Treatment for MDR-/RR-TB, pre-XDR-TB and XDR-TB For the past decades, treatment against DR-TB was recommended for a duration of at least 18 months with a combination of at least four active compounds [3, 68], was associated with a high rate of adverse drug events [69] and high costs [60], and resulted in not more than 60% treatment success overall [1]. The outcome of the Nix-TB trial changed the prospect for the treatment of patients with DR-TB substantially in 2020. The Nix-TB trial was an open-label, single-group phase 3 study in which the safety and efficacy of an all-orally available drug regimen with three compounds: bedaquiline at a dose of 400 mg once daily for 2 weeks followed by 200 mg three times a week for 24 weeks pretomanid at a dose of 200 mg daily for 26 weeks and linezolid at a dose of 1200 mg daily for up to 26 weeks (BPaL), was evaluated [70]. Patients with XDR-TB or those who failed MDR-TB regimens were included. At the end of 6 months of treatment 98 patients (90% 95% CI 83–95%) had a favourable outcome. However, 81% of patients developed peripheral neuropathy and 48% developed anaemia and/or thrombocytopenia, adverse events that were attributed to the high dose of linezolid. Subsequently, results from two phase 2–3 trials have been published aiming to confirm the efficacy of the BPaL regimen and to find the optimal dosage of linezolid with the best efficacy/ toxicity balance [71, 72]. In the ZeNiX-TB trial, published 2022 [71], patients with MDR/ RR-TB were randomly assigned to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. There was no internal control arm. Among 181 participants who received BPaL with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favourable outcome. Peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively and myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively. Although the trial was not powered to draw conclusions on the comparison between arms, the overall risk–benefit ratio seemed to favour the group that received BPaL with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. The TB PRACTECAL trial, also published in 2022 [72], was a multicentre, randomised, controlled, non-inferiority multi-arm multi-stage trial evaluating the efficacy and safety of three 24-week, BpaL-based treatment regiment with linezolid at a daily dosage of 600 mg for 16 weeks, followed by linezolid at 300 mg for 8 weeks. In the second stage of the trial, a 24-week regimen with BPaL plus moxifloxacin (BPaLM) was compared to a 9–20-month standard-of-care arm. 89% of the patients in the BPaLM arm and 52% of patients in the standard-of-care arm experience treatment success. The incidence of adverse events of grade 3 or higher or serious adverse events was significantly higher in the standard-of-care arm (59% versus 19%) than in the BPaLM arm. In 2022, the WHO summoned a guideline development group of international experts to independently review data from the ZeNix-TB and TB PRACTECAL trials. As a result of this process, the WHO issued a rapid communication in May 2022 with key changes for the treatment of DR-TB [6]. These recommendations were further consolidated in official WHO guidelines on DR-TB in December 2022 [46], recommending the BPaLM regiment as the preferred regimen for patients with MDR/RR-TB. This is a revolution for the management of DR-TB [73, 74]. https://doi.org/10.1183/2312508X.10024622 127 TREATMENT OF DS-TB AND DR-TB |C. LANGE ET AL.