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Background: New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial., Methods: This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings., Findings: BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care., Interpretation: This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system., Funding: Médecins Sans Frontières., Competing Interests: Declaration of interests B-TN, CB, EK, PJ, SM, IM, TA, PSA, and NS were employees of Médecins Sans Frontières during the trial. SS, YVL, MPS, MD, and KF received salary funding paid to the London School of Hygiene & Tropical Medicine. MR was a member of the BPAL Community Access Program data monitoring committee and a member of the BEAT Tuberculosis data monitoring committee. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks., Methods: We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda). Participants were randomly assigned 1:2:2:2 (via permuted blocks and stratified by site and HIV status plus CD4 cell count) to the 2011 WHO long regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of an injectable antituberculous drug. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome, reported previously, was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable) at week 76. Here we report efficacy outcomes at week 132, analysed in the modified intention-to-treat (mITT) population. Safety assessments continued to 132 weeks and were in all participants who received at least one dose of the study regimen. All comparisons used concurrently randomised participants. This trial is registered on ISRCTN (ISRCTN18148631) and is now completed., Findings: Between March 28, 2016, and Jan 28, 2020, 588 participants were randomly assigned to the long (n=32), control (n=202), oral (n=211), or 6-month (n=143) treatment regimens; 352 (60%) were male and 236 (40%) were female. Of the 556 participants on the three shorter regimens, 517 were included in the mITT population (187 in control group, 196 in oral group, and 134 in 6-month group) and 465 in the per-protocol analyses. Six additional participants had an unfavourable outcome that occurred between week 76 and the end of efficacy follow-up (one in control group, four in oral group, one in 6-month group). In the mITT population, the proportion of patients with an unfavourable outcome at the end of follow-up was 19·6% (95% CI 14·3 to 24·9) in the oral group and 29·3% (23·3 to 36·5) in the control group (-9·7 percentage points difference [95% CI -18·7 to -1·8]; p superiority =0·024). An estimated 9·8% (95% CI 4·6 to 14·9) of participants on the 6-month regimen had an unfavourable outcome, which was significantly lower than for those concurrently on the control regimen (32·5% [23·7 to 40·2]; p superiority <0·0001) or the oral regimen (23·8% [16·9 to 31·1]; p superiority =0·013). Few serious or severe adverse events were reported after week 76, with no indication of a difference between the regimens. At week 132, treatment-emergent hearing loss was recorded in significantly fewer participants on the oral regimen (7/205; 3%) than the control regimen (16/198; 8%; p=0.041); there was no significant difference in severe hearing loss between the oral regimen (6/139; 4%) and the 6-month regimen (5/143; 4%; p=0·72). Death rates were low: 1·01 (95% CI 0·48 to 2·12) per 100 person-years in participants allocated to bedaquiline (ie, oral and 6-month regimen, n=287) compared with 1·52 (0·63 to 3·66) in participants on the control regimen (n=140; p=0·49)., Interpretation: Both of the bedaquiline-containing regimens maintained superiority to the control regimen, without evidence of increased mortality, providing two additional evidence-based treatment options for patients; previous mortality concerns for bedaquiline were not substantiated., Funding: US Agency for International Development and Janssen Research & Development., Competing Interests: Declaration of interests MR sat on the South African Bedaquiline, Pretomanid and Linezolid Clinical Access Program data monitoring committee and the BEAT Tuberculosis Trial data monitoring committee. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT02589782., Competing Interests: The authors declare no conflict of interest.

Background: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed., Methods: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points., Results: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%)., Conclusions: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.)., (Copyright © 2022 Massachusetts Medical Society.)

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed. METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa 200 MZ) or 4 months (4Pa 200 MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa 100 MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed. RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa 200 MZ, 4Pa 200 MZ, 4Pa 100 MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa 200 MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died. CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Introduction: Current treatment regimens for multidrug-resistant tuberculosis (MDR-TB) are long, poorly tolerated and have poor outcomes. Furthermore, the costs of treating MDR-TB are much greater than those for treating drug-susceptible TB, both for health service and patient-incurred costs. Urgent action is needed to identify short, effective, tolerable and cheaper treatments for people with both quinolone-susceptible and quinolone-resistant MDR-TB. We present the protocol for an economic evaluation (PRACTECAL-EE substudy) alongside an ongoing clinical trial (TB-PRACTECAL) aiming to assess the costs to patients and providers of new regimens, as well as their cost-effectiveness and impact on participant poverty levels. This substudy is based on data from the three countries participating in the main trial., Methods and Analysis: Primary cost data will be collected from the provider and patient perspectives, following economic best practice. We will estimate the probability that new MDR-TB regimens containing bedaquiline, pretomanid and linezolid are cost-effective from a societal perspective as compared with the standard of care for MDR-TB patients in Uzbekistan, South Africa and Belarus. Analysis uses a Markov model populated with primary cost and outcome data collected at each study site. We will also estimate the impact of new regimens on prevalence of catastrophic patient costs due to TB., Ethics and Dissemination: Ethical approval has been obtained from the London School of Hygiene & Tropical Medicine and Médecins Sans Frontières. Local ethical approval will be sought in each study site. The results of the economic evaluation will be shared with the country health authorities and published in a peer-reviewed journal., Trial Registration Number: ClinicalTrials.gov Registry (NCT04207112); Pre-results., Competing Interests: Competing interests: The chief investigator of the TB-PRACTECAL trial (B-TN) is a full-time employee of Médecins sans Frontières, the funder of the research. GBG is currently employed by Sanofi Pasteur as Regional Lead for vaccine epidemiology and modelling on Europe and does not work in any project related to tuberculosis. GBG’s contribution to this work pertains to activities prior to employment at Sanofi Pasteur., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011., Methods: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority., Results: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively., Conclusions: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.)., (Copyright © 2019 Massachusetts Medical Society.)