Introduction Tuberculosis (TB) remains a significant public health challenge in many African communities, where underreporting and underdiagnosis are prevalent due to barriers in accessing care and inadequate diagnostic tools. This is particularly concerning in hard-to-reach areas with a high burden of TB/HIV co-infection, where missed or delayed diagnoses exacerbate disease transmission, increase mortality, and lead to severe economic and health consequences. To address these challenges, it is crucial to evaluate innovative, cost-effective, community-based screening strategies that can improve early detection and linkage to care. Methods and Analysis We conduct a prospective, community-based, diagnostic, pragmatic trial in communities of the Butha Buthe District in Lesotho and the Greater Edendale area of Msunduzi Municipality, KwaZulu-Natal in South Africa to compare two strategies for population-based TB screening: Computer-Aided Detection (CAD) technology alone (CAD4TBv7 approach) vs. CAD combined with point-of-care C-reactive protein (CRP) testing (CAD4TBv7-CRP approach). Following a chest X-ray, CAD produces an abnormality score, which indicates the likelihood of TB. Score thresholds informing the screening logic for both approaches were determined based on the World Health Organization (WHO) target product profile for a TB screening test. CAD scores above a threshold pre-specified for the CAD4TBv7 approach indicate confirmatory testing for TB (Xpert MTB/RIF Ultra). For the CAD4TBv7-CRP approach, a CAD score within a pre-defined window requires the conduct of the second screening test, CRP, while a score above the respective upper threshold is followed by Xpert MTB/RIF Ultra. A CRP result above the selected cut-off also requires a confirmatory TB test. Participants with CAD scores below the (lower) threshold and those with CRP levels below the cut-off are considered screen-negative. The trial aims to compare the yield of detected TB cases and cost-effectiveness between two screening approaches by applying a paired screen-positive design. 20,000 adult participants will be enrolled and will receive a posterior anterior digital chest X-ray which is analysed by CAD software.

The authors have declared no competing interest.

NCT05526885

This work was supported by the European and Developing Countries Clinical Trials Partnership (EDCTP) as part of the TB TRIAGE+ project (grant number RIA2018D-2498). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Ethics committees/IRBs of National Health Research Ethics Committee in Lesotho, Human Sciences Research Council Research Ethics Committee and the Provincial Health Research Committee of the Department of Health of KwaZulu-Natal in South Africa and the Swiss Ethics Committee Northwest and Central Switzerland gave ethical approval for this work.

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