Обратная связьEffective treatment of TB, including its drug-resistant forms, relies on the use of several medicines administered in combination for an adequate duration. Significant progress has been made in recent years in identifying more efficacious, safer medicines and shorter treatment regimens. Since the 1990s, WHO has regularly evaluated evidence on the use of specific drug compositions and combinations of regimens of different durations (2, 9–16). Historically, patients with certain drugresistance patterns were often treated for 20 months or longer. In 2016, a standardized shorter treatment regimen (9–12 months) was recommended for patients with MDR/RR-TB strains not resistant to fluoroquinolones or second-line injectable agents, although longer regimens (18–20 months) continued to be an option for patients who were not eligible for the shorter option. Subsequent modifications to these treatment regimens led WHO to assess new evidence, which in turn resulted in revised recommendations, balancing the effectiveness and harms of new regimens or modifications of recommended regimens.
Interest in reducing the duration of treatment for MDR/RR-TB has driven several initiatives in recent years to treat patients with shorter regimens under programmatic and trial conditions (17–22). When used in carefully selected patients with MDR/RR-TB who have not been previously exposed or do not have additional resistance to second-line medicines, these regimens can achieve relapse-free cure in about 80% of cases or more, even under programmatic conditions (17, 21). In 2016, on the basis of data from observational studies of the standardized shorter regimens in various countries in Africa and Asia, WHO for the first time recommended a standardized 9–12-month shorter MDR-TB regimen for eligible patients (16). In 2018, following the results of a trial – the Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients with MDR-TB (STREAM) Stage 1 trial – a revised recommendation on the use of a shorter MDR-TB regimen was released, following an evidence assessment and a ranking of benefits and harms attributed to specific drugs; the revision included a recommendation to replace the injectable agent, kanamycin (or capreomycin), with amikacin (2).
Evidence of permanent effects attributed to the toxicity of injectable agents have prompted further advances in the development of new treatments such as shorter injectable-sparing regimens. Bedaquiline was the first new medicine to be added to the group of available second-line TB medicines. In 2013, WHO issued interim guidance for using bedaquiline with other WHO-recommended MDR-TB treatments. Bedaquiline gradually became a staple drug in the treatment of DR-TB, initially featuring as an add-on agent in the longer regimens for MDR/RR-TB and then becoming a Group A medicine along with Fluoroquinolones and Linezolid. In 2019, South Africa’s Department of Health shared with WHO observational data on an all-oral bedaquiline-containing shorter regimen of 9 months duration. That regimen was reviewed and has been recommended by WHO since 2019, with the following combination of medicines: bedaquiline (used for 6 months), in combination with levofloxacin/ moxifloxacin, ethionamide, ethambutol, isoniazid (high-dose), pyrazinamide and clofazimine for 4 months (with the possibility of extending to 6 months if the patient remains sputum smear positive at the end of 4 months); followed by 5 months of treatment with levofloxacin/moxifloxacin, clofazimine, ethambutol and pyrazinamide (4–6 Bdq[6]-Lfx[Mfx]-Eto-E-Z-Hh-Cfz / 5 Lfx[Mfx]-Cfz-Z-E).
The pressing need for more effective treatment regimens for patients with extensive drug resistance, including fluoroquinolone resistance and more extensive drug-resistance profiles, has been the driver for several studies and initiatives to test more effective and novel treatment regimens, including newer and repurposed medicines. One of the first studies was the Nix-TB study, conducted by the TB Alliance. The Nix-TB study was a one-arm, Phase 3, open-label observational cohort study that assessed the safety, efficacy, tolerability and pharmacokinetic properties of a 6-month bedaquiline, pretomanid and linezolid (BPaL) treatment regimen, extendable to 9 months for those who missed doses, or remained culture positive or reverted from culture negative to positive between months 4 and 6 of treatment (23). The study was conducted between 2014 and 2019 at three study sites, all in South Africa, with the first patient enrolled in April 2015. The Nix-TB study contributed evidence to WHO that was reviewed by the GDG in November 2019 and gave rise to the recommendation for the use of the BPaL regimen in pre-XDR-TB patients, under operational research conditions.
In preparation for the 2022 guidelines update, WHO/GTB received data from another trial – the Newer and Emerging Treatment for MDR/RR-TB (NExT) trial – which was a Phase 2–3 open-label RCT evaluating the effectiveness of an all-oral 6–9-month regimen for the treatment of MDR-TB in South Africa (24) in comparison with a local standard of care (SoC) regimen at the time. Sharing of the data by the principal investigator and colleagues at the University of Cape Town and the South African Medical Research Council is gratefully acknowledged. However, during the GDG meeting the panel decided that the data from this study could not be used to complement discussion on the population, intervention, comparator and outcome (PICO) question designed for that study, owing to early termination of the trial and variability of the components in the intervention regimen. This does not undermine the high value of the trial results, which reiterate the inferiority and significantly worse safety profile of the DR-TB regimens based on injectable medicines and fluoroquinolones (but not including new and repurposed drugs). Importantly, the trial showed that better outcomes could be achieved with a 6-month all-oral regimen than with the traditional 9-month or longer injectablebased regimens, supporting the concept of a 6-month all-oral regimen for MDR/RR-TB.
Two randomized controlled trials (RCTs) that concluded in 2021 (TB-PRACTECAL and ZeNix) provided new evidence and prompted assessment by WHO to develop new or updated recommendations for wide programmatic use of the BPaLM/BPaL regimen for treatment of MDR/RR-TB and pre-XDR-TB, and two variations of the 9-month regimen for those without fluoroquinolone resistance. The latest evidence-based guidelines for the treatment of drug-resistant TB, including MDR/RR-TB and preXDR-TB, were published by WHO in December 2022 – “WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment”.
In 2024, two clinical trials, BEAT-TB and endTB, shared new evidence on the use of the novel 6-month regimen and several modified 9-month regimens for the treatment of MDR/RR-TB.