Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs.

Armine Serobyan, Catherine Hewison, Molly F Franke, Shrivani Padayachee, Zaw Myint, Mohammad Manzur-Ul-Alam, Shahid Mamsa, Olga Leonovich, Gamarly Jacques Leblanc, Andargachew Kumsa, Shirajul Islam, David Holtzman, Lusine Yeghiazaryan, Dmitry Vetushko, Dri Grium Tefera, Muhammad Rafi Siddiqui, Helena Huerga, Epifanio Sánchez, Gocha Salia, Naseem Salahuddin, Makhmujan Rashitov, Elna Osso, Francis Varaine, Michael L Rich, Saman Ahmed, Nara Melikyan, Kwonjune J Seung, Palwasha Y Khan, Nathalie Lachenal, Carole D Mitnick, Mathieu Bastard, Uzma Khan

Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2022;75(8):1307-1314

PMID: 35243494

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Abstract

BACKGROUND

Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.

METHODS

We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.

RESULTS

Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure.

CONCLUSIONS

Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.

Address: Field Epidemiology Department, Epicentre, Paris, France.; Interactive Research and Development (IRD) Global, Singapore, Singapore.; Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Partners In Health, Boston, Massachusetts, USA.; Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Pharmacovigilance Unit, Médecins Sans Frontières, Geneva, Switzerland.; Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.; Interactive Research and Development (IRD), Karachi, Pakistan.; Medical Department, Médecins Sans Frontières, Paris, France.; Partners In Health, Almaty, Kazakhstan.; Indus Hospital and Health Network (IHHN), Karachi, Pakistan.; Medical Department, Médecins Sans Frontières, Tbilisi, Georgia.; Hospital Nacional Sergio Bernales Hospital, Lima, Peru.; Medical Department, Médecins Sans Frontières, Yerevan, Armenia.; Institute of Chest Diseases (ICD) Kotri, Pakistan.; Partners In Health, Sierra Leone.; The Republican Scientific and Practical Centre for Pulmonology and TB, Minsk, Belarus.; National Center for Pulmonology, Yerevan, Armenia.; Partners In Health, Lesotho, Maseru, Lesotho.; Ministry of Health, Ethiopia.; Zanmi Lasante, Cange, Haiti.; Medical Department, Médecins Sans Frontières, Minsk, Belarus.; Interactive Research and Development (IRD), Dhaka, Bangladesh.; National Tuberculosis Program central, Yangon branch, Myanmar.; Interactive Research and Development (IRD), Durban, South Africa.

DOI: 10.1093/cid/ciac176

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MeSH Terms: Antitubercular Agents, Clofazimine, Cohort Studies, Diarylquinolines, Electrolytes, Fluoroquinolones, Humans, Linezolid, Nitroimidazoles, Oxazoles, Prospective Studies, Rifampin, Tuberculosis, Multidrug-Resistant