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Mycobacterium tuberculosis remains the leading cause of death from a single infectious pathogen globally despite decades of effective chemotherapy. In 2024, an estimated 10·7 million people developed tuberculosis, including approximately 620 000 people living with HIV (PLHIV), and tuberculosis caused an estimated 1·23 million deaths overall, including approximately 150 000 deaths among PLHIV. Men accounted for more than half of the cases, and children represented a substantial burden, reflecting ongoing transmission and diagnostic gaps. Approximately a quarter of the world's population has been infected with M tuberculosis, with immunological evidence of previous or current infection. This population includes groups at increased risk of progression to tuberculosis disease, particularly those with recent infection, HIV, undernutrition, young age, or other clinical and social vulnerabilities. Following 3 years of COVID-19-related setbacks, global tuberculosis incidence declined modestly (1%) from 2023 to 2024 but remains higher than in 2020 and far off-track to meet the 2025 WHO End TB Strategy milestones. Case detection improved to 8·3 million notifications (78% of estimated incident cases), supported by expanded molecular diagnostics; however, prevalence surveys continue to reveal substantial proportions of bacteriologically confirmed but asymptomatic tuberculosis, highlighting persistent transmission and missed diagnoses. 30 high-burden countries accounted for 87% of cases, led by India, Indonesia, the Philippines, China, Pakistan, Nigeria, the Democratic Republic of the Congo, and Bangladesh. M tuberculosis-HIV co-infection remains a major driver of mortality in sub-Saharan Africa. Drug-resistant tuberculosis threatens progress: of 390 000 estimated multidrug-resistant or rifampicin-resistant tuberculosis cases in 2024, only 42% initiated treatment, although treatment success improved to 71%. Tuberculosis-preventive treatment reached 5·3 million people, including 58% of PLHIV and 25% of eligible household contacts, well below global targets. Persistent undernutrition, poverty, HIV, diabetes, smoking, alcohol use, air pollution, migration, and conflict continue to shape tuberculosis epidemiology. With financing at only 27% of global targets, accelerated prevention, proactive case finding, social protection, and sustained political commitment are essential to eliminate tuberculosis.
Tuberculosis treatment has undergone its most profound transformation since the launch of the standardised DOTS strategy in 1994. Since 2020, a series of pivotal randomised trials, including TB-PRACTECAL, ZeNix, Nix-TB, endTB, BEAT-TB, SHINE, and Study 31/A5349, have redefined the management of both drug-susceptible and drug-resistant tuberculosis. These studies have enabled shorter, fully oral regimens with improved efficacy and safety across adult and paediatric populations, including people with HIV, and have driven major updates to WHO treatment guidelines. Despite these advances, tuberculosis remains the leading cause of death from a single infectious agent worldwide, with substantial mortality occurring before treatment initiation due to delayed diagnosis and pretreatment loss to follow-up, and additional deaths during treatment related to advanced disease, drug resistance, comorbidities, and challenges with treatment tolerance and adherence. In 2024, an estimated 10·7 million people developed tuberculosis of whom approximately 390 000 developed multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis. Tuberculosis caused an estimated 1·23 million deaths globally, including approximately 150 000 deaths attributable to MDR tuberculosis or RR tuberculosis. Outcomes remain poorest among people with HIV, young children (who rarely access treatment and prevention), migrants, and displaced populations. The tuberculosis drug development pipeline in 2026 is more advanced than at any time since the introduction of rifampicin. Novel and repurposed compounds, including DprE1 inhibitors, next-generation oxazolidinones (including TBAJ-587 and TBAJ-876), cytochrome bc1 inhibitors, and long-acting formulations, are in late-stage evaluation. Host-directed therapies are also advancing as adjunctive strategies to reduce inflammation-mediated tissue damage and long-term morbidity, although they remain investigational. This Series paper synthesises advances in adult and paediatric tuberculosis therapeutics from Nov 15, 2020, to Jan 15, 2026, and highlights priorities to translate therapeutic innovation into equitable population-level effects.
Tuberculosis remains the leading cause of death from a single infectious agent globally. The WHO Global Tuberculosis Report 2025 indicates that progress towards the WHO End TB Strategy targets remains off track despite modest declines in incidence and mortality. In 2024, an estimated 10·7 million people developed tuberculosis and 1·23 million died from the disease. In this Series paper, we examine evidence published between Jan 6, 2020, and Jan 6, 2026, to provide an updated overview of tuberculosis vaccines and tuberculosis preventive treatment (TPT). As of June 4, 2026, 18 tuberculosis vaccine candidates are in active clinical development, including six in phase 3 (M72/AS01E, MTBVAC, VPM1002, GamTBvac, Immuvac [MIP], and BCG revaccination trials), representing the most diverse and advanced pipeline since the introduction of BCG in 1921. Platforms include live-attenuated mycobacterial vaccines (eg, MTBVAC), recombinant BCG-derived approaches (eg, VPM1002), protein-adjuvant subunit vaccines (eg, M72/AS01E), viral-vectored candidates (eg, AdHu5Ag85A, ChAdOx1.85A, and TB/FLU-04L), and inactivated whole-cell strategies (eg, DAR-901, RUTI, and Immuvac [MIP]). However, only a few candidates have progressed to late-stage efficacy evaluation. Short-course rifamycin-containing TPT regimens-1 month of daily isoniazid plus rifapentine, 3 months of once-weekly isoniazid plus rifapentine, 3 months of daily isoniazid plus rifampicin, and 4 months of daily rifampicin-show non-inferior efficacy and higher completion rates than 6-9 months of daily isoniazid monotherapy and are WHO-preferred options for drug-susceptible tuberculosis. In 2024, 5·3 million people at high risk of tuberculosis initiated TPT globally, including 3·5 million household contacts and 1·8 million people with HIV. For contacts of multidrug-resistant or rifampicin-resistant tuberculosis, randomised trials and pooled analyses support 6 months of daily levofloxacin to reduce incident multidrug-resistant tuberculosis. Bedaquiline-containing preventive regimens and shorter fluoroquinolone-based combinations are under clinical evaluation, but definitive phase 3 efficacy data are not yet available. The expansion of the vaccine pipeline alongside improved short-course preventive regimens offers a credible opportunity to accelerate tuberculosis incidence decline, although translation into population-level impact will depend on shown efficacy, sustained financing, reliable drug and vaccine supply, and effective implementation in high-burden settings.
Major advances in tuberculosis diagnostics and biomarker research from 2020 to 2025 have informed updated WHO policy guidance, consolidating recommendations for the detection of tuberculosis disease and drug resistance within a single framework. These recommendations align screening, diagnosis, and drug-resistance testing across populations and specimen types. Digital chest radiography, increasingly supported by computer-aided detection, is now a core WHO-recommended screening and triage tool, improving case detection and referral for confirmatory testing at scale. Decentralised molecular diagnosis has expanded through diversified deployment of WHO-recommended rapid diagnostic test classes, particularly low-complexity automated nucleic acid amplification tests (NAATs), including the Xpert MTB/RIF Ultra and Truenat platforms. These tests are complemented by low-complexity manual NAATs such as tuberculosis loop-mediated isothermal amplification and by emerging near point-of-care molecular platforms under evaluation. Latest WHO policy updates have also introduced a new class of near point-of-care NAATs designed for decentralised use, alongside novel specimen types such as tongue swabs for individuals unable to produce sputum, and programmatic innovations, including sputum pooling, to improve efficiency. Expanded use of molecular diagnostics across non-sputum specimens, including stool, gastric aspirate, and nasopharyngeal samples, together with simplified workflows, has improved bacteriological confirmation in children and other sputum-scarce populations. Rapid molecular drug-resistance testing has advanced with Xpert MTB/XDR, and targeted next-generation sequencing is now recognised as a WHO-endorsed approach for comprehensive drug-susceptibility testing at reference laboratory level. Urine lipoarabinomannan-based assays improve diagnostic yield in people with HIV, particularly those with advanced disease, although performance limitations constrain broader use. Substantial performance, implementation, and equity gaps remain. In parallel, host blood transcriptomic signatures show strong short-term prognostic and triage performance, and additional proteomic, metabolomic, cellular, imaging, and pathogen-derived biomarkers are advancing through clinical evaluation. However, no biomarker has yet met the WHO target product profile criteria for a point-of-care test that reliably distinguishes M tuberculosis infection from tuberculosis disease, including asymptomatic or minimally symptomatic tuberculosis disease, often described in the research literature as subclinical tuberculosis.
Abstract Background Landscape features such as the Rift Valley (RV) can restrict gene flow in malaria vectors and influence resistance patterns. Here, we assessed Plasmodium infection rates, resistance alleles and profiles in Anopheles funestus s.s. populations across Kenyan malaria-endemic regions separated by the RV. Methods Anopheles funestus s.s. populations in western, coastal and Kerio Valley (KV, within the RV) were genotyped for key resistance markers using polymerase chain reaction (PCR). TaqMan assay combined with nested PCR were used to screen the samples for Plasmodium sporozoite infection and association with resistance alleles and genotype frequencies assessed using Fisher’s exact test or Pearson’s chi-square test. Following established WHO guidelines, phenotypic resistance using F1 progeny was also assessed using diagnostic, intensity and piperonyl butoxide (PBO)-synergistic assays. Results The 4.3kb-SV (n = 336) and G454A-Cyp9k1 (n = 445) alleles were nearly fixed in western Kenya but declined towards the RV and coast, whereas L119F-GSTe2 (n = 392) increased across a west-KV-coast gradient with a novel haplotype distinct from known African variants detected at the coast. There were lower odds of Plasmodium infection in mosquitoes with L119F-GSTe2-RR than RS genotype (OR 0.2, P = 0.046). Likewise, mosquitoes harboring the R allele of the 4.3 kb marker had higher Plasmodium infection rates than the S allele (OR 5.7, P = 0.049). An. funestus populations exhibited a high degree of pyrethroid resistance with intensity higher in KV compared to western Kenya, a traditional malaria hotspot. Pre-exposure to PBO increased mortality for type II (deltamethrin, alpha-cypermethrin), than I (permethrin) pyrethroids, yet mortality remained lower in KV, suggesting non-P450-mediated resistance. An. funestus mosquitoes from the coast showed extreme permethrin resistance (< 10% mortality at 10 × dose). Resistance to dichlorodiphenyltrichloroethane was widespread, while all populations remained fully susceptible to bendiocarb, pirimiphos-methyl, clothianidin, and chlorfenapyr. Conclusions Region-specific selection may drive varying resistance profiles in An. funestus across Kenyan malaria-endemic regions separated by the Rift Valley, with implications for malaria transmission and insecticide resistance management.
