Tuberculosis remains a major global health challenge, despite recent advances in drug and regimen development. Pragmatic randomised trials are needed to evaluate the effectiveness, safety, and tolerability of new tuberculosis treatments under routine care conditions to appropriately inform practice guidelines and facilitate uptake. In this Review, we propose guiding principles for pragmatic tuberculosis treatment trials. Using the PRECIS-2 framework, we address eligibility, recruitment, setting, organisation of care, adherence support, outcomes, follow-up, primary analysis, data collection, and monitoring. Pragmatic trials should maximise generalisability through broad inclusion criteria, integration within routine health systems, and flexible delivery approaches while maintaining appropriate standards for participant safety and data reliability. We discuss considerations for individually randomised and cluster-randomised designs, outcome definitions, risk-proportionate monitoring, and streamlined data collection. Adoption of these principles will improve the generation of real-world evidence and facilitate global implementation of effective tuberculosis treatments.

While a range of interventions exists for tuberculosis (TB), their potential impact and cost-effectiveness are seldom directly compared across settings with different TB epidemiologies and structural drivers. Here we calibrated a deterministic TB model to epidemiological indicators from Brazil, India and South Africa. We implemented seven interventions across countries focusing on prevention, screening and diagnosis and treatment, as well as prison screening (Brazil) and nutritional supplementation (India). We standardized scale-up (2025–2030), coverage (80% of the target population) and strength of evidence using published efficacy data. We estimated the epidemiological impact and incremental cost-effectiveness ratios (ICERs), expressed as costs per disability-adjusted life year (DALY) averted, through 2050. Only three interventions prevented >10% of incident TB episodes by 2050: vaccination (median 15–28% across countries), symptom-agnostic community-wide screening (31–38%) and prison screening (23%). Other interventions had limited impact, ranging from 0% (shorter drug-susceptible treatment) to 5% (nutritional supplementation). ICERs varied widely by intervention and setting. Shorter drug-resistant treatment was cost-saving across settings, with the next lowest ICERs for prison screening (US$146 per DALY) and nutritional supplementation (US$281 per DALY). Interventions with meaningful epidemiological impact can be cost-effective but must target populations beyond clinic-diagnosed individuals and their households. Achieving such potential requires a shift in priorities regarding funding, policy and product development. A modelling analysis at a global scale estimates that three interventions (vaccination, community-wide screening and prison screening programmes) could prevent more than 10% of tuberculosis cases between now and 2050, highlighting the need to shift policy focus towards prevention.

To end the tuberculosis (TB) epidemic, the WHO recommends implementing active case-finding to increase TB detection, as well as the provision of TB preventive treatment (TPT) in contacts of people with TB. However, the scale-up of both strategies remains limited in high TB-burden countries such as Thailand. Despite the country’s highly decentralised healthcare system, significant inequalities remain in access to care, particularly in vulnerable populations. We designed an intervention study investigating the effectiveness and feasibility of a novel strategy combining active case-finding and the implementation of short-course TPT in households of newly diagnosed adults with TB in Thailand. This is a pragmatic phase IV stepped-wedge cluster-randomised trial conducted in 20 provincial hospitals (clusters). The study population comprises household members who were exposed within the last 3 months to adults with newly detected bacteriologically confirmed TB. The intervention combines an educational video to the index TB case, provision of an invitation card to household contacts for free TB screening at the facility, with a transport voucher, and support from village or urban health volunteers. Household contacts without active TB are offered TPT regimens according to age: 1-month rifapentine-isoniazid (1HP), 3-month rifapentine-isoniazid (3HP) or 3-month rifampicin-isoniazid (3HR). In the control phase, TB staff implement the current standard of care, including verbal information to persons newly diagnosed with TB on the need to screen their household contacts and provision of standard TPT. Hospitals shift from the control to the intervention phase every 3 months in four randomised sequences until all clusters apply the intervention. Generalised linear mixed models will be used to compare the intervention outcomes versus the standard of care, controlling for clustering and confounding by time. Active case-finding and systematic TPT in at-risk populations is currently limited in Thailand. This protocol incorporates pragmatic design features with a participant-centred approach to assess the effectiveness, feasibility and acceptability of a combined strategy including systematic screening of household contacts, active case-finding and TPT provision. If successful, this strategy will likely contribute to TB elimination in Thailand and beyond. The study is registered at ClinicalTrials.gov NCT05581212 on April 3rd, 2024, and is currently recruiting.

Interventions to improve tuberculosis care for those who already seek it or their household contacts will have limited impact on the tuberculosis epidemic, whereas strategies to reach entire communities could more meaningfully reduce the burden of disease. Redirecting tuberculosis research priorities and financing toward population-wide interventions is essential to close the gap between current investment and the desired population-level impact.

The rapid emergence of resistance to novel tuberculosis drugs, such as bedaquiline, is a key threat to the long-term effectiveness of novel regimens. Given that the introduction of these agents has enabled the introduction of an all-oral regimen for rifampicin-resistant and multidrug-resistant tuberculosis, the rise of resistance underscores the urgent need to safeguard their efficacy and responsible use. A major barrier is the delay in developing reliable tools to detect resistance to novel compounds, which limits clinical decision-making and surveillance efforts. Herein, we outline a framework for integrating the development of drug susceptibility testing alongside tuberculosis drug development, including early stage resistance profiling and defining appropriate epidemiological cutoff values. We highlight key gaps, including the need for structured partnerships between drug developers, diagnostic manufacturers, regulators, research institutions, funders, and policy makers. We propose a roadmap to accelerate drug susceptibility testing and development of new tuberculosis regimens, ensuring that resistance detection maintains pace with the introduction of novel drugs. Establishing collaborative platforms for data sharing, genomic analysis, and diagnostic innovation will help ensure that resistance detection evolves in step with drug development, thereby preserving novel treatments and improving global tuberculosis care.

Background:While a range of interventions exist for tuberculosis prevention, screening, diagnosis, and treatment, their potential population impact and cost-effectiveness are seldom directly compared, or evaluated between settings with different background TB epidemiology and structural drivers. Methods:We calibrated a deterministic TB model to epidemiological indicators in Brazil, India, and South Africa. We implemented seven interventions across countries focusing on prevention, screening and diagnosis, and treatment of TB, as well as TB screening in prisons in Brazil and nutritional supplementation in India. We standardised scale-up (2025-2030), coverage (80% of target population), and strength of evidence for epidemiological impact using published efficacy data. We estimated epidemiological impact and incremental cost-effectiveness ratios (ICERs), expressed as costs per disability-adjusted life year (DALY) averted by 2050. Results:Only three interventions prevented >10% of incident TB episodes by 2050: vaccination (median 15-28% across countries), symptom-agnostic community-wide screening (32-38%) and screening in prisons (23%). The impact of other interventions was more limited, ranging from 0% (shortened drug-susceptible treatment) to 5% (nutritional supplementation). ICERs varied widely by intervention and setting. Shortened drug-resistant treatment was cost-saving across settings, with the next lowest ICERs for prison screening in Brazil (72 USD/DALY) and nutritional supplementation in India (167 USD/DALY). Within each country, both low-cost community-wide screening and TB vaccine campaigns had lower USD/DALY than TB preventive treatment. Conclusion:Interventions with meaningful epidemiological impact can also be cost-effective, but need to target populations beyond clinic-diagnosed individuals or their households. Achieving such potential requires a priority shift in funding, policy and product development.

Antimicrobial resistance (AMR) is a major global health threat estimated to have caused the deaths of 1.27 million people in 2019, which is more than HIV/AIDS and malaria deaths combined. AMR also has significant consequences on the global economy. If not properly addressed, AMR could immensely impact the world’s economy, further increasing the poverty burden in low- and middle-income countries. To mitigate the risk of a post-antibiotic society, where the ability to effectively treat common bacterial infections is being severely threatened, it is necessary to establish a continuous supply of new and novel antibacterial medicines. However, there are gaps in the current pipeline that will prove difficult to address, given the time required to develop new agents. To understand the status of upstream antibiotic development and the challenges faced by drug developers in the early development stage, the World Health Organization has regularly assessed the preclinical and clinical antibacterial development pipeline. The review identifies potential new classes of antibiotics or novel mechanisms of action that can better address resistant bacterial strains. This proactive approach is necessary to stay ahead of evolving resistance patterns and to support the availability of effective treatment options. This review examines the trends in preclinical development and attempts to identify gaps and potential opportunities to overcome the numerous hurdles in the early stages of the antibacterial research and development space.

Background Within the International Health Regulations framework, the French High Council for Public Health was mandated in 2022 by health authorities to establish a list of priority infectious diseases for public health, surveillance and research in mainland and overseas France. Aim Our objective was to establish this list. Methods A multi-criteria decision analysis was used, as recommended by the European Centre for Disease Prevention and Control. A list of 95 entities (infectious diseases or groups of these, including the World Health Organization (WHO)-labelled ‘Disease X’) was established by 17 infectious disease experts. Ten criteria were defined to score entities: incidence rate, case fatality rate, potential for emergence and spread, impact on the individual, on society, on socially vulnerable groups, on the healthcare system, and need for new preventive tools, new curative therapies, and surveillance. Each criterion was assigned a relative weight by 77 multidisciplinary experts. For each entity, 98 physicians from various specialties rated each criterion against the entity, using a four-class Likert-type scale; the ratings were converted into numeric values with a nonlinear scale and respectively weighted to calculate the entity score. Results Fifteen entities were ranked as high-priorities, including Disease X and 14 known pathologies (e.g. haemorrhagic fevers, various respiratory viral infections, arboviral infections, multidrug-resistant bacterial infections, invasive meningococcal and pneumococcal diseases, prion diseases, rabies, and tuberculosis). Conclusion The priority entities agreed with those of the WHO in 2023; almost all were currently covered by the French surveillance and alert system. Repeating this analysis periodically would keep the list updated.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

L’émergence de la résistance aux antibiotiques constitue une réelle menace de santé publique dans les pays en développement, où la situation est particulièrement inquiétante du fait de l'endémicité des infections.

Tuberculosis infection (TBI) is defined as a state of infection in which individuals host live Mycobacterium tuberculosis with or without clinical signs of active TB. It is now understood as a dynamic process covering a spectrum of responses to infection resulting from the interaction between the TB bacilli and the host immune system. The global burden of TBI is about one-quarter of the world’s population, representing a reservoir of approximately 2 billion people. On average, 5–10% of people who are infected will develop TB disease over the course of their lives, but this risk is enhanced in a series of conditions, such as co-infection with HIV. The End-TB strategy promotes the programmatic management of TBI as a crucial endeavor to achieving global targets to end the TB epidemic. The current development of new diagnostic tests capable of discriminating between simple TBI and active TB, combined with novel short-course preventive treatments, will help achieve this goal. In this paper, we present the current situation and recent developments of management of TBI and the operational challenges.

BACKGROUND:Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. OBJECTIVES:This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. SOURCES:A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). CONTENT:This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. IMPLICATIONS:Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB.

Background European-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening. Aim We aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening. Methods The Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin. Results Data on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea. Conclusions Country of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

Abstract The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

Knowledge is at the heart of health research, and production of relevant evidence along the overall spectrum of research—from basic science for discovery to the development of new tools or strategies, and their optimal uptake—is essential to improve health globally. The intention of this chapter is to present how thinking along the research continuum provides a solid basis to identify where and how interactions and synergies can take place profitably towards a common goal, and avoid dispersion of means, energies and funding. Mapping institutions, programmes and teams involved in research for a given health condition and matching these to research needs and priorities at national and international levels is fundamental to improve the relevance, quality and efficiency of research. Capitalizing on greater recognition of the value of research for health and society, an end-to-end vision is proposed, encompassing the full continuum of research to gain evidence from multiple sources, for ultimately linking research, policy and practice.

Background People who are incarcerated are at high risk of developing tuberculosis. We aimed to estimate the annual global, regional, and national incidence of tuberculosis among incarcerated populations from 2000 to 2019. Methods We collected and aggregated data for tuberculosis incidence and prevalence estimates among incarcerated individuals in published and unpublished literature, annual tuberculosis notifications among incarcerated individuals at the country level, and the annual number of incarcerated individuals at the country level. We developed a joint hierarchical Bayesian meta-regression framework to simultaneously model tuberculosis incidence, notifications, and prevalence from 2000 to 2019. Using this model, we estimated trends in absolute tuberculosis incidence and notifications, the incidence and notification rates, and the case detection ratio by year, country, region, and globally. Findings In 2019, we estimated a total of 125 105 (95% credible interval [CrI] 93 736-165 318) incident tuberculosis cases among incarcerated individuals globally. The estimated incidence rate per 100 000 person-years overall was 1148 (95% CrI 860-1517) but varied greatly by WHO region, from 793 (95% CrI 430-1342) in the Eastern Mediterranean region to 2242 (1515-3216) in the African region. Global incidence per 100 000 person-years between 2000 and 2012 among incarcerated individuals decreased from 1884 (95% CrI 1394-2616) to 1205 (910-1615); however, from 2013 onwards, tuberculosis incidence per 100 000 person-years was stable, from 1183 (95% CrI 876-1596) in 2013 to 1148 (860-1517) in 2019. In 2019, the global case detection ratio was estimated to be 53% (95% CrI 42-64), the lowest over the study period. Interpretation Our estimates suggest a high tuberculosis incidence rate among incarcerated individuals globally with large gaps in tuberculosis case detection. Tuberculosis in incarcerated populations must be addressed with interventions specifically tailored to improve diagnoses and prevent transmission as a part of the broader global tuberculosis control effort.

Vaccines can be highly effective tools in combating antimicrobial resistance as they reduce infections caused by antibiotic-resistant bacteria and antibiotic consumption associated with disease. This Review looks at vaccine candidates that are in development against pathogens on the 2017 WHO bacterial priority pathogen list, in addition to Clostridioides difficile and Mycobacterium tuberculosis. There were 94 active preclinical vaccine candidates and 61 active development vaccine candidates. We classified the included pathogens into the following four groups: Group A consists of pathogens for which vaccines already exist-ie, Salmonella enterica serotype Typhi, Streptococcus pneumoniae, Haemophilus influenzae type b, and M tuberculosis. Group B consists of pathogens with vaccines in advanced clinical development-ie, extra-intestinal pathogenic Escherichia coli, Salmonella enterica serotype Paratyphi A, Neisseria gonorrhoeae, and C difficile. Group C consists of pathogens with vaccines in early phases of clinical development-ie, enterotoxigenic E coli, Klebsiella pneumoniae, non-typhoidal Salmonella, Shigella spp, and Campylobacter spp. Finally, group D includes pathogens with either no candidates in clinical development or low development feasibility-ie, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Helicobacter pylori, Enterococcus faecium, and Enterobacter spp. Vaccines are already important tools in reducing antimicrobial resistance and future development will provide further opportunities to optimise the use of vaccines against resistance.