trials aim to optimise the successful TBTC S31/ACTG 5349 regimen [31] by identifying the optimal dosageof rifapentine (ORIENT) or by adding clofazimine (CLO-Fast). Another common design is testing experimental regimens that include new/repurposed drugs in combination with fluoroquinolones and first-line drugs (PRESCIENT, SimpliciTB, TRUNCATE-TB). Finally, one trial adds a fluoroquinolone to the standard regimen (NCT02901288), similarly to previous trials which failed to show non-inferiority [98]. Overall, the duration of the experimental regimens in these trials ranges from 2 to 4 months. The trial design is conventional in most cases, with a few exceptions including Phase 2C (CLO-FAST, PRESCIENT) [99], and multi-arm multi-stage designs (TRUNCATE-TB). Ongoing trials on DR-TB (table 7) enrol all patients with rifampicin-resistance (i.e. A5356) or only those with susceptibility to fluoroquinolones (i.e. endTB). Another approach, exemplified by BEAT TB, is to include all RR-TB patients and adapt the regimen to results of rapid molecular testing for fluoroquinolone resistance. Almost all experimental regimens include a bedaquiline–linezolid backbone, with the possible addition of a nitroimidazole (delamanid or pretomanid), clofazimine, a fluoroquinolone, and/or pyrazinamide. Tested durations range between 4 and 9 months. Novel trial designs are increasingly frequent, including Bayesian adaptive [100, 101] (endTB) and duration-randomised designs (DRAMATIC) [102, 103]. Two trials (GRACE-TB and InDEX) compare individualised treatment guided by next-generation sequencing to a control. Concerningly, clinical research on the most advanced forms of DR-TB is lacking. No more than a couple of trials specifically target pre-XDR-TB, only one including an internal control arm [104]. To date, no trials are ongoing/planned on XDR-TB. Overall, a wealth of clinical trial results will be available in the coming years. Further innovations in trial methodology [105], increased resources [106], and harmonisation of trial conduct, implementation, and assessments [107, 108], will optimise the impact of future clinical research. Conclusion Recent years have seen much-awaited improvements in TB treatment. The historical paradigm of the 6-month “short course” treatment for DS-TB has fallen [31] and treatment duration for RR-TB has been reduced to one-third of the previous time [71, 72, 109]. In addition, recent reports suggest that further treatment shortening may be possible [61]. This news has been welcomed by the scientific community with understandable excitement. However, a few reasons for concern exist. History has shown how quickly new TB drugs can be followed by the emergence of drug resistance [110]. By introducing new regimens with scarce global capacity for DST, past mistakes are being repeated [74]. Furthermore, implementation of conditional recommendations based on very low certainty of evidence, like the recent WHO DR-TB guidelines, should be performed carefully and considering patient choice among treatment options [46]. Finally, access to new drugs and regimens is a global emergency that requires commitment and adequate investments. Future efforts should be directed to protect these recent advances, while striving for further breakthroughs. References 1 World Health Organization. Global tuberculosis report 2022. Geneva, World Health Organization, 2022. 2 Horsburgh CR, Jr, Barry CE 3rd, Lange C. Treatment of tuberculosis. N Engl J Med 2015 373: 2149–2160. 3 World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. 2019. 4 World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care (2017 update). Geneva, World Health Organization, 2017. 134 https://doi.org/10.1183/2312508X.10024622 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY