Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report
- Sergey Borisov1,*,
- Edvardas Danila2,
- Andrei Maryandyshev3,
- Margareth Dalcolmo4,
- Skaidrius Miliauskas5,
- Liga Kuksa6,
- Selene Manga7,
- Alena Skrahina8,
- Saulius Diktanas9,
- Luigi Ruffo Codecasa10,
- Alena Aleksa11,
- Judith Bruchfeld12,*,
- Antoniya Koleva13,
- Alberto Piubello14,15,*,
- Zarir Farokh Udwadia16,
- Onno W. Akkerman17,18,*,
- Evgeny Belilovski1,
- Enrique Bernal19,
- Martin J Boeree20,
- Julen Cadiñanos Loidi21,
- Qingshan Cai22,
- Jose Joaquín Cebrian Gallardo23,
- Masoud Dara24,
- Edita Davidavičienė25,
- Lina Davies Forsman12,
- Jorge De Los Rios Jefe26,
- Justin Denholm27,*,
- Jacinta Drakšienė9,
- Raquel Duarte28,
- Seifeldin Eltaeb Elamin29,
- Nadia Escobar Salinas30,
- Maurizio Ferrarese10,
- Aleksey Filippov1,
- Ana Garcia31,
- José-María García-García32,
- Ieva Gaudiesiute5,
- Blagovesta Gavazova33,
- Regina Gayoso4,
- Roscio Gomez Rosso34,
- Vygantas Gruslys1,
- Gina Gualano35,
- Wouter Hoefsloot20,
- Jerker Jonsson36,
- Elena Khimova3,
- Heinke Kunst37,
- Rafael Laniado-Laborín38,*,
- Yang Li39,
- Cecile Magis-Escurra20,
- Vinicio Manfrin40,
- Valentina Marchese41,
- Elena Martínez Robles42,
- Alberto Matteelli41,
- Jesica Mazza-Stalder43,*,
- Charalampos Moschos44,
- Marcela Munoz-Torrico45,*,
- Hamdan Mustafa Hamdan29,
- Birutė Nakčerienė25,
- Lauren Nicod43,
- Magnolia Nieto Marcos46,
- Domingo Juan Palmero31,
- Fabrizio Palmieri35,
- Apostolos Papavasileiou44,
- Marie-Christine Payen47,
- Agostina Pontarelli48,
- Sarai Quirós49,
- Adrian Rendon50,
- Laura Saderi51,*,
- Agnese Šmite6,
- Ivan Solovic52,
- Mahamadou Bassirou Souleymane15,
- Marina Tadolini53,
- Martin van den Boom24,*,
- Marisa Vescovo31,
- Pietro Viggiani48,
- Askar Yedilbayev24,
- Rolandas Zablockis2,
- Dmitry Zhurkin8,
- Matteo Zignol54,
- Dina Visca55,56,*,
- Antonio Spanevello55,56,
- Jose A. Caminero57,58,*,
- Jan-Willem Alffenaar59,60,61,*,
- Simon Tiberi37,65,*,
- Rosella Centis62,*,
- Lia D'Ambrosio63,*,
- Emanuele Pontali64,*,
- Giovanni Sotgiu51,* and
- Giovanni Battista Migliori62,*⇑
- 1Moscow Research and Clinical Center for TB Control, Moscow Government's Health Department, Moscow, Russian Federation
- 2Clinic of Chest Diseases, Immunology and Allergology, Vilnius University Medical Faculty, Centre of Pulmonology and Allergology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- 3Northern State Medical University, Arkhangelsk, Russian Federation
- 4Reference Center Hélio Fraga, Fundação Oswaldo Cruz (Fiocruz)/Ministry of Health, Rio de Janeiro, Brazil
- 5Department of Pulmonology, Lithuanian University of Health Sciences, Kaunas, Lithuania
- 6MDR-TB department, Riga East University Hospital for TB and Lung Disease Centre, Riga, Latvia
- 7Department of Infectious Diseases, University National San Antonio Abad Cusco, Cusco, Peru
- 8Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus
- 9Tuberculosis Department, 3rd Tuberculosis Unit, Republican Klaipėda Hospital, Klaipėda, Lithuania
- 10TB Reference Centre, Villa Marelli Institute, Niguarda Hospital, Milan, Italy
- 11Department of Phthisiology and Pulmonology, Grodno State Medical University, Grodno, Belarus
- 12Division of Infectious Diseases, Department of Medicine, Solna, Karolinska Institute; Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- 13Pulmonology and Physiotherapy Department, Gabrovo Lung Diseases Hospital, Gabrovo, Bulgaria
- 14Tuberculosis Division, International Union against Tuberculosis and Lung Disease (The Union), Paris, France
- 15Tuberculosis Division, Damien Foundation, Niamey, Niger
- 16Department of Respiratory Medicine, P.D. Hinduja National Hospital and MRC, Mumbai, India
- 17University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands
- 18University of Groningen, University Medical Center Groningen, TB Center Beatrixoord, Haren, The Netherlands
- 19Unidad de Enfermedades Infecciosas, Hospital General Universitario Reina Sofia, Murcia, Spain
- 20Radboud University Medical Center, Center Dekkerswald, Nijmegen, The Netherlands
- 21Internal Medicine Department, Hospital General de Villalba, Collado Villalba, Spain
- 22Zhejiang Integrated Traditional and Western Medicine Hospital, Hangzhou, China
- 23Unidad de Neumología. Agencia Sanitaria Costa del Sol, Marbella, Spain
- 24World Health Organization Regional office for Europe, Copenhagen, Denmark
- 25National TB Registry, Public Health Department, Ministry of Health, Vilnius, Lithuania; Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- 26Centro de Excelencia de TBMDR, Hospital Nacional Maria Auxiliadora, Lima, Peru
- 27Victorian Tuberculosis Program, Melbourne Health; Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
- 28National Reference Centre for MDR-TB, Hospital Centre Vila Nova de Gaia, Department of Pneumology, Public Health Science and Medical Education Department, Faculty of Medicine, University of Porto, Porto, Portugal
- 29MDR-TB Department, Abu anga Teaching Hospital, Khartoum, Sudan
- 30Division of Disease Prevention and Control, Department of Communicable Diseases, National Tuberculosis Control and Elimination Programme, Ministry of Health, Santiago, Chile
- 31Pulmonology Division, Municipal Hospital F. J. Muñiz, Buenos Aires, Argentina
- 32Tuberculosis Research Programme, SEPAR, Barcelona, Spain
- 33“Improve the Sustainability of the National TB Programme”, Sofia, Bulgaria
- 34National Institute of Respiratory and Environmental Diseases Prof. Dr. Juan Max Boettner Asunción, Paraguay
- 35Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “L. Spallanzani”, IRCCS, Rome, Italy
- 36Department of Public Health Analysis and Data Management, Public Health Agency of Sweden, Solna, Sweden
- 37Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- 38Universidad Autónoma de Baja California, Baja California, Mexico; Clínica de Tuberculosis del Hospital General de Tijuana, Tijuana, Baja California, Mexico
- 39Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- 40S. Bortolo Hospital, Vicenza, Italy
- 41Clinic of Infectious and Tropical Diseases, WHO Collaborating Centre for TB elimination and TB/HIV co-infection, University of Brescia, Brescia, Italy
- 42Internal Medicine Department, Tuberculosis Hospital de Cantoblanco- Hospital La Paz, Madrid, Spain
- 43Division of Pulmonary Medicine, University Hospital of Lausanne CHUV, Lausanne, Switzerland
- 44Department of Tuberculosis, Sotiria Athens Hospital of Chest Diseases, Athens, Greece
- 45Clínica de Tuberculosis, Instituto Nacional De Enfermedades Respiratorias Ismael Cosio Villegas, Ciudad De Mexico, Mexico
- 46Internal Medicine Department, Hospital Doctor Moliner, Valencia, Spain
- 47Division of Infectious Diseases, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium
- 48Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital, Sondalo, Italy
- 49Pneumology Department, Tuberculosis Unit, Hospital de Cantoblanco- Hospital General Universitario La Paz, Madrid, Spain
- 50Centro de Investigación, Prevención y Tratamiento de Infecciones Respiratorias CIPTIR, University Hospital of Monterrey UANL (Universidad Autonoma de Nuevo Leon), Monterrey, Mexico
- 51Clinical Epidemiology and Medical Statistics Unit, Department of z, University of Sassari, Sassari, Italy
- 52National Institute for TB, Lung Diseases and Thoracic Surgery, Vysne Hagy, Catholic University Ruzomberok, Slovakia
- 53Unit of Infectious Diseases, Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna, Bologna, Italy
- 54Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland
- 55Division of Pulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS, Tradate, Italy
- 56Department of Medicine and Surgery, Respiratory Diseases, University of Insubria, Tradate, Varese-Como, Italy
- 57Pneumology Department, Hospital General de Gran Canaria “Dr. Negrin”, Las Palmas de Gran Canaria, Spain
- 58MDR-TB Unit. Tuberculosis Division. International Union against Tuberculosis and Lung Disease (The Union), Paris, France
- 59University of Sydney, Faculty of Medicine and Health, School of Pharmacy, Sydney, Australia
- 60Westmead Hospital, Sydney, Australia
- 61University of Groningen, University Medical Center Groningen, Department of Pharmacy and Pharmacology, Groningen, The Netherlands
- 62Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy
- 63Public Health Consulting Group, Lugano, Switzerland
- 64Department of Infectious Diseases, Galliera Hospital, Genova, Italy
- 65Department of Infection, Royal London and Newham Hospitals, Barts Health NHS Trust, London, United Kingdom
- Giovanni Battista Migliori, Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Via Roncaccio 16, Tradate, Varese, 21049, Italy. E-mail: giovannibattista.migliori{at}icsmaugeri.it
* Equally contributed
Abstract
WHO (World Health Organization) recommends countries to implement pharmacovigilance and to collect information on aDSM (active drug safety monitoring and management of adverse events-AEs).
Aim of this prospective study was to evaluate the frequency and severity of AEs to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e.. clofazimine, linezolid) drugs, based on the WHO aDSM project.
AEs were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.
Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% males, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall 504 AE episodes were reported: 447 (447/504, 88.7%) were classified as minor (grade 1–2) and 57 (57/504, 11.3%) as serious (grade 3–5).
The majority of the 57 serious AEs reported by 55 patients (51/57; 89.5%) ultimately resolved. Among patients reporting serious AEs some drugs held responsible were discontinued: bedaquiline in 0.35% (2/577), delamanid in 0.8% (1/121), linezolid in 1.9% (10/536) and clofazimine in 1.4% (3/213) of patients.
Serious AEs were reported in 6.9% (9/131) of patients treated with amikacin, 0.4% (1/221) with ethionamide/prothionamide, 2.8% (15/536) with linezolid and 1.8% (8/498) with cycloserine/terizidone.
The aDSM study provided valuable information but implementation needs scaling-up to support patient-centred care.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Maryandyshev has nothing to disclose.
Conflict of interest: Dr. Miliauskas has nothing to disclose.
Conflict of interest: Dr. Kuksa reports personal fees from Tibotec, personal fees from Otsuka , during the conduct of the study; personal fees from Johnson & Johnson Services Inc., outside the submitted work.
Conflict of interest: Dr. Manga has nothing to disclose.
Conflict of interest: Dr. Skrahina has nothing to disclose.
Conflict of interest: Dr. Aleksa has nothing to disclose.
Conflict of interest: Dr. Bruchfeld has nothing to disclose.
Conflict of interest: Dr. Koleva has nothing to disclose.
Conflict of interest: Dr. Piubello has nothing to disclose.
Conflict of interest: Dr. Udwadia has nothing to disclose.
Conflict of interest: Dr. Akkerman has nothing to disclose.
Conflict of interest: Dr. Bernal has nothing to disclose.
Conflict of interest: Dr. Boeree has nothing to disclose.
Conflict of interest: Dr. Cadiñanos Loidi has nothing to disclose.
Conflict of interest: Dr. Cai has nothing to disclose.
Conflict of interest: Dr. García-García has nothing to disclose.
Conflict of interest: Dr. Davidavičienė has nothing to disclose.
Conflict of interest: Dr. Denholm has nothing to disclose.
Conflict of interest: Dr. Drakšienė has nothing to disclose.
Conflict of interest: Dr. Duarte has nothing to disclose.
Conflict of interest: Dr. Elamin has nothing to disclose.
Conflict of interest: Dr. Ferrarese has nothing to disclose.
Conflict of interest: Dr. Filippov has nothing to disclose.
Conflict of interest: Dr. Garcia has nothing to disclose.
Conflict of interest: Dr. García-García has nothing to disclose.
Conflict of interest: Dr. Gaudiesiute has nothing to disclose.
Conflict of interest: Dr. Gavazova has nothing to disclose.
Conflict of interest: Dr. Gayoso has nothing to disclose.
Conflict of interest: Dr. Gruslys has nothing to disclose.
Conflict of interest: Dr. Gualano has nothing to disclose.
Conflict of interest: Dr. Hoefsloot has nothing to disclose.
Conflict of interest: Dr. Jonsson has nothing to disclose.
Conflict of interest: Dr. Khimova has nothing to disclose.
Conflict of interest: Dr. Kunst has nothing to disclose.
Conflict of interest: Dr. Laniado- Laborín has nothing to disclose.
Conflict of interest: Dr. Li has nothing to disclose.
Conflict of interest: Dr. Magis-Escurra has nothing to disclose.
Conflict of interest: Dr. Marchese has nothing to disclose.
Conflict of interest: Dr. Martínez Robles has nothing to disclose.
Conflict of interest: Dr. Matteelli has nothing to disclose.
Conflict of interest: Dr. Mazza-Stalder has nothing to disclose.
Conflict of interest: Dr. Moschos has nothing to disclose.
Conflict of interest: Dr. MUÑOZ-TORRICO has nothing to disclose.
Conflict of interest: Dr. Nakčerienė has nothing to disclose.
Conflict of interest: Dr. Nicod has nothing to disclose.
Conflict of interest: Dr. Nieto Marcos has nothing to disclose.
Conflict of interest: Dr. Palmero has nothing to disclose.
Conflict of interest: Dr. Palmieri has nothing to disclose.
Conflict of interest: Dr. Papavasileiou has nothing to disclose.
Conflict of interest: Dr. Payen has nothing to disclose.
Conflict of interest: Dr. PONTARELLI has nothing to disclose.
Conflict of interest: Dr. Rendon has nothing to disclose.
Conflict of interest: Dr. Solovic has nothing to disclose.
Conflict of interest: Dr. Souleymane has nothing to disclose.
Conflict of interest: Dr. Tadolini has nothing to disclose.
Conflict of interest: Dr. Vescovo has nothing to disclose.
Conflict of interest: Dr. Viggiani has nothing to disclose.
Conflict of interest: Dr. Yedilbayev has nothing to disclose.
Conflict of interest: Dr. Zablockis has nothing to disclose.
Conflict of interest: Dr. Zignol has nothing to disclose.
Conflict of interest: Dr. Visca has nothing to disclose.
Conflict of interest: Dr. Spanevello has nothing to disclose.
Conflict of interest: Dr. Tiberi has nothing to disclose.
Conflict of interest: Dr. Pontali has nothing to disclose.
Conflict of interest: Dr. Migliori has nothing to disclose.
Conflict of interest: Dr. Alffenaar has nothing to disclose.
Conflict of interest: Dr. Belilovski has nothing to disclose.
Conflict of interest: Dr. Borisov has nothing to disclose.
Conflict of interest: Dr. Caminero has nothing to disclose.
Conflict of interest: Dr. D'Ambrosio has nothing to disclose.
Conflict of interest: Dr. Danila has nothing to disclose.
Conflict of interest: Dr. Diktanas reports personal fees from Otsuka, grants from Janssen (Sirturo), outside the submitted work.
Conflict of interest: Dr. Escobar Salinas has nothing to disclose.
Conflict of interest: Dr. Vinicio has nothing to disclose.
Conflict of interest: Dr. Mustafa Hamdan has nothing to disclose.
Conflict of interest: Dr. Smite has nothing to disclose.
Conflict of interest: Dr. van den Boom has nothing to disclose.
Conflict of interest: Dr. Quiros has nothing to disclose.
Conflict of interest: Dr. Centis has nothing to disclose.
Conflict of interest: Dr. Codecasa has nothing to disclose.
Conflict of interest: Dr. Dalcolmo has nothing to disclose.
Conflict of interest: Dr. Dara has nothing to disclose.
Conflict of interest: Dr. Davies Forsman has nothing to disclose.
Conflict of interest: Dr. Gomez Rosso has nothing to disclose.
Conflict of interest: Dr. Saderi has nothing to disclose.
Conflict of interest: Dr. Zhurkin has nothing to disclose.
Conflict of interest: Dr. Cebrian Gallardo has nothing to disclose.
Conflict of interest: Dr. De Los Rios Jefe has nothing to disclose.
Conflict of interest: Dr. Sotgiu has nothing to disclose.
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