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  • Perspective
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Strategies for shortening tuberculosis therapy

Nature Medicine volume 31, pages 1765–1775 (2025)Cite this article

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Abstract

In the absence of effective patient-stratification approaches, tuberculosis (TB) treatment relies on overtreating most patients to ensure high cure rates. Shortening treatment duration without compromising efficacy is therefore high on the agenda of the global TB community. While new and better drugs are certainly needed, we argue that innovative but rational treatment strategies, using both new and existing therapies, will help achieve this goal. There is growing recognition that patient stratification, based on host and pathogen factors, is key to delivering the right drug regimen for the right duration. In this Perspective, we review the current knowledge on the heterogeneity of TB disease and propose approaches to optimize treatment duration in distinct patient groups, taking into consideration the realities of TB control globally. We emphasize key insights that improve the understanding of bacterial vulnerabilities in patients with easy-to-treat and hard-to-treat TB, helping to reduce diagnostic uncertainties. We explore how the TB research community can integrate disease biology, pathology and symptoms, to rethink therapeutic strategies and reduce TB treatment duration.

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Fig. 1: Microbiological relapse rates as a function of treatment duration.
Fig. 2: Immunopathological features of typical ETT and HTT TB.
Fig. 3: Patient-stratification approach.

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References

  1. Esmail, H., Macpherson, L., Coussens, A. K. & Houben, R. Mind the gap - managing tuberculosis across the disease spectrum. EBioMedicine 78, 103928 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Imperial, M. Z. et al. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat. Med. 24, 1708–1715 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. World Health Organization. Target regimen profile for tuberculosis treatment. https://www.who.int/publications/i/item/9789240081512 (Geneva, 2023).

  4. Aldridge, B. B. et al. The Tuberculosis Drug Accelerator at year 10: what have we learned? Nat. Med. https://doi.org/10.1038/s41591-021-01442-2 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Berger, C. A. et al. Variation in tuberculosis treatment outcomes and treatment supervision practices in Uganda. J. Clin. Tuberc. Other Mycobact. Dis. 21, 100184 (2020).

    PubMed  PubMed Central  Google Scholar 

  6. World Health Organization. Global Tuberculosis Report 2023. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023 (Geneva, 2023).

  7. Kendall, E. A., Shrestha, S. & Dowdy, D. W. The epidemiological importance of subclinical tuberculosis. A critical reappraisal. Am. J. Respir. Crit. Care Med. 203, 168–174 (2021).

    PubMed  PubMed Central  Google Scholar 

  8. Barry, C. E. 3rd et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat. Rev. Microbiol. 7, 845–855 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Drain, P. K. et al. Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection. Clin. Microbiol. Rev. https://doi.org/10.1128/CMR.00021-18 (2018).

  10. Emery, J. C. et al. Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease. Proc. Biol. Sci. 288, 20201635 (2021).

    PubMed  PubMed Central  Google Scholar 

  11. Zaidi, S. M. A. et al. Beyond latent and active tuberculosis: a scoping review of conceptual frameworks. EClinicalMedicine 66, 102332 (2023).

    PubMed  PubMed Central  Google Scholar 

  12. Richards, A. S. et al. Quantifying progression and regression across the spectrum of pulmonary tuberculosis: a data synthesis study. Lancet Glob. Health 11, e684–e692 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Frascella, B. et al. Subclinical tuberculosis disease-a review and analysis of prevalence surveys to inform definitions, burden, associations, and screening methodology. Clin. Infect. Dis. 73, e830–e841 (2021).

    PubMed  Google Scholar 

  14. Long, R. et al. The association between phylogenetic lineage and the subclinical phenotype of pulmonary tuberculosis: a retrospective 2-cohort study. J. Infect. 88, 123–131 (2024).

    CAS  PubMed  Google Scholar 

  15. Reed, M. B. et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431, 84–87 (2004).

    CAS  PubMed  Google Scholar 

  16. Stanley, S. et al. Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains. Lancet Microbe https://doi.org/10.1016/S2666-5247(24)00022-3 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gagneux, S. Host–pathogen coevolution in human tuberculosis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 850–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Stucki, D. et al. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages. Nat. Genet. 48, 1535–1543 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Malherbe, S. T. et al. PET/CT guided tuberculosis treatment shortening: a randomized trial. Preprint at medRxiv https://doi.org/10.1101/2024.10.03.24314723 (2024).

  20. Zhao, L., Gao, F., Zheng, C. & Sun, X. The impact of optimal glycemic control on tuberculosis treatment outcomes in patients with diabetes mellitus: systematic review and meta-analysis. JMIR Public Health Surveill. 10, e53948 (2024).

    PubMed  PubMed Central  Google Scholar 

  21. Seddon, J. A., Chiang, S. S., Esmail, H. & Coussens, A. K. The wonder years: what can primary school children teach us about immunity to Mycobacterium tuberculosis? Front. Immunol. 9, 2946 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. World Health Organization. WHO consolidated guidelines on tuberculosis, module 4: treatment, drug-susceptible tuberculosis treatment. https://www.who.int/publications/i/item/9789240048126 (Geneva, 2022).

  23. Jain, S. K. et al. Tuberculous meningitis: a roadmap for advancing basic and translational research. Nat. Immunol. 19, 521–525 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wasserman, S. & Harrison, T. S. Tuberculous meningitis - new approaches needed. N. Engl. J. Med. 389, 1425–1426 (2023).

    PubMed  Google Scholar 

  25. Wasserman, S. et al. Advancing the chemotherapy of tuberculous meningitis: a consensus view. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(24)00512-7 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chabala, C. et al. Clinical outcomes in children living with HIV treated for non-severe tuberculosis in the SHINE Trial. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciae193 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Morey, S. S. ATS adopts diagnostic standards for tuberculosis. Am. Fam. Physician 63, 979–980 (2001).

    Google Scholar 

  28. Coussens, A. K. et al. Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise. Lancet Respir. Med. 12, 484–498 (2024).

    PubMed  PubMed Central  Google Scholar 

  29. Sossen, B. et al. The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis. Lancet Respir. Med. 11, 367–379 (2023).

    PubMed  Google Scholar 

  30. Lau, A. et al. The radiographic and mycobacteriologic correlates of subclinical pulmonary TB in canada: a retrospective cohort study. Chest 162, 309–320 (2022).

    PubMed  Google Scholar 

  31. Esmail, H. et al. High resolution imaging and five-year tuberculosis contact outcomes. Preprint at medRxiv https://doi.org/10.1101/2023.07.03.23292111 (2023).

  32. Nathavitharana, R. R., Garcia-Basteiro, A. L., Ruhwald, M., Cobelens, F. & Theron, G. Reimagining the status quo: how close are we to rapid sputum-free tuberculosis diagnostics for all? EBioMedicine 78, 103939 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ryckman, T. S., Dowdy, D. W. & Kendall, E. A. Infectious and clinical tuberculosis trajectories: Bayesian modeling with case finding implications. Proc. Natl Acad. Sci. USA 119, e2211045119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Patterson, B. et al. Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status. Proc. Natl Acad. Sci. USA 121, e2314813121 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Nahid, P. et al. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin. Infect. Dis. 63, 853–867 (2016).

    PubMed  PubMed Central  Google Scholar 

  36. Dorman, S. E. et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N. Engl. J. Med. 384, 1705–1718 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Fox, W., Ellard, G. A. & Mitchison, D. A. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int. J. Tuberc. Lung Dis. 3, 231–279 (1999).

    Google Scholar 

  38. Merle, C. S. et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N. Engl. J. Med. 372, 1677 (2015).

  39. Gillespie, S. H. et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N. Engl. J. Med. 371, 1577–1587 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. Jindani, A. et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N. Engl. J. Med. 371, 1599–1608 (2014).

    PubMed  PubMed Central  Google Scholar 

  41. Gopalan, N. et al. Predictors of unfavorable responses to therapy in rifampicin-sensitive pulmonary tuberculosis using an integrated approach of radiological presentation and sputum mycobacterial burden. PLoS ONE 16, e0257647 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Romanowski, K. et al. Predicting tuberculosis relapse in patients treated with the standard 6-month regimen: an individual patient data meta-analysis. Thorax 74, 291–297 (2019).

    PubMed  Google Scholar 

  43. Campbell, J. R. et al. Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis. Thorax 79, 169–178 (2024).

    PubMed  Google Scholar 

  44. Chang, K. C., Leung, C. C., Yew, W. W., Ho, S. C. & Tam, C. M. A nested case-control study on treatment-related risk factors for early relapse of tuberculosis. Am. J. Respir. Crit. Care Med 170, 1124–1130 (2004).

    PubMed  Google Scholar 

  45. Canetti, G. The Tubercle Bacillus (Springer, 1955).

  46. Koch, R. Die aetiologie der tuberculose. Berliner Klinische Wochenschrift Vol. 19, No. 15, 221–230 (1882).

  47. Loring, W. W., Melvin, I., Vandiviere, H. M. & Willis, H. S. The death and resurrection of the tubercle bacillus. Trans. Am. Clin. Climatol. Assoc. 67, 132–138 (1955).

    PubMed  Google Scholar 

  48. Mishra, S. & Saito, K. Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: a review. Front. Cell Infect. Microbiol. 12, 1029111 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Wells, G. et al. Micro-computed tomography analysis of the human tuberculous lung reveals remarkable heterogeneity in 3D granuloma morphology. Am. J. Respir. Crit. Care Med. 204, 583–595 (2021).

  50. Chen, R. Y. et al. Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis. Lancet Microbe https://doi.org/10.1016/S2666-5247(21)00058-6 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Prosser, G. et al. The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition. Microbes Infect. 19, 177–192 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Conradie, F. et al. Treatment of highly drug-resistant pulmonary tuberculosis. N. Engl. J. Med. 382, 893–902 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Goig, G. A. et al. Transmission as a key driver of resistance to the new tuberculosis drugs. N. Engl. J. Med. 392, 97–99 (2025).

    PubMed  PubMed Central  Google Scholar 

  54. Shaw, E. S. et al. Bedaquiline: what might the future hold? Lancet Microbe https://doi.org/10.1016/S2666-5247(24)00149-6 (2024).

  55. Nimmo, C. et al. Evolution of Mycobacterium tuberculosis drug resistance in the genomic era. Front. Cell Infect. Microbiol. 12, 954074 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Perumal, R. et al. Baseline and treatment-emergent bedaquiline resistance in drug-resistant tuberculosis: a systematic review and meta-analysis. Eur. Respir. J. https://doi.org/10.1183/13993003.00639-2023 (2023).

  57. Zhao, B. et al. Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China. Ann. Clin. Microbiol. Antimicrob. 23, 40 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Miotto, P., Cirillo, D. M., Schon, T. & Koser, C. U. The exceptions that prove the rule—a historical view of bedaquiline susceptibility. Genome Med. 16, 39 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Rockwood, N., Abdullahi, L. H., Wilkinson, R. J. & Meintjes, G. Risk factors for acquired rifamycin and isoniazid resistance: a systematic review and meta-analysis. PLoS ONE 10, e0139017 (2015).

    PubMed  PubMed Central  Google Scholar 

  60. Barilar, I. et al. CRyPTIC Consortium. Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach. Nat. Commun. 15, 488 (2024).

    Google Scholar 

  61. Sarathy, J. P. et al. Extreme drug tolerance of Mycobacterium tuberculosis in caseum. Antimicrob. Agents Chemother. 62, e02266–e02317 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Waller, N. J. E., Cheung, C. Y., Cook, G. M. & McNeil, M. B. The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis. Nat. Commun. 14, 1517 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Roemhild, R., Bollenbach, T. & Andersson, D. I. The physiology and genetics of bacterial responses to antibiotic combinations. Nat. Rev. Microbiol. https://doi.org/10.1038/s41579-022-00700-5 (2022).

    Article  PubMed  Google Scholar 

  64. Sullivan, G. J., Delgado, N. N., Maharjan, R. & Cain, A. K. How antibiotics work together: molecular mechanisms behind combination therapy. Curr. Opin. Microbiol. 57, 31–40 (2020).

    CAS  PubMed  Google Scholar 

  65. Wang, Z. et al. Mode-of-action profiling reveals glutamine synthetase as a collateral metabolic vulnerability of M. tuberculosis to bedaquiline. Proc. Natl Acad. Sci. USA 116, 19646–19651 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Poulton, N. C. et al. Beyond antibiotic resistance: the whiB7 transcription factor coordinates an adaptive response to alanine starvation in mycobacteria. Cell Chem. Biol. https://doi.org/10.1101/2023.06.02.543512 (2023).

    Article  Google Scholar 

  67. Morris, R. P. et al. Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 102, 12200–12205 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Schrader, S. M. et al. Multiform antimicrobial resistance from a metabolic mutation. Sci. Adv. 7, eabh2037 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Dheda, K. et al. Multidrug-resistant tuberculosis. Nat. Rev. Dis. Primers 10, 22 (2024).

    PubMed  Google Scholar 

  70. Li, S. et al. CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis. Nat. Microbiol. 7, 766–779 (2022).

    PubMed  PubMed Central  Google Scholar 

  71. Eckartt, K. A. et al. Compensatory evolution in NusG improves fitness of drug-resistant M. tuberculosis. Nature 628, 186–194 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dooley, K. E., Hanna, D., Mave, V., Eisenach, K. & Savic, R. M. Advancing the development of new tuberculosis treatment regimens: the essential role of translational and clinical pharmacology and microbiology. PLoS Med. 16, e1002842 (2019).

    PubMed  PubMed Central  Google Scholar 

  73. Xie, Y. L. et al. Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abd7618 (2021).

  74. Lin, P. L. et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat. Med. 20, 75–79 (2014).

    CAS  PubMed  Google Scholar 

  75. Ernest, J. P. et al. Development of new tuberculosis drugs: translation to regimen composition for drug-sensitive and multidrug-resistant tuberculosis. Annu. Rev. Pharmacol. Toxicol. 61, 495–516 (2021).

    CAS  PubMed  Google Scholar 

  76. Sarathy, J. P. et al. A novel tool to identify bactericidal compounds against vulnerable targets in drug-tolerant M. tuberculosis found in caseum. mBio 14, e0059823 (2023).

    PubMed  Google Scholar 

  77. Lovewell, R. R., Sassetti, C. M. & VanderVen, B. C. Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr. Opin. Microbiol. 29, 30–36 (2016).

    CAS  PubMed  Google Scholar 

  78. Gold, B. & Nathan, C. Targeting phenotypically tolerant Mycobacterium tuberculosis. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.TBTB2-0031-2016 (2017).

  79. Lanni, F. et al. Adaptation to the intracellular environment of primary human macrophages influences drug susceptibility of Mycobacterium tuberculosis. Tuberculosis 139, 102318 (2023).

    CAS  PubMed  Google Scholar 

  80. Liu, Y. et al. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J. Exp. Med. 213, 809–825 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Perumal Kannabiran, B. et al. Safety and efficacy of 25 mg/kg and 35 mg/kg vs 10 mg/kg rifampicin in pulmonary TB: a phase IIb randomized controlled trial. Open Forum Infect. Dis. 11, ofae034 (2024).

    PubMed  PubMed Central  Google Scholar 

  82. Onorato, L. et al. Standard versus high dose of rifampicin in the treatment of pulmonary tuberculosis: a systematic review and meta-analysis. Clin. Microbiol Infect. 27, 830–837 (2021).

    CAS  PubMed  Google Scholar 

  83. Espinosa-Pereiro, J. et al. Safety of rifampicin at high dose for difficult-to-treat tuberculosis: protocol for RIAlta phase 2b/c trial. Pharmaceutics https://doi.org/10.3390/pharmaceutics15010009 (2022).

  84. Diacon, A. H. et al. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob. Agents Chemother. 51, 2994–2996 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Yun, H. Y. et al. Model-based efficacy and toxicity comparisons of moxifloxacin for multidrug-resistant tuberculosis. Open Forum Infect. Dis. 9, ofab660 (2022).

    PubMed  Google Scholar 

  86. Kusmiati, T. et al. Moxifloxacin concentration correlate with QTc interval in rifampicin-resistant tuberculosis patients on shorter treatment regimens. J. Clin. Tuberc. Other Mycobact. Dis. 28, 100320 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chang, A. et al. Circulating cell-free RNA in blood as a host response biomarker for the detection of tuberculosis. Nat. Commun. https://doi.org/10.1038/s41467-024-49245-6 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Zhang, F., Zhang, F., Dong, Y., Li, L. & Pang, Y. New insights into biomarkers for evaluating therapy efficacy in pulmonary tuberculosis: a narrative review. Infect. Dis. Ther. 12, 2665–2689 (2023).

    PubMed  PubMed Central  Google Scholar 

  89. Corrigan, D. T., Ishida, E., Chatterjee, D., Lowary, T. L. & Achkar, J. M. Monoclonal antibodies to lipoarabinomannan/arabinomannan - characteristics and implications for tuberculosis research and diagnostics. Trends Microbiol. 31, 22–35 (2023).

    CAS  PubMed  Google Scholar 

  90. Gong, X., He, Y., Zhou, K., Hua, Y. & Li, Y. Efficacy of Xpert in tuberculosis diagnosis based on various specimens: a systematic review and meta-analysis. Front. Cell Infect. Microbiol. 13, 1149741 (2023).

    PubMed  PubMed Central  Google Scholar 

  91. Tabone, O. et al. Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis. J. Exp. Med. https://doi.org/10.1084/jem.20210915 (2021).

  92. Pierneef, L. et al. Host biomarker-based quantitative rapid tests for detection and treatment monitoring of tuberculosis and COVID-19. iScience 26, 105873 (2023).

    CAS  PubMed  Google Scholar 

  93. Paton, N. I. et al. Treatment strategy for rifampin-susceptible tuberculosis. N. Engl. J. Med. 388, 873–887 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Hermans, S., Horsburgh, C. R. Jr. & Wood, R. A century of tuberculosis epidemiology in the northern and southern hemisphere: the differential impact of control interventions. PLoS ONE 10, e0135179 (2015).

    PubMed  PubMed Central  Google Scholar 

  95. Gillespie, S. H. et al. Developing biomarker assays to accelerate tuberculosis drug development: defining target product profiles. Lancet Microbe https://doi.org/10.1016/S2666-5247(24)00085-5 (2024).

    Article  PubMed  Google Scholar 

  96. Moyo, S. et al. Prevalence of bacteriologically confirmed pulmonary tuberculosis in South Africa, 2017-19: a multistage, cluster-based, cross-sectional survey. Lancet Infect. Dis. 22, 1172–1180 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Johnson, J. L. et al. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am. J. Respir. Crit. Care Med 180, 558–563 (2009).

    PubMed  PubMed Central  Google Scholar 

  98. A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 5 years. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. Am. Rev. Respir. Dis. 139, 871–876 (1989).

  99. Teo, S. K., Tan, K. K. & Khoo, T. K. Four-month chemotherapy in the treatment of smear-negative pulmonary tuberculosis: results at 30 to 60 months. Ann. Acad. Med. Singap. 31, 175–181 (2002).

    CAS  PubMed  Google Scholar 

  100. James, L. P. et al. Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: a mathematical modeling analysis. PLoS Med. 21, e1004401 (2024).

    PubMed  PubMed Central  Google Scholar 

  101. Knight, G. M. et al. The impact and cost-effectiveness of a four-month regimen for first-line treatment of active tuberculosis in South Africa. PLoS ONE 10, e0145796 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. Goh, J. J. N. et al. Prospectively predicting BPaMZ phase IIb/III trial outcomes using a translational mouse-to-human platform. Antimicrob. Agents Chemother. 68, e0061524 (2024).

    PubMed  Google Scholar 

  103. Walter, N. D. et al. Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens. Nat. Commun. 12, 2899 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Zainabadi, K. et al. Transcriptional biomarkers of differentially detectable mycobacterium tuberculosis in patient sputum. mBio 13, e0270122 (2022).

    PubMed  Google Scholar 

  105. Zainabadi, K. et al. Characterization of differentially detectable mycobacterium tuberculosis in the sputum of subjects with drug-sensitive or drug-resistant tuberculosis before and after two months of therapy. Antimicrob. Agents Chemother. 65, e0060821 (2021).

    PubMed  Google Scholar 

  106. Peters, J. S. et al. Differentially culturable tubercle bacteria as a measure of tuberculosis treatment response. Front. Cell Infect. Microbiol. 12, 1064148 (2022).

    PubMed  Google Scholar 

  107. Fox, W. Whither short-course chemotherapy? Br. J. Dis. Chest 75, 331–357 (1981).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to G. Meintjes, M. Hatherill and D. Warner from the University of Cape Town for thoroughly reviewing the manuscript and providing constructive suggestions. We express our gratitude to all members of the TBDA (https://www.tbdrugaccelerator.org/) for their research input, thoughts and fruitful discussions that helped to define the scope and direction of this Perspective, which reflects the views of the TBDA membership. The listed authors are members who directly contributed to the manuscript.

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Authors and Affiliations

  1. Center for Discovery and Innovation, Hackensack Meridian School of Medicine, Nutley, NJ, USA

    Véronique A. Dartois

  2. Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine & Department of Pathology, University of Cape Town, Cape Town, South Africa

    Valerie Mizrahi

  3. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

    Radojka M. Savic

  4. Gates Medical Research Institute, Cambridge, MA, USA

    Jared A. Silverman

  5. Gates Foundation, Seattle, WA, USA

    David Hermann

  6. Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institutes of Health, Bethesda, MD, USA

    Clifton E. Barry III

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  1. Véronique A. Dartois
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Dartois, V.A., Mizrahi, V., Savic, R.M. et al. Strategies for shortening tuberculosis therapy. Nat Med 31, 1765–1775 (2025). https://doi.org/10.1038/s41591-025-03742-3

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