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Abstract Background Zambia’s national HIV testing algorithm specifies use of two rapid blood based antibody assays, Determine®HIV-1/2 (Inverness Medical) and if positive then Uni-GoldTM Recombigen HIV-1/2 (Trinity Biotech). Little is known about the performance of oral fluid based HIV testing in Zambia. The aims of this study are two-fold: 1) to compare the diagnostic accuracy (sensitivity and specificity) under field conditions of the OraQuick® ADVANCE® Rapid HIV-1/2 (OraSure Technologies, Inc.) to two blood-based rapid antibody tests currently in use in the Zambia National Algorithm, and 2) to perform a cost analysis of large-scale field testing employing the OraQuick®. Methods This was a operational retrospective research of HIV testing and questionnaire data collected in 2010 as part of the ZAMSTAR (Zambia South Africa TB and AIDS reduction) study. Randomly sampled individuals in twelve communities were tested consecutively with OraQuick® test using oral fluid versus two blood-based rapid HIV tests, Determine® and Uni-GoldTM. A cost analysis of four algorithms from health systems perspective were performed: 1) Determine® and if positive, then Uni-GoldTM (Determine®/Uni-GoldTM); based on current algorithm, 2) Determine® and if positive, then OraQuick® (Determine®/OraQuick®), 3) OraQuick® and if positive, then Determine® (OraQuick®/Determine®), 4) OraQuick® and if positive, then Uni-GoldTM (OraQuick®/Uni-GoldTM). This information was then used to construct a model using a hypothetical population of 5,000 persons with varying prevalence of HIV infection from 1–30%. Results 4,458 participants received both a Determine® and OraQuick® test. The sensitivity and specificity of the OraQuick® test were 98.7 (95%CI, 97.5–99.4) and 99.8 (95%CI, 99.6–99.9), respectively when compared to HIV positive serostatus. The average unit costs per algorithm were US$3.76, US$4.03, US$7.35, and US$7.67 for Determine®/Uni-GoldTM, Determine®/OraQuick®, OraQuick®/Determine®, and OraQuick®/Uni-GoldTM, respectively, for an HIV prevalence of 15%. Conclusions An alternative HIV testing algorithm could include OraQuick® test which had a high sensitivity and specificity. The current Determine®/Uni-GoldTM testing algorithm is the least expensive when compared to Determine®/OraQuick®, OraQuick®/Determine®, and OraQuick®/Uni-GoldTM in the Zambian setting. From our field experience, oral fluid based testing offers many advantages over blood-based testing, especially with self testing on the horizon.

Background: A vaccine to interrupt the transmission of tuberculosis is needed.Methods: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both.Results: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.Conclusions: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .). [ABSTRACT FROM AUTHOR]

Systematic screening for TB in children, especially among those at high risk of TB, can promote early diagnosis and treatment of TB. The World Health Organization (WHO) recently recommended C-Reactive Protein as a TB screening tool in adults and adolescents living with HIV (PLHIV). Thus, we aimed to assess the performance of point-of-care (POC) CRP as a screening tool for TB in children. A cross-sectional study was conducted at 2 primary health care facilities in Lusaka, Zambia between September 2020 -August 2021. Consecutive children (aged 5-14 years) presenting for TB services were enrolled irrespective of TB symptoms. All participants were screened for the presence of TB symptoms and signs, asked about TB contact history, and undertook a POC CRP test, chest X-ray, and sputum Xpert MTB/RIF Ultra test. The accuracy of CRP (≥10 mg/L cutoff) was determined using a microbiological reference standard (MRS) and a composite reference standard (CRS). Of 280 children enrolled and with complete results available, the median age was 10 years (IQR 7-12), 56 (20.0%) were HIV positive, 228 (81.4%) had a positive WHO symptom screen for TB, 62 (22.1%) had a close TB contact, and 79 (28.2%) had a positive CRP POC test. Five (1.8%) participants had confirmed TB, 71 (25.4%) had unconfirmed TB, and 204 (72.3%) had unlikely TB. When the MRS was used, the sensitivity of CRP was 80.0% (95%CI: 28.4-99.5%) and the specificity was 72.7% (95%CI: 67.1-77.9%). When the CRS was used, the sensitivity of CRP was 32.0% (95%CI: 23.3% - 42.5%), while the specificity was 74.0% (95%CI: 67.0% - 80.3%). Using the CRS, there were no statistically significant differences in sensitivity and specificity of CRP in the HIV positive and HIV negative individuals. Among children in Zambia, POC CRP had limited utility as a screening tool for TB. There remains a continued urgent need for better tools and strategies to improve TB detection in children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kagujje 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.)

Objectives: Computer-aided detection (CAD) software packages quantify tuberculosis (TB)-compatible chest X-ray (CXR) abnormality as continuous scores. In practice, a threshold value is selected for binary CXR classification. We assessed the diagnostic accuracy of an alternative approach to applying CAD for TB triage: incorporating CAD scores in multivariable modeling., Methods: We pooled individual patient data from four studies. Separately, for two commercial CAD, we used logistic regression to model microbiologically confirmed TB. Models included CAD score, study site, age, sex, human immunodeficiency virus status, and prior TB. We compared specificity at target sensitivities ≥90% between the multivariable model and the current threshold-based approach for CAD use., Results: We included 4,733/5,640 (84%) participants with complete covariate data (median age 36 years; 45% female; 22% with prior TB; 22% people living with human immunodeficiency virus). A total of 805 (17%) had TB. Multivariable models demonstrated excellent performance (areas under the receiver operating characteristic curve [95% confidence interval]: software A, 0.91 [0.90-0.93]; software B, 0.92 [0.91-0.93]). Compared with threshold scores, multivariable models increased specificity (e.g., at 90% sensitivity, threshold vs model specificity [95% confidence interval]: software A, 71% [68-74%] vs 75% [74-77%]; software B, 69% [63-75%] vs 75% [74-77%])., Conclusion: Using CAD scores in multivariable models outperformed the current practice of CAD-threshold-based CXR classification for TB diagnosis., Competing Interests: Declarations of competing interest FAK currently holds a grant from CIHR to study CAD in Canada. FAK also reports salary support from the Fonds de Recherche du Quebec Santé. FAK reports that the following developers of computer-aided detection software provided his research group with either free or reduced pricing access to their software for evaluative research, governed by contracts with the Research Institute of the McGill University Health Centre that ensure that the groups did not have any role in the study design, analysis, result interpretation, or decision to publish previous research and the submitted work: Delft (Netherlands, makers of CAD4TB), qure.ai (India, makers of qXR), and Lunit (South Korea, makers of LUNIT INSIGHT). MB reports grants from European and Development Countries Clinical Trials Partnership during the conduct of the study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled human immunodeficiency virus (HIV) vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at 2 dose levels in healthy HIV-uninfected adults., Methods: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200 μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40 μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses., Results: We enrolled 160 participants, 55% women, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40 μg gp120/AS01B group were higher than in either of the 200 μg gp120 groups., Conclusions: The 40 μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses. Clinical Trials Registration . NCT03122223., Competing Interests: Potential conflicts of interest. S. G. is an employee of Sanofi Pasteur and C. A. D. G. was employed by Sanofi Pasteur at the time of the study. M. Ko. and O. V. D. M. are employees of GSK and hold shares in GSK. All other authors report no potential conflicts. Funding to pay the Open Access publication charges for this article was provided by the NIH. 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: People in correctional settings are a key population for HIV epidemic control. We sought to demonstrate scale-up of universal test and treat in correctional facilities in South Africa and Zambia through a virtual cross-sectional analysis., Methods: We used routine data on 2 dates: At the start of universal test and treat implementation (time 1, T1) and 1 year later (time 2, T2). We obtained correctional facility census lists for the selected dates and matched HIV testing and treatment data to generate virtual cross-sections of HIV care continuum indicators., Results: In the South African site, there were 4193 and 3868 people in the facility at times T1 and T2; 43% and 36% were matched with HIV testing or treatment data, respectively. At T1 and T2, respectively, 1803 (43%) and 1386 (36%) had known HIV status, 804 (19%) and 845 (21%) were known to be living with HIV, and 60% and 56% of those with known HIV were receiving antiretroviral therapy (ART). In the Zambian site, there were 1467 and 1366 people in the facility at times T1 and T2; 58% and 92% were matched with HIV testing or treatment data, respectively. At T1 and T2, respectively, 857 (59%) and 1263 (92%) had known HIV status, 277 (19%) and 647 (47%) were known to be living with HIV, and 68% and 68% of those with known HIV were receiving ART., Conclusions: This virtual cross-sectional analysis identified gaps in HIV testing coverage, and ART initiation that was not clearly demonstrated by prior cohort-based studies., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: CD4 measurement is pivotal in the management of advanced HIV disease. VISITECT® CD4 Advanced Disease (AccuBio Limited, Alva, UK; VISITECT) is an instrument-free, point-of-care, semi-quantitative test allowing visual identification of a CD4 ≤200 cells/µl, or >200 cells/µl from finger-prick or venous blood., Methods: As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM (clinicaltrials.gov: NCT04089423), people living with HIV of ≥18 years old were prospectively recruited in seven countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine a CD4 ≤200 cells/µl were evaluated., Results: Among 1604 participants, the median flow cytometry CD4 was 367 (IQR 128-626) cells/µl and 521 (32.5%) had a CD4 ≤200 cells/µl. VISITECT sensitivity was 92.7% (483/521, 95% CI 90.1-94.7%) and specificity was 61.4% (665/1083, 95% CI 58.4-64.3%). For participants with a CD4 between 0-100, 101-200, 201-300, 301-500, and >500 cells/µl, VISITECT misclassified 4.5% (95% CI 2.5-7.2%), 12.5 (95% CI 8.0-18.2%), 74.1% (95% CI 67.0-80.5%), 48.0% (95% CI 42.5-53.6%), and 22.6% (95% CI 19.3-26.3%), respectively., Conclusions: VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT´s utility as CD4 triage test should be investigated., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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.)

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423)., Competing Interests: RS, AM, CMD and MR are or were employed by FIND at the time of the study. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND’s independence and neutrality with regard to these private sector companies. TB reports patents in the field of TB detection and is a shareholder of Avelo Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Székely 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.)

This study aimed to estimate the incidence and risk factors for Enterotoxigenic Escherichia coli (ETEC) diarrhea. This was a prospective cohort study of children recruited in a household census. Children were enrolled if they were 36 months or below. A total of 6828 children were followed up passively for 12 months to detect episodes of ETEC diarrhea. Diarrheal stool samples were tested for ETEC using colony polymerase chain reaction (cPCR). Among the 6828 eligible children enrolled, a total of 1110 presented with at least one episode of diarrhea. The overall incidence of ETEC diarrhea was estimated as 2.47 (95% confidence interval (CI): 2.10-2.92) episodes per 100 child years. Children who were HIV-positive (adjusted Hazard ratio (aHR) = 2.14, 95% CI: 1.14 to 3.99; p = 0.017) and those whose source of drinking water was public tap/borehole/well (aHR = 2.45, 95% CI: 1.48 to 4.06; p < 0.002) were at increased risk of ETEC diarrhea. This study found that children whose mothers have at least senior secondary school education (aHR = 0.49, 95% CI: 0.29 to 0.83; p = 0.008) were at decreased risk of ETEC diarrhea. Our study emphasizes the need for integrated public health strategies focusing on water supply improvement, healthcare for persons living with HIV, and maternal education.

Background: Globally, at least 3 million TB patients are missed every year. In Zambia, the TB treatment coverage increased from 66% in 2020 to 92% in 2022. Involvement of all levels of health care service delivery is critical to finding all the missing TB patients., Methods: A survey was undertaken in 15 private facilities in Lusaka district of Zambia using a structured tool administered by project team and a district health team member. Data collected during the survey was analysed and results were used to determine the type of TB services that were offered as well as barriers and enablers to TB service provision. This was followed by a set of interventions that included; training and mentorship on active case finding and systematic TB screening, increased diagnostic capacity, provision of national recording and reporting tools and provision of TB medication through linkage with the National TB program (NTP). We report findings from the baseline survey and changes in presumptive TB identification and notification following interventions., Results: Major barriers to TB service delivery were the high cost of TB diagnostic testing and treatment in facilities where services were not supported by the National TB program; the mean cost was 33 (SD 33) and 93 (SD 148) for GeneXpert testing and a full course of treatment respectively. Pre-intervention, presumptive TB identification appeared to increase monthly by 4 (P = 0.000, CI=[3.00-5.00]). The monthly trends of presumptive TB identification during the intervention period increased by 5.32 (P = 0.000, [CI 4.31-6.33. Pre-intervention, the notification of TB appeared to decrease every month by -4.0 (P = 0.114, CI=[-9.00-0.10]) followed by an immediate increase in notifications of 13.94 TB patients (P = 0.001, CI [6.51, 21.36] in the first month on intervention. The monthly trends of notification during the intervention period changed by 0.34 (P = 0.000 [CI 0.19-0.48]). Private facility contribution to TB notification increased from 3 to 7%., Conclusion: Engagement and inclusion of private health facilities in TB service provision through a systems strengthening approach can increase contribution to TB notification by private health facilities., (© 2024. The Author(s).)

Background: Zambia is among the 30 high-burden countries for tuberculosis (TB), Human Immunodeficiency Virus (HIV)-associated TB, and multi-drug resistant/rifampicin resistant TB with over 5000 children developing TB every year. However, at least 32% of the estimated children remain undiagnosed. We assessed healthcare workers' (HCWs) knowledge, attitudes, and practices (KAP) towards childhood TB and the factors associated with good KAP towards childhood TB., Methods: Data was collected at two primary healthcare facilities in Lusaka, Zambia from July to August 2020. Structured questionnaires were administered to HCWs that were selected through stratified random sampling. Descriptive analysis was done to determine KAP. A maximum knowledge, attitude, and practice scores for a participant were 44, 10, and 8 points respectively. The categorization as either "poor" or "good" KAP was determined based on the mean/ median. Logistic regression analysis was performed to assess the associations between participant characteristics and KAP at statistically significant level of 0.05%., Results: Among the 237 respondents, majority were under 30 years old (63.7%) and were female (72.6%). Half of the participants (50.6%) were from the outpatient department (OPD) and antiretroviral therapy (ART) clinic, 109 (46.0) had been working at the facility for less than 1 year, 134 (56.5%) reported no previous training in TB. The median/mean KAP scores were 28 (IQR 24.0-31.0), 7 (IQR = 6.0-8.0) and 5 points (SD = 1.9) respectively. Of the participants, 43.5% (103/237) had good knowledge, 48.1% (114/237) had a good attitude, and 54.4% (129/237) had good practice scores on childhood TB. In the multivariate analysis, clinical officers and individuals with 1-5 years' work experience at the facility had higher odds, 2.61 (95% CI = 1.18-5.80, p = 0.018) and 3.09 (95% CI = 1.69-5.65, p = 0.001) of having good attitude respectively, and medical doctors had 0.17 lower odds (95% CI = 0.18-5.80, p = 0.018) of good childhood TB practice. Other participant characteristics didn't show a significant association with the scores., Conclusion: The study found suboptimal levels of knowledge, attitude, and practices regarding childhood TB among HCWs. Targeted programmatic support needs to be provided to address the above gaps., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kaumba 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 2022, fewer than half of persons with tuberculosis (TB) had access to molecular diagnostic tests for TB due to their high costs. Studies have found that the use of artificial intelligence (AI) software for chest X-ray (CXR) interpretation and sputum specimen pooling can each reduce the cost of testing. We modeled the combination of both strategies to estimate potential savings in consumables that could be used to expand access to molecular diagnostics., Methods: We obtained Xpert testing and positivity data segmented into deciles by AI probability scores for TB from the community- and healthcare facility-based active case finding conducted in Bangladesh, Nigeria, Viet Nam, and Zambia. AI scores in the model were based on CAD4TB version 7 (Zambia) and qXR (all other countries). We modeled four ordinal screening and testing approaches involving AI-aided CXR interpretation to indicate individual and pooled testing. Setting a false negative rate of 5%, for each approach we calculated additional and cumulative savings over the baseline of universal Xpert testing, as well as the theoretical expansion in diagnostic coverage., Results: In each country, the optimal screening and testing approach was to use AI to rule out testing in deciles with low AI scores and to guide pooled vs individual testing in persons with moderate and high AI scores, respectively. This approach yielded cumulative savings in Xpert tests over baseline ranging from 50.8% in Zambia to 57.5% in Nigeria and 61.5% in Bangladesh and Viet Nam. Using these savings, diagnostic coverage theoretically could be expanded by 34% to 160% across the different approaches and countries., Conclusions: Using AI software data generated during CXR interpretation to inform a differentiated pooled testing strategy may optimize TB diagnostic test use, and could extend molecular tests to more people who need them. The optimal AI thresholds and pooled testing strategy varied across countries, which suggests that bespoke screening and testing approaches may be needed for differing populations and settings., Supplementary Information: The online version contains supplementary material available at 10.1186/s44263-024-00081-2., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Care cascades represent the proportion of people reaching milestones in care for a disease and are widely used to track progress towards global targets for HIV and other diseases. Despite recent progress in estimating care cascades for tuberculosis (TB) disease, they have not been routinely applied at national and subnational levels, representing a lost opportunity for public health impact. As researchers who have estimated TB care cascades in high-incidence countries (India, Madagascar, Nigeria, Peru, South Africa, and Zambia), we describe the utility of care cascades and identify measurement challenges, including the lack of population-based disease burden data and electronic data capture, the under-reporting of people with TB navigating fragmented and privatised health systems, the heterogeneity of TB tests, and the lack of post-treatment follow-up. We outline an agenda for rectifying these gaps and argue that improving care cascade measurement is crucial to enhancing people-centred care and achieving the End TB goals., Competing Interests: Declaration of interests MP serves on the Scientific Advisory Committee of the Foundation of Innovative New Diagnostics (FIND), a non-profit global alliance for diagnostics. MP is also an adviser to the Bill & Melinda Gates Foundation. He has no financial or industry conflicts. CU-G has received research support from the International Development Research Centre (Canada) and the Canadian Institutes of Health Research, the National Institutes of Health, FIND, and Abbott for projects unrelated to this work. CU-G has also received honoraria from Molbio for presentations unrelated to this work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Diarrhoea is a major contributor to childhood morbidity and mortality in developing countries, with diarrhoeagenic Escherichia coli being among the top aetiological agents. We sought to investigate the burden and describe the diarrhoeagenic E. coli pathotypes causing diarrhoea among children in peri-urban areas of Lusaka, Zambia. This was a facility-based surveillance study conducted over an 8-month period from 2020 to 2021. Stool samples were collected from children aged 0-3 years presenting with diarrhoea at five peri-urban health facilities in Lusaka. Stool samples were tested for diarrhoeagenic E. coli using the Novodiag bacterial GE+ ® panel, a platform utilising real-time PCR and microarray technology to detect bacterial pathogens. Of the 590 samples tested, diarrhoeagenic E. coli were detected in 471 (76.1%). The top three pathogens were enteropathogenic E. coli 45.4% ( n = 268), enteroaggregative E. coli 39.5% ( n = 233), and enterotoxigenic E. coli 29.7% ( n = 176). Our results revealed that 50.1% of the diarrhoeagenic E. coli positive samples comprised multiple pathotypes of varying virulence gene combinations. Our study demonstrates a high prevalence of diarrhoeagenic E. coli in childhood diarrhoea and the early exposure (<12 months) of children to enteric pathogens. This calls for the early implementation of preventive interventions for paediatric diarrhoea.

Background: Non-communicable diseases (NCDs) are increasing among people living with HIV (PLHIV), especially in Sub-Saharan Africa (SSA). We determined the prevalence of NCDs and NCD risk factors among PLHIV in SSA to inform health policy makers., Methods: We conducted a systematic review and meta-analysis on the prevalence of NCDs and risk factors among PLHIV in SSA. We comprehensively searched PubMed/MEDLINE, Scopus, and EBSCOhost (CINAHL) electronic databases for sources published from 2010 to July 2023. We applied the random effects meta-analysis model to pool the results using STATA. The systematic review protocol was registered on PROSPERO (registration number: CRD42021258769)., Findings: We included 188 studies from 21 countries in this meta-analysis. Our findings indicate pooled prevalence estimates for hypertension (20.1% [95% CI:17.5-22.7]), depression (30.4% [25.3-35.4]), diabetes (5.4% [4.4-6.4]), cervical cancer (1.5% [0.1-2.9]), chronic respiratory diseases (7.1% [4.0-10.3]), overweight/obesity (32.2% [29.7-34.7]), hypercholesterolemia (21.3% [16.6-26.0]), metabolic syndrome (23.9% [19.5-28.7]), alcohol consumption (21.3% [17.9-24.6]), and smoking (6.4% [5.2-7.7])., Interpretation: People living with HIV have a high prevalence of NCDs and their risk factors including hypertension, depression, overweight/obesity, hypercholesterolemia, metabolic syndrome and alcohol consumption. We recommend strengthening of health systems to allow for improved integration of NCDs and HIV services in public health facilities in SSA. NCD risk factors such as obesity, hypercholesterolemia, and alcohol consumption can be addressed through health promotion campaigns. There is a need for further research on the burden of NCDs among PLHIV in most of SSA., Funding: This study did not receive any funding., Competing Interests: The authors declare that they have no competing interests both financial and non-financial., (© 2023 The Author(s).)

In this Policy Forum piece, Aditya Narayan and colleagues discuss the challenges and opportunities for tuberculosis preventive treatment in carceral settings., Competing Interests: The spouse of SS was employed by Merck Pharmaceuticals 1997-2007 and retains stock in his retirement account. There is no conflict of interest with the submitted work, but is included in the interest of full disclosure. The other authors have declared that no competing interests exist., (Copyright: © 2023 Narayan 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.)

Introduction: In high TB burden settings, it is estimated that 10-20% of total notifications should be children, however, currently only 6-8% of the total TB notifications in Zambia are children. We assessed whether the implementation of a multicomponent strategy, at primary healthcare facilities, that systematically targets barriers at each step of the childhood TB diagnostic cascade can increase childhood TB case detection., Methods: We conducted a controlled, interrupted time series analysis to compare childhood TB case notifications before (January 2018-December 2019), and during implementation (January 2020-September 2021) in two intervention and two control Level 1 hospitals in Lusaka, Zambia. At each of the intervention facilities, we implemented a multicomponent strategy constituting: (1) capacity development on childhood TB and interpretation of chest x-ray, (2) TB awareness-raising and demand creation activities, (3) setting up fast track TB services, (4) strengthening of household contact tracing, and (5) improving access to digital chest X-ray for TB screening and Xpert MTB/Rif Ultra for TB diagnosis, through strengthening sample collection in children., Findings: Among 5,150 children < 15 years screened at the two intervention facilities during the study period, 503 (9.8% yield) were diagnosed with TB. Of these, 433 (86.1%) were identified through facility-based activities (10.5% yield) and 70 (13.9%) were identified through household contact tracing (6.9% yield). Overall, 446 children (88.7%) children with TB were clinically diagnosed. Following implementation of the multicomponent strategy, the proportion children contributed to total TB notifications immediately changed by +1.5% (95%CI: -3.5, 6.6) and -4.4% (95%CI: -7.5, 1.4) at the intervention and control sites, respectively (difference 6.0% [95%CI: -0.7, 12.7]), p = 0.08); the proportion of childhood notifications increased 0.9% (95%CI: -0.7, 2.5%) each quarter at the intervention sites relative to pre-implementation trends, while declining 1.2% (-95%CI: -1.8, -0.6) at the control sites (difference 2.1% [95%CI: 0.1, 4.2] per quarter between, p = 0.046); this translated into 352 additional and 85 fewer childhood TB notifications at the intervention and control sites, respectively, compared to the pre-implementation period., Conclusion: A standardized package of strategies to improve childhood TB detection at primary healthcare facilities was feasible to implement and was associated with a sustained improvement in childhood TB notifications., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Kagujje 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.)

Men and women with undiagnosed tuberculosis (TB) in high burden countries may have differential factors influencing their healthcare seeking behaviors and access to TB services, which can result in delayed diagnoses and increase TB-related morbidity and mortality. A convergent, parallel, mixed-methods study design was used to explore and evaluate TB care engagement among adults (≥18 years) with newly diagnosed, microbiologically-confirmed TB attending three public health facilities in Lusaka, Zambia. Quantitative structured surveys characterized the TB care pathway (time to initial care-seeking, diagnosis, and treatment initiation) and collected information on factors influencing care engagement. Multinomial multivariable logistic regression was used to determine predicted probabilities of TB health-seeking behaviors and determinants of care engagement. Qualitative in-depth interviews (IDIs; n = 20) were conducted and analyzed using a hybrid approach to identify barriers and facilitators to TB care engagement by gender. Overall, 400 TB patients completed a structured survey, of which 275 (68.8%) and 125 (31.3%) were men and women, respectively. Men were more likely to be unmarried (39.3% and 27.2%), have a higher median daily income (50 and 30 Zambian Kwacha [ZMW]), alcohol use disorder (70.9% [AUDIT-C score ≥4] and 31.2% [AUDIT-C score ≥3]), and a history of smoking (63.3% and 8.8%), while women were more likely to be religious (96.8% and 70.8%) and living with HIV (70.4% and 36.0%). After adjusting for potential confounders, the probability of delayed health-seeking ≥4 weeks after symptom onset did not differ significantly by gender (44.0% and 36.2%, p = 0.14). While the top reasons for delayed healthcare-seeking were largely similar by gender, men were more likely to report initially perceiving their symptoms as not being serious (94.8% and 78.7%, p = 0.032), while women were more likely to report not knowing the symptoms of TB before their diagnosis (89.5% and 74.4%; p = 0.007) and having a prior bad healthcare experience (26.4% and 9.9%; p = 0.036). Notably, women had a higher probability of receiving TB diagnosis ≥2 weeks after initial healthcare seeking (56.5% and 41.0%, p = 0.007). While men and women reported similar acceptability of health-information sources, they emphasized different trusted messengers. Also, men had a higher adjusted probability of stating that no one influenced their health-related decision making (37.9% and 28.3%, p = 0.001). In IDIs, men recommended TB testing sites at convenient community locations, while women endorsed an incentivized, peer-based, case-finding approach. Sensitization and TB testing strategies at bars and churches were highlighted as promising approaches to reach men and women, respectively. This mixed-methods study found important differences between men and women with TB in Zambia. These differences suggest the need for gender-tailored TB health promotion, including addressing harmful alcohol use and smoking among men, and sensitizing HCWs to prolonged delays in TB diagnosis among women, and also using gender-specific approaches as part of community-based, active case-finding strategies to improve TB diagnosis in high burden settings., Competing Interests: The authors have read the journal’s policy and have the following competing interests: ADK is an Academic Editor for PLOS Global Public Health. JMP is a guest editor for PLOS Global Public Health. KAC has received investigator-initiated research support from and served as a medical advisory board member for Gilead Sciences outside of the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Kerkhoff 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.)

Objectives: To evaluate the performance of point-of-care C-reactive protein (CRP) as a screening tool for tuberculosis (TB) using a threshold of 10 mg/L in both people living with HIV (PLHIV) and HIV-negative individuals and compare it to symptom screening using a composite reference for bacteriological confirmation of TB., Methods: Prospective cross-sectional study., Setting: A primary healthcare facility in Lusaka, Zambia., Participants: Consecutive adults (≥18 years) presenting for routine outpatient healthcare were enrolled. Of the 816 individuals approached to participate in the study, 804 eligible consenting adults were enrolled into the study, of which 783 were included in the analysis., Primary Outcome Measures: Sensitivity, specificity, positive predictive value and negative predictive value (NPV) of CRP and symptom screening., Results: Overall, sensitivity of WHO-recommended four-symptom screen (W4SS) and CRP were 87.2% (80.0-92.5) and 86.6% (79.6-91.8) while specificity was 30.3% (26.7-34.1) and 34.8% (31.2-38.6), respectively. Among PLHIV, sensitivity of W4SS and CRP was 92.2% (81.1-97.8) and 94.8% (85.6-98.9) while specificity was 37.0% (31.3-43.0) and 27.5% (22.4-33.1), respectively. Among those with CD4≥350, the NPV for CRP was 100% (92.9-100). In the HIV negative, sensitivity of W4SS and CRP was 83.8% (73.4-91.3) and 80.3% (69.5-88.5) while specificity was 25.4% (20.9-30.2) and 40.5% (35.3-45.6), respectively. Parallel use of CRP and W4SS yielded a sensitivity and NPV of 100% (93.8-100) and 100% (91.6-100) among PLHIV and 93.3% (85.1-97.8) and 90.0% (78.2-96.7) among the HIV negatives, respectively., Conclusion: Sensitivity and specificity of CRP were similar to symptom screening in HIV-positive outpatients. Independent use of CRP offered limited additional benefit in the HIV negative. CRP can independently accurately rule out TB in PLHIV with CD4≥350. Parallel use of CRP and W4SS improves sensitivity irrespective of HIV status and can accurately rule out TB in PLHIV, irrespective of CD4 count., 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.)

People deprived of liberty have among the highest rates of tuberculosis globally. The incidence of tuberculosis is ten times greater than the incidence of tuberculosis in the general population. In 2021, WHO updated its guidance to strongly recommend systematic screening for tuberculosis in prisons and penitentiary systems. Which case-finding strategies should be adopted, and how to effectively implement these strategies in these settings, will be crucial questions facing ministries of health and justice. In this Viewpoint, we review the evidence base for tuberculosis screening and diagnostic strategies in prisons, highlighting promising approaches and knowledge gaps. Drawing upon past experiences of implementing active case-finding and care programmes in settings with a high tuberculosis burden, we discuss challenges and opportunities for improving the tuberculosis diagnosis and treatment cascade in these settings. We argue that improved transparency in reporting of tuberculosis notifications and outcomes in prisons and renewed focus and resourcing from WHO and other stakeholders will be crucial for building the commitment and investments needed from countries to address the continued crisis of tuberculosis in prisons., 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-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Digital chest X-ray (dCXR) computer-aided detection (CAD) technology uses lung shape and texture analysis to determine the probability of tuberculosis (TB). However, many patients with previously treated TB have sequelae, which also distort lung shape and texture. We evaluated the diagnostic performance of 2 CAD systems for triage of active TB in patients with previously treated TB., Methods: We conducted a retrospective analysis of data from a cross-sectional active TB case finding study. Participants ≥15 years, with ≥1 current TB symptom and complete data on history of previous TB, dCXR, and TB microbiological reference (Xpert MTB/RIF) were included. dCXRs were evaluated using CAD4TB (v.7.0) and qXR (v.3.0). We determined the diagnostic accuracy of both systems, overall and stratified by history of TB, using a single threshold for each system that achieved 90% sensitivity and maximized specificity in the overall population., Results: Of 1884 participants, 452 (24.0%) had a history of previous TB. Prevalence of microbiologically confirmed TB among those with and without history of previous TB was 12.4% and 16.9%, respectively. Using CAD4TB, sensitivity and specificity were 89.3% (95% CI: 78.1-96.0%) and 24.0% (19.9-28.5%) and 90.5% (86.1-93.3%) and 60.3% (57.4-63.0%) among those with and without previous TB, respectively. Using qXR, sensitivity and specificity were 94.6% (95% CI: 85.1-98.9%) and 22.2% (18.2-26.6%) and 89.7% (85.1-93.2%) and 61.8% (58.9-64.5%) among those with and without previous TB, respectively., Conclusions: The performance of CAD systems as a TB triage tool is decreased among persons previously treated for TB., Competing Interests: Potential conflicts of interests. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

To reach the millions of people with tuberculosis (TB) undiagnosed each year, there is an important need to provide people-centered screening and testing services. Despite people-centered care being a key pillar of the WHO END-TB Strategy, there have been few attempts to formally characterize and integrate the preferences of people most affected by TB - including those who have increased exposure to TB, limited access to services, and/or are at increased risk for TB - into new tools and strategies to improve screening and diagnosis. This perspective emphasizes the importance of preference research among people most affected by TB, provides an overview of qualitative preference exploration and quantitative preference elicitation research methods, and outlines how preferences can be applied to improve the acceptability, accessibility, and appropriateness of TB screening and testing services via four key opportunities. These include the following: (1) Defining the most preferred features of novel screening, triage, and diagnostic tools, (2) exploring and prioritizing setting-specific barriers and facilitators to screening and testing, (3) understanding what features of community- and facility-based strategies for improving TB detection and treatment are most valued, and (4) identifying the most relevant and resonant communication strategies to increase individual- and community-level awareness and demand. Preference research studies and translation of their findings into policy/guidance and operationalization have enormous potential to close the existing gaps in detection in high burden settings by enhancing the people-centeredness and reach of screening and diagnostic services to people most affected by TB who are currently being missed and left behind., Competing Interests: Competing interests The authors declare no competing interests.

Background The World Health Organization (WHO) recommends chest radiography to facilitate tuberculosis (TB) screening. However, chest radiograph interpretation expertise remains limited in many regions. Purpose To develop a deep learning system (DLS) to detect active pulmonary TB on chest radiographs and compare its performance to that of radiologists. Materials and Methods A DLS was trained and tested using retrospective chest radiographs (acquired between 1996 and 2020) from 10 countries. To improve generalization, large-scale chest radiograph pretraining, attention pooling, and semisupervised learning ("noisy-student") were incorporated. The DLS was evaluated in a four-country test set (China, India, the United States, and Zambia) and in a mining population in South Africa, with positive TB confirmed with microbiological tests or nucleic acid amplification testing (NAAT). The performance of the DLS was compared with that of 14 radiologists. The authors studied the efficacy of the DLS compared with that of nine radiologists using the Obuchowski-Rockette-Hillis procedure. Given WHO targets of 90% sensitivity and 70% specificity, the operating point of the DLS (0.45) was prespecified to favor sensitivity. Results A total of 165 754 images in 22 284 subjects (mean age, 45 years; 21% female) were used for model development and testing. In the four-country test set (1236 subjects, 17% with active TB), the receiver operating characteristic (ROC) curve of the DLS was higher than those for all nine India-based radiologists, with an area under the ROC curve of 0.89 (95% CI: 0.87, 0.91). Compared with these radiologists, at the prespecified operating point, the DLS sensitivity was higher (88% vs 75%, P < .001) and specificity was noninferior (79% vs 84%, P = .004). Trends were similar within other patient subgroups, in the South Africa data set, and across various TB-specific chest radiograph findings. In simulations, the use of the DLS to identify likely TB-positive chest radiographs for NAAT confirmation reduced the cost by 40%-80% per TB-positive patient detected. Conclusion A deep learning method was found to be noninferior to radiologists for the determination of active tuberculosis on digital chest radiographs. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by van Ginneken in this issue.

Background: Zambia has an estimated TB incidence of 319/100,000 population and a HIV prevalence of 11.1%. In 2020, only 49% of new people living with HIV (PLHIV) received TB preventive therapy (TPT) in Zambia. Misconceptions about the reliability of symptom screening and drug resistance among people who develop TB while on TPT are barriers to TPT scale-up. We determined the incidence and predictors of breakthrough TB during TPT among PLHIV in Zambia., Method: This was a retrospective analysis of routine TPT programme data among PLHIV collected between October 2016 and October 2019 from select primary health facilities in Zambia., Results: Of 48,581 PLHIV enrolled on TPT, 130 (0.3%) developed breakthrough TB during TPT. Of the 130, 90 client records were accessed. The median age of the breakthrough TB cases was 35 years; 68% were males. Overall, 96% of the breakthrough TB cases had been on antiretroviral therapy (ART) for ⩽3 months; 24% were symptomatic at the beginning of TPT, 22% were asymptomatic and others had missing data. Of the 130 breakthrough TB cases, 79% developed TB in the first month after TPT initiation. The median time to TB diagnosis was 10 days (IQR 4-16)., Conclusion: Breakthrough TB during TPT is rare among PHLIV on ART, and very rare after the first month of TPT initiation. It should therefore not be a barrier to TPT scale-up., Competing Interests: Conflicts of interest: none declared., (© 2022 The Union.)

Importance: Delayed engagement in tuberculosis (TB) services is associated with ongoing transmission and poor clinical outcomes., Objective: To assess whether patients with TB have differential preferences for strategies to improve the public health reach of TB diagnostic services., Design, Setting, and Participants: A cross-sectional study was undertaken in which a discrete choice experiment (DCE) was administered between September 18, 2019, and January 17, 2020, to 401 adults (>18 years of age) with microbiologically confirmed TB in Lusaka, Zambia. The DCE had 7 attributes with 2 to 3 levels per attribute related to TB service enhancements. Latent class analysis was used to identify segments of participants with unique preferences. Multiscenario simulations were used to estimate shares of preferences for different TB service improvement strategies., Main Outcomes and Measures: The main outcomes were patient preference archetypes and estimated shares of preferences for different strategies to improve TB diagnostic services. Collected data were analyzed between January 3, 2022, to July 2, 2022., Results: Among 326 adults with TB (median [IQR] age, 34 [27-42] years; 217 [66.8%] male; 158 [48.8%] HIV positive), 3 groups with distinct preferences for TB service improvements were identified. Group 1 (192 participants [58.9%]) preferred a facility that offered same-day TB test results, shorter wait times, and financial incentives for testing. Group 2 (83 participants [25.4%]) preferred a facility that provided same-day TB results, had greater privacy, and was closer to home. Group 3 (51 participants [15.6%]) had no strong preferences for service improvements and had negative preferences for receiving telephone-based TB test results. Groups 1 and 2 were more likely to report at least a 4-week delay in seeking health care for their current TB episode compared with group 3 (29 [51.3%] in group 1, 95 [35.8%] in group 2, and 10 [19.6%] in group 3; P < .001). Strategies to improve TB diagnostic services most preferred by all participants were same-day TB test results alone (shares of preference, 69.9%) and combined with a small financial testing incentive (shares of preference, 79.3%), shortened wait times (shares of preference, 76.1%), or greater privacy (shares of preference, 75.0%). However, the most preferred service improvement strategies differed substantially by group., Conclusions and Relevance: In this study, patients with TB had heterogenous preferences for TB diagnostic service improvements associated with differential health care-seeking behavior. Tailored strategies that incorporate features most valued by persons with undiagnosed TB, including same-day results, financial incentives, and greater privacy, may optimize reach by overcoming key barriers to timely TB care engagement.

Widely available tuberculosis (TB) diagnostics use sputum samples. However, many patients, particularly children and patients living with HIV (PLHIV), struggle to provide sputum. Urine diagnostics are a promising approach to circumvent this challenge while delivering reliable and timely diagnosis. This qualitative study in two high TB/HIV burden countries assesses values and preferences of end-users, along with potential barriers for the implementation of the novel Fujifilm SILVAMP TB-LAM (FujiLAM, Fujifilm, Japan) urine test. Between September 2020 and March 2021, we conducted 42 semi-structured interviews with patients, health care providers (HCPs) and decision makers (DMs) (e.g., in national TB programs) in Malawi and Zambia. Interviews were transcribed verbatim and analyzed using a framework approach supported by NVIVO. Findings aligned with the pre-existing Health Equity Implementation Framework, which guided the presentation of results. The ease and convenience of urine-based testing was described as empowering among patients and HCPs who lamented the difficulty of sputum collection, however HCPs expressed concerns that a shift in agency to the patient may affect clinic workflows (e.g., due to less control over collection). Implementation facilitators, such as shorter turnaround times, were welcomed by operators and patients alike. The decentralization of diagnostics was considered possible with FujiLAM by HCPs and DMs due to low infrastructure requirements. Finally, our findings support efforts for eliminating the CD4 count as an eligibility criterion for LAM testing, to facilitate implementation and benefit a wider range of patients. Our study identified barriers and facilitators relevant to scale-up of urine LAM tests in Malawi and Zambia. FujiLAM could positively impact health equity, as it would particularly benefit patient groups currently underserved by existing TB diagnostics. Participants view the approach as a viable, acceptable, and likely sustainable option in low- and middle-income countries, though adaptations may be required to current health care processes for deployment. Trial registration: German Clinical Trials Register, DRKS00021003. URL: https://www.drks.de/drks&#95;web/setLocale&#95;EN.do., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CMD was working for FIND until April 2019. FIND at the time partnered with Fujifilm to develop the the SILVAMP TB Assay., (Copyright: © 2022 Herrmann 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: Automated radiologic analysis using computer-aided detection software (CAD) could facilitate chest X-ray (CXR) use in tuberculosis diagnosis. There is little to no evidence on the accuracy of commercially available deep learning-based CAD in different populations, including patients with smear-negative tuberculosis and people living with human immunodeficiency virus (HIV, PLWH)., Methods: We collected CXRs and individual patient data (IPD) from studies evaluating CAD in patients self-referring for tuberculosis symptoms with culture or nucleic acid amplification testing as the reference. We reanalyzed CXRs with three CAD programs (CAD4TB version (v) 6, Lunit v3.1.0.0, and qXR v2). We estimated sensitivity and specificity within each study and pooled using IPD meta-analysis. We used multivariable meta-regression to identify characteristics modifying accuracy., Results: We included CXRs and IPD of 3727/3967 participants from 4/7 eligible studies. 17% (621/3727) were PLWH. 17% (645/3727) had microbiologically confirmed tuberculosis. Despite using the same threshold score for classifying CXR in every study, sensitivity and specificity varied from study to study. The software had similar unadjusted accuracy (at 90% pooled sensitivity, pooled specificities were: CAD4TBv6, 56.9% [95% confidence interval {CI}: 51.7-61.9]; Lunit, 54.1% [95% CI: 44.6-63.3]; qXRv2, 60.5% [95% CI: 51.7-68.6]). Adjusted absolute differences in pooled sensitivity between PLWH and HIV-uninfected participants were: CAD4TBv6, -13.4% [-21.1, -6.9]; Lunit, +2.2% [-3.6, +6.3]; qXRv2: -13.4% [-21.5, -6.6]; between smear-negative and smear-positive tuberculosis was: were CAD4TBv6, -12.3% [-19.5, -6.1]; Lunit, -17.2% [-24.6, -10.5]; qXRv2, -16.6% [-24.4, -9.9]. Accuracy was similar to human readers., Conclusions: For CAD CXR analysis to be implemented as a high-sensitivity tuberculosis rule-out test, users will need threshold scores identified from their own patient populations and stratified by HIV and smear status., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The "trace call" results on Xpert® Ultra indicates extremely low TB levels and may be difficult to interpret. The prevalence of trace results among presumptive TB patients in high TB-HIV infection settings is unknown, as is the significance of divergent "trace call" result interpretations., Methods: Presumptive TB patients attending a public health facility in Lusaka, Zambia, were prospectively enrolled. Participants underwent several TB investigations, including sputum smear microscopy, Ultra testing, and culture. The diagnostic accuracy of Ultra (culture-based reference) and the number of patients recommended for TB treatment was assessed according to several different interpretation criteria for "trace call" results., Results: Among the 740 participants, 78 (10.5%) were Ultra-positive and an additional 37 (5.0%) had a "trace call" result. The prevalence of trace results did not differ according to HIV status (5.3% vs. 4.8%) or prior TB status (5.6% vs. 4.9%). Differing interpretations of trace results had modest effects on Ultra's sensitivity (range 79.3-82.6%) and specificity (range 94.3-99.2%), but increased the number of patients recommended for treatment by up to 44.9%., Conclusions: Ultra trace results were common in this setting. The interpretation of trace results may substantially impact TB case yield., (© 2022 The Union.)

Objective: To evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic and the subsequent implementation of tuberculosis response measures on tuberculosis notifications in Zambia., Methods: We used an interrupted time-series design to compare monthly tuberculosis notifications in Zambia before the pandemic (January 2019 to February 2020), after implementation of national pandemic mitigation measures (April 2020 to June 2020) and after response measures to improve tuberculosis detection (August 2020 to September 2021). The tuberculosis response included enhanced data surveillance, facility-based active case-finding and activities to generate demand for services. We used nationally aggregated, facility-level tuberculosis notification data for the analysis., Findings: Pre-pandemic tuberculosis case notifications rose steadily from 2890 in January 2019 to 3337 in February 2020. After the start of the pandemic and mitigation measures, there was a -22% (95% confidence interval, CI: -24 to -19) immediate decline in notifications in April 2020. Larger immediate declines in notifications were seen among human immunodeficiency virus (HIV)-positive compared with HIV-negative individuals (-36%; 95% CI: -38 to -35; versus -12%; 95% CI: -17 to -6). Following roll-out of tuberculosis response measures in July 2020, notifications immediately increased by 45% (95% CI: 38 to 51) nationally and across all subgroups and provinces. The trend in notifications remained stable through September 2021, with similar numbers to the predicted number had the pandemic not occurred., Conclusion: Implementation of a coordinated public health response including active tuberculosis case-finding was associated with reversal of the adverse impact of the pandemic and mitigation measures. The gains were sustained throughout subsequent waves of the pandemic., ((c) 2022 The authors; licensee World Health Organization.)

Background: Persistent respiratory symptoms and radiographic abnormalities are common among individuals previously treated for tuberculosis (TB) and may contribute to misdiagnosis and incorrect treatment when they seek care. We sought to determine if clinical and radiographic characteristics differed among previously treated, presumptive TB patients according to their current TB disease status., Methods: Adults (>18 years of age) seeking care at a public health facility in Lusaka, Zambia were systematically evaluated for active TB using symptom screening and chest X-ray. All patients with presumptive TB submitted a sputum sample for microbiological TB testing. Patients who reported a prior history of TB treatment were included in the present analysis. 'Confirmed TB' was defined by the detection of TB using Xpert Ultra and/or liquid culture, while 'possible TB' was defined by the receipt of TB treatment without a positive Xpert Ultra or culture result. We evaluated the positive predictive value (PPV) of clinical symptoms and radiographic features for active TB alone and in combination., Results: Of 740 presumptive TB patients, 144 (19%) had been previously treated for active TB. Of these, 19 (13%) patients had confirmed TB, 14 (10%) had possible TB, and 111 (77%) had no pulmonary TB. Overall, 119 (83%) patients had ≥1 current respiratory symptom-this did not differ according to current TB disease classification (95%, 93%, 79%; p = 0.23). Sixty-one patients (56%) had radiographic abnormalities suggestive of active TB and such findings were more common among patients with confirmed or possible TB compared to those without TB (93%, 71%, vs. 47%; p = 0.002). Most patients (n = 91, 83%) had at least one radiographic abnormality-no difference by current TB classification was observed (93%, 100%, 79%; p = 0.08). The PPV of any current respiratory symptom, active TB radiographic finding, or any radiographic abnormality for TB was 13% (95%CI: 7-21%), 21% (95%CI: 12-34) and 14% (95%CI: 9-23), respectively; combining clinical and radiographic characteristics did not significantly improve the PPV for active TB., Conclusions: Among presumptive TB patients previously treated for TB, respiratory symptoms and radiographic abnormalities were common and poorly differentiated those with current active TB from those without current active TB. Reliance on clinical and radiographic characteristics alone in this patient population may result in substantial overtreatment and therefore, microbiological investigations should be used to inform TB treatment decisions whenever possible., Competing Interests: The authors declared that they have no competing interests.

Background: A novel, rapid, point-of-care urine-based lipoarabinomannan assay (Fujifilm SILVAMP TB LAM ("FujiLAM")) has previously demonstrated substantially higher sensitivity for tuberculosis (TB) compared with the commercially available Determine TB LAM assay using biobanked specimens. However, FujiLAM has not been prospectively evaluated using fresh urine specimens. Therefore, we determined the diagnostic accuracy of FujiLAM among HIV-positive and HIV-negative outpatients with presumptive TB in Zambia., Methods: Adult (≥18 years old) presumptive TB patients presenting to two outpatient public health facilities in Lusaka were included. All patients submitted sputa samples for smear microscopy, Xpert MTB/RIF and mycobacterial culture, and urine samples for the FujiLAM assay. Microbiologically confirmed TB was defined by the detection of Mycobacterium tuberculosis in sputum using culture; this served as the reference standard to assess the diagnostic accuracy of FujiLAM., Results: 151 adults with paired sputum microbiological tests and urine FujiLAM results were included; 45% were HIV-positive. Overall, 34 out of 151 (23%) patients had culture-confirmed pulmonary TB. The overall sensitivity and specificity of FujiLAM was 77% (95% CI 59-89%) and 92% (95% CI 86-96%), respectively. FujiLAM's sensitivity among HIV-positive patients was 75% (95% CI 43-95%) compared with 75% (95% CI 51-91%) among HIV-negative patients. The sensitivity of FujiLAM in patients with smear-positive, confirmed pulmonary TB was 87% (95% CI 60-98%) compared with 68% (95% CI 43-87%) among patients with smear-negative, confirmed pulmonary TB., Conclusions: FujiLAM demonstrated high sensitivity for the detection of TB among both HIV-positive and HIV-negative adults, and also demonstrated good specificity despite the lack of systematic extrapulmonary sampling to inform a comprehensive microbiological reference standard., Competing Interests: Conflict of interest: M. Muyoyeta has nothing to disclose. Conflict of interest: A.D. Kerkhoff has nothing to disclose. Conflict of interest: L. Chilukutu has nothing to disclose. Conflict of interest: E. Moreau reports working for FIND. FIND is a non-for-profit foundation, whose mission is to find diagnostic solutions to overcome diseases of poverty in LMICs. It works closely with the private and public sectors and receives funding from some of its industry partners (no funding received from Cepheid for the development or the evaluation of Xpert). It has organisational firewalls to protect it against any undue influences in its work or the publication of its findings. All industry partnerships are subject to review by an independent scientific advisory committee or another independent review body, based on due diligence, TTPs and public sector requirements. FIND catalyses product development, leads evaluations, takes positions and accelerates access to tools identified as serving its mission. It provides indirect support to industry (e.g. access to open specimen banks, a clinical trial platform, technical support, expertise, laboratory capacity strengthening in LMICs) to facilitate the development and use of products in these areas. FIND also supports the evaluation of publicly prioritised TB assays and the implementation of WHO-approved (guidance and PQ) assays using donor grants. In order to carry out test evaluations, FIND has product evaluation agreements with several private sector companies for TB and other diseases, which strictly define its independence and neutrality vis-à-vis the companies whose products get evaluated and describes roles and responsibilities. Conflict of interest: S.G. Schumacher reports working for FIND. FIND is a non-for-profit foundation, whose mission is to find diagnostic solutions to overcome diseases of poverty in LMICs. It works closely with the private and public sectors and receives funding from some of its industry partners. It has organisational firewalls to protect it against any undue influences in its work or the publication of its findings. All industry partnerships are subject to review by an independent scientific advisory committee or another independent review body, based on due diligence, TPPs and public sector requirements. FIND catalyses product development, leads evaluations, takes positions and accelerates access to tools identified as serving its mission. It provides indirect support to industry (e.g. access to open specimen banks, a clinical trial platform, technical support, expertise, laboratory capacity strengthening in LMICs) to facilitate the development and use of products in these areas. FIND also supports the evaluation of prioritised assays and the early stages of implementation of WHO-approved (guidance and PQ) assays using donor grants. In order to carry out test validations and evaluations, FIND has product evaluation agreements with several private sector companies for the diseases FIND works in which strictly define its independence and neutrality vis-à-vis the companies whose products get evaluated, and describes roles and responsibilities. Conflict of interest: M. Ruhwald has nothing to disclose., (Copyright ©The authors 2021.)

Objective: To determine the prevalence of tuberculosis (TB) and HIV in 13 Zambian correctional facilities., Methods: Cross-sectional study., Setting: 13 correctional facilities in seven of the 10 provinces in Zambia., Participants: All incarcerated individuals were eligible for TB and HIV screening and testing. Of the total study population of 9695 individuals, which represent 46.2% of total correctional population at the beginning of the study, 8267 and 8160 were screened for TB and HIV, respectively., Interventions: TB and HIV screening and testing was done between July 2018 and February 2019., Primary Outcome Measures: All forms of TB, bacteriologically confirmed TB, drug-resistant TB, HIV., Results: Prevalence of all forms of TB and bacteriologically confirmed TB was 1599 (1340-1894) per 100 000 population and 1056 (847-1301) per 100 000 population, respectively. Among those with bacteriologically confirmed TB, 4.6% (1.3%-11.4%) had drug-resistant TB.There was no statistically significant difference in the prevalence of all forms of TB, bacteriologically confirmed TB and drug resistant TB between adults and juveniles: (p=0.82), (p=0.23), (p=0.68) respectively. Of the bacteriologically confirmed TB cases, 28.7% were asymptomatic. The prevalence of HIV was 14.3% (13.6%-15.1%). The prevalence of HIV among females was 1.8 times the prevalence of HIV among males (p=0.01)., Conclusion: Compared with the study in 2011 which screened inmates representing 30% of the country's inmate population, then the prevalence of all forms of TB and HIV in correctional facilities has reduced by about 75% and 37.6%, respectively. However, compared with the general population, the prevalence of all forms of TB and HIV was 3.5 and 1.3 times higher, respectively. TB/HIV programmes in correctional facilities need further strengthening to include aspects of juvenile-specific TB programming and gender responsive HIV programming., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Active-case finding (ACF) programs have an important role in addressing case detection gaps and halting tuberculosis (TB) transmission. Evidence is limited on the cost-effectiveness of ACF interventions, particularly on how their value is impacted by different operational, epidemiological and patient care-seeking patterns., Methods: We evaluated the costs and cost-effectiveness of a combined facility and community-based ACF intervention in Zambia that utilized mobile chest X-ray with computer-aided reading/interpretation software and laboratory-based Xpert MTB/RIF testing. Programmatic costs (in 2018 US dollars) were assessed from the health system perspective using prospectively collected cost and operational data. Cost-effectiveness of the ACF intervention was assessed as the incremental cost per TB death averted over a five-year time horizon using a multi-stage Markov state-transition model reflecting patient symptom-associated care-seeking and TB care under ACF compared to passive care., Results: Over 18 months of field operations, the ACF intervention costed $435 to diagnose and initiate treatment for one person with TB. After accounting for patient symptom-associated care-seeking patterns in Zambia, we estimate that this one-time ACF intervention would incrementally diagnose 407 (7,207 versus 6,800) TB patients and avert 502 (611 versus 1,113) TB-associated deaths compared to the status quo (passive case finding), at an incremental cost of $2,284 per death averted over the next five-year period. HIV/TB mortality rate, patient symptom-associated care-seeking probabilities in the absence of ACF, and the costs of ACF patient screening were key drivers of cost-effectiveness., Conclusions: A one-time comprehensive ACF intervention simultaneously operating in public health clinics and corresponding catchment communities can have important medium-term impact on case-finding and be cost-effective in Zambia. The value of such interventions increases if targeted to populations with high HIV/TB mortality, substantial barriers (both behavioral and physical) to care-seeking exist, and when ACF interventions can optimize screening by achieving operational efficiency., Competing Interests: The authors have declared that no competing interests exist.

Background: Delays in the diagnosis of tuberculosis (TB) contribute to a substantial proportion of TB-related mortality, especially among people living with HIV (PLHIV). We sought to characterize the diagnostic journey for HIV-positive and HIV-negative patients with a new TB diagnosis in Zambia, to understand drivers of delay, and characterize their preferences for service characteristics to inform improvements in TB services., Methods: We assessed consecutive adults with newly microbiologically-confirmed TB at two public health treatment facilities in Lusaka, Zambia. We administered a survey to document critical intervals in the TB care pathway (time to initial care-seeking, diagnosis and treatment initiation), identify bottlenecks and their reasons. We quantified patient preferences for a range of characteristics of health services using a discrete choice experiment (DCE) that assessed 7 attributes (distance, wait times, hours of operation, confidentiality, sex of provider, testing incentive, TB test speed and notification method)., Results: Among 401 patients enrolled (median age of 34 years, 68.7% male, 46.6% HIV-positive), 60.9% and 39.1% were from a first-level and tertiary hospital, respectively. The median time from symptom onset to receipt of TB treatment was 5.0 weeks (IQR: 3.6-8.0) and was longer among HIV-positive patients seeking care at a tertiary hospital than HIV-negative patients (6.4 vs. 4.9 weeks, p = 0.002). The time from symptom onset to initial presentation for evaluation accounted for the majority of time until treatment initiation (median 3.0 weeks, IQR: 1.0-5.0)-an important minority of 11.0% of patients delayed care-seeking ≥8 weeks. The DCE found that patients strongly preferred same-day TB test results (relative importance, 37.2%), facilities close to home (18.0%), and facilities with short wait times (16.9%). Patients were willing to travel to a facility up to 7.6 kilometers further away in order to access same-day TB test results. Preferences for improving current TB services did not differ according to HIV status., Conclusions: Prolonged intervals from TB symptom onset to treatment initiation were common, especially among PLHIV, and were driven by delayed health-seeking. Addressing known barriers to timely diagnosis and incorporating patients' preferences into TB services, including same-day TB test results, may facilitate earlier TB care engagement in high burden settings., Competing Interests: The authors have declared that no competing interests exist.