The COVID-19 pandemic had a devastating impact on tuberculosis (TB) control. In 2020, the number of people newly diagnosed with TB decreased by 18% despite a rising global TB burden. Intensified efforts to improve TB case detection are critically needed, especially in populations in whom bacteriological confirmation is suboptimal, such as children and people living with HIV (PLHIV) who have also been disproportionately affected by the pandemic. The need for highly sensitive sputum-free diagnostic tools for TB has never been greater. STool4TB, an EDCTP-2 funded diagnostic trial, began its activities in 2020 shortly after the onset of the COVID-19 pandemic. The study aims to validate a novel quantitative PCR assay utilizing a stool homogenization and DNA isolation method that yields a highly sensitive and specific detection of Mycobacterium tuberculosis. STool4TB is implemented in high TB & HIV burden settings of Mozambique, Eswatini, and Uganda under the hypothesis that it will contribute to narrow the large TB case detection gap by improving TB lab-confirmation rates in children and PLHIV, while proving feasible and acceptable. New evidence suggests that this platform has a higher sensitivity when compared to sputum culture and Xpert Ultra and could have an additive lab-confirmation yield of up to 20%. STool4TB is also evaluating the qPCR platform as a treatment monitoring tool. This assay has the potential to be adapted to a POC diagnostic test which could be easily implemented in decentralized levels of care. Given the impact of the COVID-19 pandemic on TB notifications at the three participating sites and on several STool4TB core activities, we request additional funding to finalize recruitment of participants and achieve the target sample size, ensuring full execution of all project’s objectives. The observed upward trend in global TB burden makes the development of promising diagnostic tools, such as this novel stool-based qPCR, more important than ever.

In 2022, the World Health Organization (WHO) recommended bedaquiline (BDQ)-based, all-oral regimens including pretomanid (Pa), linezolid (L), and moxifloxacin (M) (BPaLM), lasting 6-9 months However, BDQ-resistance is rising dramatically and threatening these advancements. Mozambique has reported BDQ resistance in 28% of MDR-TB isolates in 2024, up from 3% in 2016 and at 10% in South Africa (Ndjeka N, personal communication). Spread of BDQ-R TB must be slowed by antibiotic stewardship through more rapid, accurate, and near-patient diagnostics, and optimized management; until new treatment options with drugs that have no pre-existing resistance or are able to overcome small shifts in MIC will be available. The proposed EX-DR TB project includes diagnostic capacity strengthening, adapting treatment recommendations, and a trial of two new regimens composed of new drugs. The EDCTP EX-DR TB project will: 1. Develop treatment recommendations by a Delphi process with stakeholders - to make use of targeted next generation sequencing (tNGS) that is being rolled out by most national TB programmes - this will yield short-term benefit for patients and NTPs; and will slow the spread of BDQ-resistant bacteria; 2. Rigorously evaluate two treatment regimens composed of new drugs, in a phase 3 clinical trial conducted to the highest regulatory standard – this will be the main focus of EX-DR TB. The trial objective will be to move a regimen towards regulatory approval by FDA and/or EMA, and WHO if supported by results. Thus, EX-DR will create the tools for containing the nascent epidemic of BDQ-R TB and make them available to healthcare providers and TB Programmes. EX-DR TB will be embedded in a larger coalition of funders and partners focused on implementing and evaluating diagnostics and performing the trial beyond of the EDCTP funded area.