Abstract
The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.
The aim of this prospective study was to evaluate the frequency and severity of adverse events 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. Adverse events 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% male, 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 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.
The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.
Abstract
Previous evidence on adverse events is available from single studies. This global project (658 patients from 26 countries) demonstrates aDSM is feasible and serious adverse events of recommended drugs are reasonably low (overall 57 out of 504, 11.3%). http://bit.ly/2kzvbqe
Footnotes
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Author contributions: The manuscript was conceived, planned, written, edited and approved using a collaborative approach, following the internal GTN (Global Tuberculosis Network) and internationally acknowledged rules on authorship, based on major intellectual contribution to the steps mentioned above. The study represents a global effort involving 26 countries in all continents. G. Sotgiu, S. Tiberi, R. Centis, L. D'Ambrosio and G.B. Migliori wrote the protocol. G. Sotgiu, L. Saderi and R. Duarte revised it for methodological content. G. Sotgiu, L. Saderi, R. Centis and L. D'Ambrosio performed the analysis. S. Tiberi, R. Centis, L. D'Ambrosio, E. Pontali, J-W. Alffenaar, J.A. Caminero, G. Sotgiu and G.B. Migliori wrote the first draft of the manuscript. S. Borisov, J. Bruchfeld, A. Piubello, O.W. Akkermann, J. Denholm, J-M. García-García, R. Laniado-Laborín, J. Mazza-Stalder, A. Matteelli, M. Muñoz-Torrico, M. van den Boom, D. Visca, J.A. Caminero and G. Sotgiu wrote the sections of the manuscript (second draft). A. Spanevello, J-M. García-García, Z.F. Udwadia, E. Danila, A. Maryandyshev and M. Dalcolmo provided comments to the second draft (third draft). A. Maryandyshev, S. Miliauskas, L. Kuksa, S. Manga, A. Skrahina, S. Diktanas, L.R. Codecasa, A. Aleksa, A. Koleva, E. Belilovski, E. Bernal, M.J. Boeree, J. Cadiñanos Loidi, Q. Cai, J.J. Cebrian Gallardo, M. Dara, E. Davidavičienė, L. Davies Forsman, J. De Los Rios, S.E. Elamin, N. Escobar Salinas, M. Ferrarese, A. Filippov, B. Gadzheva, A. Garcia, R. Gayoso, R. Gomez Rosso, V. Gruslys, G. Gualano, W. Hoefsloot, J. Jonsson, E. Khimova, H. Kunst, Y. Li, C. Magis-Escurra, V. Manfrin, V. Marchese, E. Martínez Robles, C. Moschos, H. Mustafa Hamdan, B. Nakčerienė, L. Nicod, M. Nieto Marcos, D.J. Palmero, F. Palmieri, A. Papavasileiou, M-C. Payen, A. Pontarelli, S. Quirós, A. Rendon, L. Saderi, A. Šmite, I. Solovic, M.B. Souleymane, M. Tadolini, M. Vescovo, P. Viggiani, A. Yedilbayev, R. Zablockis, D. Zhurkin and M. Zignol provided additions to the fourth draft. S. Tiberi and J. Denholm proofread the manuscript. All co-authors approved the final manuscript.
Conflict of interest: S. Borisov has nothing to disclose.
Conflict of interest: E. Danila has nothing to disclose.
Conflict of interest: A. Maryandyshev has nothing to disclose.
Conflict of interest: M. Dalcolmo has nothing to disclose.
Conflict of interest: S. Miliauskas has nothing to disclose.
Conflict of interest: L. Kuksa reports personal fees for trial participation from Otsuka and Tibotec, personal fees for lectures from Johnson and Johnson Services Inc., outside the submitted work.
Conflict of interest: S. Manga has nothing to disclose.
Conflict of interest: A. Skrahina has nothing to disclose.
Conflict of interest: S. Diktanas reports personal fees for trial participation from Otsuka, grants for meeting attendance from Janssen (Sirturo), outside the submitted work.
Conflict of interest: L.R. Codecasa has nothing to disclose.
Conflict of interest: A. Aleksa has nothing to disclose.
Conflict of interest: J. Bruchfeld has nothing to disclose.
Conflict of interest: A. Koleva has nothing to disclose.
Conflict of interest: A. Piubello has nothing to disclose.
Conflict of interest: Z.F. Udwadia has nothing to disclose.
Conflict of interest: O.W. Akkerman has nothing to disclose.
Conflict of interest: E. Belilovski has nothing to disclose.
Conflict of interest: E. Bernal has nothing to disclose.
Conflict of interest: M.J. Boeree has nothing to disclose.
Conflict of interest: J. Cadiñanos Loidi has nothing to disclose.
Conflict of interest: Q. Cai has nothing to disclose.
Conflict of interest: J.J. Cebrian Gallardo has nothing to disclose.
Conflict of interest: M. Dara has nothing to disclose.
Conflict of interest: E. Davidavičienė has nothing to disclose.
Conflict of interest: L. Davies Forsman has nothing to disclose.
Conflict of interest: J. De Los Rios has nothing to disclose.
Conflict of interest: J. Denholm has nothing to disclose.
Conflict of interest: J. Drakšienė has nothing to disclose.
Conflict of interest: R. Duarte has nothing to disclose.
Conflict of interest: S.E. Elamin has nothing to disclose.
Conflict of interest: N. Escobar Salinas has nothing to disclose.
Conflict of interest: M. Ferrarese has nothing to disclose.
Conflict of interest: A. Filippov has nothing to disclose.
Conflict of interest: A. Garcia has nothing to disclose.
Conflict of interest: J.M. García-García has nothing to disclose.
Conflict of interest: I. Gaudiesiute has nothing to disclose.
Conflict of interest: B. Gavazova has nothing to disclose.
Conflict of interest: R. Gayoso has nothing to disclose.
Conflict of interest: R. Gomez Rosso has nothing to disclose.
Conflict of interest: V. Gruslys has nothing to disclose.
Conflict of interest: G. Gualano has nothing to disclose.
Conflict of interest: W. Hoefsloot has nothing to disclose.
Conflict of interest: J. Jonsson has nothing to disclose.
Conflict of interest: E. Khimova has nothing to disclose.
Conflict of interest: H. Kunst has nothing to disclose.
Conflict of interest: R. Laniado-Laborín has nothing to disclose.
Conflict of interest: Y. Li has nothing to disclose.
Conflict of interest: C. Magis-Escurra has nothing to disclose.
Conflict of interest: V. Manfrin has nothing to disclose.
Conflict of interest: V. Marchese has nothing to disclose.
Conflict of interest: E. Martínez Robles has nothing to disclose.
Conflict of interest: A. Matteelli has nothing to disclose.
Conflict of interest: J. Mazza-Stalder has nothing to disclose.
Conflict of interest: C. Moschos has nothing to disclose.
Conflict of interest: M. Muñoz-Torrico has nothing to disclose.
Conflict of interest: H. Mustafa Hamdan has nothing to disclose.
Conflict of interest: B. Nakčerienė has nothing to disclose.
Conflict of interest: L. Nicod has nothing to disclose.
Conflict of interest: M. Nieto Marcos has nothing to disclose.
Conflict of interest: D.J. Palmero has nothing to disclose.
Conflict of interest: F. Palmieri has nothing to disclose.
Conflict of interest: A. Papavasileiou has nothing to disclose.
Conflict of interest: M-C. Payen has nothing to disclose.
Conflict of interest: A. Pontarelli has nothing to disclose.
Conflict of interest: S. Quirós has nothing to disclose.
Conflict of interest: A. Rendon has nothing to disclose.
Conflict of interest: L. Saderi has nothing to disclose.
Conflict of interest: A. Šmite has nothing to disclose.
Conflict of interest: I. Solovic has nothing to disclose.
Conflict of interest: M.B. Souleymane has nothing to disclose.
Conflict of interest: M. Tadolini has nothing to disclose.
Conflict of interest: M. van den Boom has nothing to disclose.
Conflict of interest: M. Vescovo has nothing to disclose.
Conflict of interest: P. Viggiani has nothing to disclose.
Conflict of interest: A. Yedilbayev has nothing to disclose.
Conflict of interest: R. Zablockis has nothing to disclose.
Conflict of interest: D. Zhurkin has nothing to disclose.
Conflict of interest: M. Zignol has nothing to disclose.
Conflict of interest: D. Visca has nothing to disclose.
Conflict of interest: A. Spanevello has nothing to disclose.
Conflict of interest: J.A. Caminero has nothing to disclose.
Conflict of interest: J-W. Alffenaar has nothing to disclose.
Conflict of interest: S. Tiberi has nothing to disclose.
Conflict of interest: R. Centis has nothing to disclose.
Conflict of interest: L. D'Ambrosio has nothing to disclose.
Conflict of interest: E. Pontali has nothing to disclose.
Conflict of interest: G. Sotgiu has nothing to disclose.
Conflict of interest: G.B. Migliori has nothing to disclose.
Support statement: The project is supported by the Global Tuberculosis Network (GTN; Committees on TB Treatment, Clinical Trials and Global TB Consilium) and was part of the European Respiratory Society Latin American project in collaboration with ALAT (Asociación Latino Americana de Torax – Latino American Thoracic Association) and SBPT (Brazilian Society of Pulmonology and Tuberculosis). This article belongs to the scientific activities of the WHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate, ITA-80, 2017–2020- GBM/RC/LDA.
- Received August 1, 2019.
- Accepted September 17, 2019.
- Copyright ©ERS 2019
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