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One approach to improving tuberculosis therapy is to shorten the duration from 6 months to 4 months. In this trial in over 1900 patients with smear-positive tuberculosis, two 4-month moxifloxacin-based regimens did not perform as well as the standard 6-month regimen. A short-term tuberculosis treatment regimen could improve rates of adherence, reduce rates of adverse events, and lower costs. Fluoroquinolones have shown promising activity against mycobacteria 1 and are established as a critical component of the treatment of multidrug-resistant tuberculosis, 2 , 3 with later fluoroquinolones recognized as having a more potent effect. It has been proposed that these drugs may have a role in reducing the duration of tuberculosis treatment. 4 Moxifloxacin has been approved for a range of indications globally. 5 It has favorable pharmacokinetics, a large volume of distribution, and penetration into epithelial-lining fluid and macrophages. 6 – 8 The activity of moxifloxacin in vitro . . .

Globally, there are more than 500,000 new infections with drug-resistant tuberculosis each year. In this trial involving patients with rifampin-resistant tuberculosis, a shorter, more intense course of treatment (9 to 11 months) was found to be noninferior to a standard 20-month regimen.

A previous study demonstrated noninferior efficacy of 4-month rifapentine/moxifloxacin regimen for tuberculosis (TB) treatment compared with the standard regimen. We explored results among study participants with diabetes. Among 2,516 randomized participants, 181 (7.2%) had diabetes. Of 166 participants with diabetes in the microbiologically eligible analysis group, 26.3% (15/57) had unfavorable outcomes in the control regimen, 13.8% (8/58) in the rifapentine/moxifloxacin regimen, and 29.4% (15/51) in the rifapentine regimen. The difference in proportion of unfavorable outcomes between the control and rifapentine/moxifloxacin arms in the microbiologically eligible analysis group was -12.5% (95% CI -27.0% to 1.9%); the difference between the control and rifapentine arms was 3.1% (95% CI -13.8% to 20.0%). Safety outcomes were similar in the rifapentine/moxifloxacin regimen and control arms. Among participants with TB and diabetes, the rifapentine/moxifloxacin arm had fewest unfavorable outcomes and was safe. Our findings indicate that the rifapentine/moxifloxacin regimen can be used in persons with TB and diabetes.

Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

To the Editor: Dorman et al. (May 6 issue) 1 found that a 4-month rifapentine-based, moxifloxacin-containing regimen was noninferior to the standard 6-month course of treatment for tuberculosis, but little attention is paid to the per-protocol 95% analysis (which excluded participants who did not complete 95% of the treatment doses). In that analysis, the 4-month regimen was associated with a higher percentage of participants having treatment failure (5.8%) than the standard regimen (2.7%). The per-protocol analyses remove the statistical noise that may be associated with poor adherence, revealing the difference between the treatments. 2 Shared decision making 3 on the basis of the . . .

Furthermore, knowledge about the epidemic itself continues to evolve with a recognition of the growing importance of the transmission of DR-TB [18,19] and increasing levels of second-line drug resistance [20]. [...]in 2017, among the 10.0 million people developing TB disease, 558,000 (5.6%) developed a form that was resistant to at least rifampicin, the most effective first-line drug, and 230,000 died of it. Key dates are also included from the case study of the STREAM trial, a trial comparing a 9- to 11-month regimen containing high-dose moxifloxacin and clofazimine with the 20- to 24-month WHO-recommended standard of care regimen for MDR-TB, which is discussed further in Box 1. https://doi.org/10.1371/journal.pmed.1002767.t001 Given the unavoidably protracted duration of phase III TB trials in the 21st century, the status of TB as a global health priority (the first ever United Nations [UN] General Assembly high-level meeting on TB was held in September, 2018), and the increasing trial costs relative to a huge shortfall in research and development funding [21], those who conduct clinical trials are obligated to design them in such a way that they will have a direct impact on policy and practice of TB treatment at the projected time of trial completion. Conclusions Just over 10 years ago, calls to action were published for innovations in drug development, capacity building for TB trials, and execution of clinical trials of treatment for DR-TB [72–74]. Since November, 2007, 538 TB clinical trials have been posted on clinicaltrials.gov; 27 (5%) of these have been for DR-TB. [...]we strongly believe that TB treatment trials today should favor innovative approaches that are able to produce high-quality evidence for high-quality, patient-centered care that can be made accessible to all 10 million new TB patients, including the half-million with DR-TB, each year.

Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens.

[phrase omitted] [phrase omitted] Metodos Se compararon los costos para los sistemas sanitarios y los participantes de los planes de tratamiento a largo (20 a 22 meses) y a corto plazo (9 a 11 meses) de la tuberculosis en Etiopia y Sudafrica. Se recopilaron datos sobre los costos de los participantes en el ensayo

Abstract Background Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high-TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AEs) could differ in routine settings. Real-world data on AE type, frequency, and timing are crucial for health systems considering 3HP programmatic scale-up. Methods We reviewed AEs among people with human immunodeficiency virus (HIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including laboratory tests, diagnoses made, medications prescribed, and treatment interruptions. Results Among 1655 people with HIV treated between July 2020 and September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE. Conclusions In a routine setting, 3HP was safe, with 16% of people with HIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention. Clinical Trials Registration. NCT03934931. Weekly isoniazid and rifapentine is being rolled out for tuberculosis prevention in high-burden countries. We describe the incidence and clinical management of adverse events in a real-world clinical setting among people with HIV participating in a pragmatic implementation study in Uganda.

To the Editor: Gillespie et al. (Oct. 23 issue) 1 report that two moxifloxacin-containing regimens for the treatment of tuberculosis were not effective with a shortened treatment period of 4 months. The authors used a moxifloxacin dose of 400 mg per day, which may have contributed to the unfavorable results. Rifampin decreases the average exposure to moxifloxacin (assessed according to the area under the curve [AUC]) by approximately 30%, 2 which can be compensated for by an increase in the dose of moxifloxacin. 3 In addition, preclinical data combined with pharmacokinetic and pharmacodynamic modeling showed that a higher moxifloxacin dose, of 800 mg . . .