PEth results using Spearman rank correlation and receiver-operating characteristic (ROC) curves to calculate the area under the curve (AUC). We assessed associations between categorical PEth results and self-reported drinking behaviors using prevalence ratios calculated with regression models and generalized estimating equations., Results: Among 1221 study visits (n = 439 participants; 425 (97%) men), the median PEth result was 71 ng/mL (Interquartile range (IQR): 20, 212), and participants reported a median of 11 (IQR: 4, 24) drinking days and 25 (IQR: 8, 71) standard drinks in the previous 28 days. Quantitative PEth results were moderately correlated with drinking days (ρ = 0.26-0.35) and standard drinks consumed (ρ = 0.23-0.38) in the same period. AUCs ranged from 0.54 (any binge drinking in the past 28 days) to 0.82 (any alcohol consumed in the past 21 days). Positive PEth results (≥50 ng/mL) were 2.24 (95% Confidence Interval [CI]: 1.49, 3.35) times as prevalent among participants who reported drinking in the previous 28 days compared with those who did not., Conclusions: Although PEth values and self-reported alcohol use were correlated, the observed associations were modest. Additional research into the dynamics of PEth production and elimination is warranted across diverse populations to better understand how PEth assessments can best be integrated into research and clinical care., (© 2023 Research Society on Alcohol.)

Background: Household contact investigation for people newly diagnosed with tuberculosis (TB) is poorly implemented, particularly in low- and middle-income countries. Conditional cash incentives may improve uptake., Methods: We conducted a pragmatic, cluster-randomized, crossover trial of 2 TB contact investigation approaches (household-based and incentive-based) in 28 public primary care clinics in South Africa. Each clinic used 1 approach for 18 months, followed by a 6-month washout period, after which the opposite approach was used. Fourteen clinics were randomized to each approach. In the household-based arm, we conducted TB screening and testing of contacts at the household. In the incentive-based arm, both index patients and ≤10 of their close contacts (either within or outside the household) were given small cash incentives for presenting to study clinics for TB screening. The primary outcome was the number of people with incident TB who were diagnosed and started on treatment at study clinics., Results: From July 2016 to January 2020, we randomized 28 clinics to each study arm, and enrolled 782 index TB patients and 1882 contacts in the household-based arm and 780 index patients and 1940 contacts in the incentive-based arm. A total of 1413 individuals started on TB treatment in the household-based arm and 1510 in the incentive-based arm. The adjusted incidence rate ratio of TB treatment initiation in the incentive- versus household-based arms was 1.05 (95% confidence interval: .97-1.13)., Conclusions: Incentive-based contact investigation for TB has similar effectiveness to traditional household-based approaches and may be a viable alternative or complementary approach to household-based investigation., Competing Interests: Potential conflicts of interest. N. M. reports a grant to their institution unrelated to this work from Pfizer; unpaid participation on a Data Safety and Monitoring Board (DSMB) of a trial of novel treatments for disseminated TB; and an unpaid role on the board of Setshaba Research Centre. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mukora 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.)

BACKGROUND: Population-based active case-finding (ACF) identifies people with TB in communities but can be costly. METHODS: We conducted an empiric costing study within a door-to-door household ACF campaign in an urban community in Uganda, where all adults, regardless of symptoms, were screened by sputum Xpert Ultra testing. We used a combination of direct observation and self-reported logs to estimate staffing requirements. Study budgets were reviewed to collect costs of overheads, equipment, and consumables. Our primary outcome was the cost per person diagnosed with TB. RESULTS: Over a 28-week period, three teams of two people collected sputum from 11,341 adults, of whom 48 (0.4%) tested positive for TB. Screening 1,000 adults required 258 person-hours of effort at a cost of US$35,000, 70% of which was for GeneXpert cartridges. The estimated cost per person screened was $36 (95% uncertainty range [95% UR] 34–38), and the cost per person diagnosed with Xpert-positive TB was $8,400 (95% UR 8,000–8,900). The prevalence of TB in the underlying community was the primary modifiable determinant of the cost per person diagnosed. CONCLUSION: Door-to-door screening can be feasibly performed at scale, but will require effective triage and identification of high-prevalence populations to be affordable and cost-effective.

Background: Integrated health systems with strong laboratory networks are critical in improving public health. The current study assessed the laboratory network in Ghana and its functionality using the Assessment Tool for Laboratory Services (ATLAS)., Intervention: A national-level laboratory network survey was conducted among stakeholders of the Ghanaian laboratory network in Accra. Face-to-face interviews were conducted from December 2019 to January 2020, with follow-up phone interviews between June and July 2020. Also, we reviewed supporting documents provided by stakeholders for supplementary information and transcribed these to identify themes. Where possible, we completed the Laboratory Network scorecard using data obtained from the ATLAS., Lessons Learnt: The Laboratory Network (LABNET) scorecard assessment was a valuable addition to the ATLAS survey as it quantified the functionality of the laboratory network and its overall advancement toward achieving International Health Regulations (2005) and Global Health Security Agenda targets. Two significant challenges indicated by respondents were laboratory financing and delayed implementation of the Ghana National Health Laboratory Policy., Recommendations: Stakeholders recommended a review of the country's funding landscape, such as funding laboratory services from the country's internally generated funds. Also, they recommended laboratory policy implementation to ensure adequate laboratory workforce and standards., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2023. The Authors.)

The COVID-19 pandemic has disrupted systems of care for infectious diseases-including tuberculosis-and has exposed pervasive inequities that have long marred efforts to combat these diseases. The resulting health disparities often intersect at the individual and community levels in ways that heighten vulnerability to tuberculosis. Effective responses to tuberculosis (and other infectious diseases) must respond to these realities. Unfortunately, current tuberculosis programmes are generally not designed from the perspectives of affected individuals and fail to address structural determinants of health disparities. We describe a person-centred, equity-oriented response that would identify and focus on communities affected by disparities, tailor interventions to the mechanisms by which disparities worsen tuberculosis, and address upstream determinants of those disparities. We detail four key elements of the approach (data collection, programme design, implementation, and sustainability). We then illustrate how organisations at multiple levels might partner and adapt current practices to incorporate these elements. Such an approach could generate more substantial, sustainable, and equitable reductions in tuberculosis burden at the community level, highlighting the urgency of restructuring post-COVID-19 health systems in a more person-centred, equity-oriented way., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., 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.)

The importance of finding people with undiagnosed tuberculosis (TB) hinges on their future disease trajectories. Assays for systematic screening should be optimized to find those whose TB will contribute most to future transmission or morbidity. In this study, we constructed a mathematical model that tracks the future trajectories of individuals with TB at a cross-sectional timepoint ("baseline"), classifying them by bacterial burden (smear positive/negative) and symptom status (symptomatic/subclinical). We used Bayesian methods to calibrate this model to targets derived from historical survival data and notification, mortality, and prevalence data from five countries. We combined resulting disease trajectories with evidence on infectiousness to estimate each baseline TB state's contribution to future transmission. For a person with smear-negative subclinical TB at baseline, the expected future duration of disease was short (mean 4.8 [95% uncertainty interval 3.3 to 8.4] mo); nearly all disease courses ended in spontaneous resolution, not treatment. In contrast, people with baseline smear-positive subclinical TB had longer undiagnosed disease durations (15.9 [11.1 to 23.5] mo); nearly all eventually developed symptoms and ended in treatment or death. Despite accounting for only 11 to 19% of prevalent disease, smear-positive subclinical TB accounted for 35 to 51% of future transmission-a greater contribution than symptomatic or smear-negative TB. Subclinical TB with a high bacterial burden accounts for a disproportionate share of future transmission. Priority should be given to developing inexpensive, easy-to-use assays for screening both symptomatic and asymptomatic individuals at scale-akin to rapid antigen tests for other diseases-even if these assays lack the sensitivity to detect paucibacillary disease.

Competing Interests: Declarations of Conflicts of Interest: None

Objectives: Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approaches which are useful when considering equity in the priority setting process, and outline the technical choices concerning model structure, outputs, and data requirements needed to use transmission models in analyses of health equity., Methods: We reviewed the literature on equity concepts and approaches to their application in economic evaluation and undertook a technical consultation on how equity can be incorporated in priority setting for infectious disease control. The technical consultation brought together health economists with an interest in equity-informative economic evaluation, ethicists specialising in public health, mathematical modellers from various disease backgrounds, and representatives of global health funding and technical assistance organisations, to formulate key areas of consensus and recommendations., Results: We provide a series of recommendations for applying the Reference Case for Economic Evaluation in Global Health to infectious disease interventions, comprising guidance on 1) the specification of equity concepts; 2) choice of evaluation framework; 3) model structure; and 4) data needs. We present available conceptual and analytical choices, for example how correlation between different equity- and disease-relevant strata should be considered dependent on available data, and outline how assumptions and data limitations can be reported transparently by noting key factors for consideration., Conclusions: Current developments in economic evaluations in global health provide a wide range of methodologies to incorporate equity into economic evaluations. Those employing infectious disease models need to use these frameworks more in priority setting to accurately represent health inequities. We provide guidance on the technical approaches to support this goal and ultimately, to achieve more equitable health policies., Competing Interests: Declarations of interest none., (Copyright © 2022. Published by Elsevier B.V.)

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)., (© 2022. The Author(s).)