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.

Tuberculosis is a leading cause of morbidity and mortality worldwide. Current TB treatments are inadequate, requiring patients closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated. These concerns are greatly magnified in rifampicin-resistant (RIF-R) TB, an urgent global and EU public health priority. WHO estimates that only 54% of patients who began RIF-R TB treatment in 2016 were cured. In addition to these well-recognized shortcomings, current TB treatments, particularly those for RIF-R TB, leave a majority of cured patients with permanent, clinically significant lung impairment and radiographic evidence of bronchiectasis and fibrosis. This project will determine if two adjunctive host-directed therapies (HDTs) can prevent these poor outcomes. 330 patients with RIF-R TB and baseline risk factors for poor outcome will be enrolled in a randomized, controlled, 3-armed multi-centre trial, with clinical sites in Romania, Moldova, Georgia, Mozambique, and South Africa. All patients will receive standard multidrug therapy according to national guidelines. Those patients randomized to the experimental arms will in addition receive either CC-11050 or metformin. These selected HDT candidates represent 2 complementary HDT strategies: reducing inflammation vs inducing host cell anti-microbial activity, respectively. Both candidates are supported by data from preclinical and clinical studies. Co-primary efficacy endpoints will examine effects on lung function (measured by spirometry) and infection (measured as time to stable sputum culture conversion). A sub-study will examine quantitative change in lung radiodensity by CT scan. If successful, this ground-breaking project will increase Europe’s capacity to control RIF-R-TB by developing new treatments that increase the likelihood of cure and reduce the risk of life-long disability.

TB-SPECTRUM aims to strengthen international research collaboration among different sectors and disciplines, and to structure a network to perform high-quality, translational, and multidisciplinary research for (i) a better understanding of tuberculosis (TB) spectrum immune mechanisms; and (ii) increasing the capacities of the involved staff fostering training and networking activities, as well as increasing their inter-sectoral employability opportunities. Understanding the host-pathogen interactions in the different phases of the spectrum is fundamental for detecting biomarkers of disease progression that can lead to new diagnostic approaches for identifying those individuals with a high-risk of developing disease if infected or for detecting subclinical TB forms. However, it is still unknown which immunological mechanisms are involved in infection/disease progression. To unravel this knowledge gap, it is mandatory to develop collaborative research which combines different expertise in the TB field (clinics, diagnostics, treatment, clinical studies management, cellular/humoral immunology, genomics, and technology transfer, among others). For that purpose, a Consortium of nine academic and non-academic Institutions harboring TB-renowned experts has been constituted. This network is formed by specialists in the clinical management of active TB cases and their contacts (from high and low incident countries); experts in basic/applied science; and a small and medium-sized enterprise (SME) involved in the development of immune assays. Altogether, the proposed goals will be achieved through secondments among the different sectors, which will be extremely important for progressing to a better understanding of the requirements needed in TB management and control; and will expose participants to new research environments that will reinforce multidisciplinarity. Moreover, the interaction with an SME will improve knowledge transference skills, stimulating entrepreneurship.

The objective of INNOVA4TB is to enhance and strengthen the collaborative research among sectors and to form a network aimed to perform high-quality and translational research in the field of diagnosis and management of tuberculosis (TB). The consortium is constituted by 12 institutions from 8 countries that combine complementary and synergic expertise: clinical management (hospitals), basic science and new technologies (academic institutions), and industrial development and entrepreneurship culture (SMEs). The exchanges between the institutions allow the participants to progress in their career perspectives. TB is one of the major infectious diseases worldwide, and the emergence and spread of drug resistant cases is a public health threat. However, the conventional methods used for diagnosis and drug-susceptibility testing are not enough for controlling the disease. In addition, all TB patients, independently of their age, gender, severity of the disease and type of responsible strain, follow the same treatment duration (up to 20 months in drug resistant cases), which often leads to high frequency of adverse events, suboptimal adherence to treatment, and poor outcome. A transition from programmatic to personalized management of TB is needed. Our proposal will develop innovative technologies and approaches in order to improve the individual risk assessment for TB development, to rapidly diagnose active TB, to detect the drug susceptibility of the strain, to design tailor-made therapies, and to use biomarkers to guide and individualize the duration of antimicrobial therapy. This is of great importance for improving the quality of life of patients and ensuring treatment success, as well as for economic reasons for the healthcare system.

CARE brings together distinguished scientists and highly representative networks in the European region, including Russia, in the fight against HIV/TB/HCV. CARE research objectives are based on already established European cohort networks with extensive and longitudinal data and/or sample collections. Together with new data and sample collections and cohorts created during the project, CARE will produce high-level researchoutputs during the two years of the project timeframe. The specific short term objectives are to: ● Discover and validate novel soluble biomarkers of MDR-TB treatment success and of pulmonary TB. ● Explore host genetic mechanisms of susceptibility to extrapulmonary TB. ● Analyse genotype to phenotype correlations in MDR-TB and develop a decision making support tool. ● Define epidemiology and pathways of drug-resistant HIV, including their relationship with HIV subtypes and TB coinfection to support an evidence-based introduction of INSTIs as part of first line antiretroviral therapy. ● Discover and validate host genomic variants influencing susceptibility to contracting AIDS and serious non-AIDS clinical events and adverse reactions to drugs. ● Derive best practice recommendations for DAA prioritisation strategies for HCV treatment. The longer-term objective of CARE is to implement a research infrastructure that allows the expansion of activities beyond the funding frame, permitting the partners to share technology, protocols, structured data collections and knowledge. Finally, CARE activities include realization of recommendations and intervention plans, communication to the stakeholders, dissemination and training activities in order to develop and distribute the highest expertise and competence throughout the European region for the containment of the epidemics.CARE is fully in line with the call topic and addresses all its subtopics. It involves a recognised Russian partner coordinating 5 top level institutions covering the regions of Russia.