Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis

For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant t...

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Published in:	The New England journal of medicine Vol. 392; no. 5; pp. 468 - 482
Main Authors:	Guglielmetti, Lorenzo, Khan, Uzma, Velásquez, Gustavo E., Gouillou, Maelenn, Abubakirov, Amanzhan, Baudin, Elisabeth, Berikova, Elmira, Berry, Catherine, Bonnet, Maryline, Cellamare, Matteo, Chavan, Vijay, Cox, Vivian, Dakenova, Zhanna, de Jong, Bouke Catherine, Ferlazzo, Gabriella, Karabayev, Aydarkhan, Kirakosyan, Ohanna, Kiria, Nana, Kunda, Mikanda, Lachenal, Nathalie, Lecca, Leonid, McIlleron, Helen, Motta, Ilaria, Toscano, Sergio Mucching, Mushtaque, Hebah, Nahid, Payam, Oyewusi, Lawrence, Panda, Samiran, Patil, Sandip, Phillips, Patrick P. J., Ruiz, Jimena, Salahuddin, Naseem, Garavito, Epifanio Sanchez, Seung, Kwonjune J., Ticona, Eduardo, Trippa, Lorenzo, Vasquez, Dante E. Vargas, Wasserman, Sean, Rich, Michael L., Varaine, Francis, Mitnick, Carole D.
Format:	Journal Article
Language:	English
Published:	United States Massachusetts Medical Society 30.01.2025
Subjects:	Administration, Oral Adolescent Adult Aged Antibiotics Antitubercular Agents - pharmacology Antitubercular Agents - therapeutic use Bayes Theorem Bayesian analysis Clinical trials Clofazimine Drug Administration Schedule Drug dosages Drug Resistance, Bacterial Drug Therapy, Combination - adverse effects Drug Therapy, Combination - methods Female Fluoroquinolones - pharmacology Fluoroquinolones - therapeutic use Global Health Humans Infectious Disease Infectious Disease General Intention to Treat Analysis Levofloxacin Linezolid Lung - diagnostic imaging Lung - microbiology Male Middle Aged Moxifloxacin Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - isolation & purification Patients Pharmacovigilance Pyrazinamide Rifampin Rifampin - pharmacology Rifampin - therapeutic use Sputum Sputum - microbiology Time Factors Treatment Outcome Tuberculosis Tuberculosis, Multidrug-Resistant - drug therapy Tuberculosis, Pulmonary - diagnosis Tuberculosis, Pulmonary - drug therapy Tuberculosis, Pulmonary - microbiology Young Adult South Africa
ISSN:	0028-4793, 1533-4406, 1533-4406
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Summary:	For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis. We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points. Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy. Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).
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ISSN:	0028-4793 1533-4406 1533-4406
DOI:	10.1056/NEJMoa2400327