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Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study

Open AccessPublished:April 03, 2019DOI:https://doi.org/10.1016/j.ijid.2019.03.036

      Highlights

      • WHO recommends countries monitor the safety profile of new drugs and regimens.
      • WHO developed the active TB drug safety monitoring and management (aDSM) package.
      • aDSM data are not yet available globally.
      • A project to prove aDSM feasibility was launched by the Global Tuberculosis Network; 41 centres in 27 countries participated.
      • 309 cases were fully reported as of February 2019 out of 781 cases countries committed to report in 2019.

      Abstract

      The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries.
      The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs.
      Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile.
      A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

      Keywords

      The World Health Organization (WHO) seeks global evidence on the safety and tolerability of new treatment regimens for drug-resistant tuberculosis, including multidrug-resistant tuberculosis (MDR-TB) (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ).
      The WHO launched a comprehensive approach, known as aDSM (active TB drug safety monitoring and management) (
      • World Health Organization
      Active TB drug-safety monitoring and management (aDSM). WHO/HTM/TB/2015.28.
      ), proposing that national programmes implement ‘active and systematic clinical and laboratory assessment of patients on treatment with new TB medicines, or novel MDR-TB or XDR (extensively drug-resistant)-TB regimens to detect, manage and report suspected or confirmed drug toxicities’ (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ). This initiative is really important as, after more than 40 years without any new drug specifically licensed to manage TB, we finally have bedaquiline and delamanid (
      • Borisov S.E.
      • Dheda K.
      • Enwerem M.
      • Romero Leyet R.
      • D'Ambrosio L.
      • Centis R.
      • et al.
      Effectiveness and safety of bedaquiline-containing regimens in the treatment of multidrug and extensively drug-resistant tuberculosis: a multicentre study.
      ,
      • Kim C.T.
      • Kim T.O.
      • Shin H.J.
      • Ko Y.C.
      • Hun Choe Y.
      • Kim H.R.
      • et al.
      Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis:a multi-center cohort study in Korea.
      ,
      • Kuksa L.
      • Barkane L.
      • Hittel N.
      • Gupta R.
      Final treatment outcomes of multidrug and extensively drug-resistant tuberculosis patients in Latvia receiving delamanid-containing regimens.
      ,
      • Mohr E.
      • Hughes J.
      • Reuter A.
      • Trivino Duran L.
      • Ferlazzo G.
      • Daniels J.
      • et al.
      Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa.
      ,
      • Pontali E.
      • Sotgiu G.
      • Tiberi S.
      • D'Ambrosio L.
      • Centis R.
      • Migliori G.B.
      Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence.
      ,
      • Pontali E.
      • Sotgiu G.
      • Tiberi S.
      • Tadolini M.
      • Visca D.
      • D'Ambrosio L.
      • et al.
      Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review.
      ,
      • Pym A.S.
      • Diacon A.H.
      • Tang S.J.
      • Conradie F.
      • Danilovits M.
      • Chuchottaworn C.
      • et al.
      Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis.
      ).
      Although some information on safety of the new drugs has been made available, more clinical details (to obtain through extensive surveillance of adverse events (AEs)) are required. This is particularly relevant in view of the potential bedaquiline, delamanid, clofazimine, and quinolones have to increase the QT interval (
      • Pontali E.
      • Sotgiu G.
      • Tiberi S.
      • D'Ambrosio L.
      • Centis R.
      • Migliori G.B.
      Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence.
      ) and generate an arrhythmic event. Therefore, the real-time monitoring of anti-TB regimens is fully justified (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ,
      • World Health Organization
      Active TB drug-safety monitoring and management (aDSM). WHO/HTM/TB/2015.28.
      ). Of course, although any kind of AE requires prompt clinical action, special attention is necessary on serious AEs, as they are potentially life-threatening. In particular, according to the WHO aDSM project serious AEs include death or a life-threatening experience, hospitalization or prolongation of hospitalization, persistent or significant disability, or congenital anomaly (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ,
      • World Health Organization
      Active TB drug-safety monitoring and management (aDSM). WHO/HTM/TB/2015.28.
      ).
      The WHO proposal to national programmes was to initiate regular monitoring of AEs, as well as collect and report information on bacteriological status at diagnosis (sputum smear, culture, drug resistance profile), bacteriological conversion/reversion (sputum smear and culture conversion rates) and treatment outcomes (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ). The surveillance methodology has been left to countries which were supposed to use electronic registers or existing electronic medical record systems (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ), complementing, rather than duplicating, national pharmacovigilance initiatives.
      WHO also launched a global aDSM database to collect a standard set of variables including anonymised individual-level patient data on serious AEs (
      • Halleux C.M.
      • Falzon D.
      • Merle C.
      • Jaramillo E.
      • Mirzayev F.
      • Olliaro P.
      • et al.
      The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis.
      ), and provided clear guidance on how to implement aDSM at a national level (
      • World Health Organization
      Active TB drug-safety monitoring and management (aDSM). WHO/HTM/TB/2015.28.
      ).
      National TB Programmes faced difficulties in implementing aDSM and contributing to the global database. Taking advantage of a newly implemented global network (Global Tuberculosis Network-GTN) (
      • Borisov S.E.
      • Dheda K.
      • Enwerem M.
      • Romero Leyet R.
      • D'Ambrosio L.
      • Centis R.
      • et al.
      Effectiveness and safety of bedaquiline-containing regimens in the treatment of multidrug and extensively drug-resistant tuberculosis: a multicentre study.
      ,
      • Silva D.R.
      • Rendon A.
      • Alffenaar J.W.
      • Chakaya J.M.
      • Sotgiu G.
      • Esposito S.
      • et al.
      Global TB Network: working together to eliminate tuberculosis.
      ) a large aDSM project was launched to demonstrate the feasibility of implementing national aDSM registers. The GTN research addressed clinical centres with the goal of assessing the safety and tolerability profile, as well as the effectiveness of anti-TB drugs and regimens in MDR-TB patients treated with new drugs (bedaquiline, delamanid) worldwide. The WHO initiative is focused on National Tuberculosis Programmes in order to evaluate the safety of anti-TB regimens. The two initiatives are co-ordinated.
      After a pilot study was implemented in 2016 in a few centres to assess the suitability of the project and its potential implementation, and following the approval of the coordinating centre’s Ethics Committee (July 11th, 2017), the project was proposed to the clinical centres or national programmes participating in the network. Each centre or country signed a confidentiality and data-sharing agreement with the coordinating centre and obtained local Ethics Committee clearance as per legislation in force.
      All consecutive cases for which bedaquiline and/or delamanid were prescribed since the moment the centre or country adhered to the project were enrolled. The AEs of any drug involved in the treatment regimen were prospectively collected, ensuring a probabilistic mechanism of causality assignment (e.g. attribution of the AE to a specific drug based on its evidence-based profile). The data collection form in an electronic format was based on the WHO-recommended template, although more clinical details were requested (
      • World Health Organization
      Active TB drug-safety monitoring and management (aDSM). WHO/HTM/TB/2015.28.
      ).
      This article reports on the initial results of the aDSM project.
      As of January 31st 2019 (interim analysis), 41 centres in 27 countries (Figure 1, Table 1) provided aDSM information on new anti-TB drugs: 14 in Europe, 6 in Latin America, 4 in Asia, 2 in Africa, and 1 in Oceania. 5 countries participated in the aDSM project although no case has yet been treated with bedaquiline and/or delamanid.
      Figure 1
      Figure 1Map of the participating countries.
      Red: Countries which regularly reported; Green: Countries in the process of reporting; Blue: Countries which activated active monitoring of adverse events with no cases yet treated with new drugs.
      Table 1Participating countries and details on the cases reported.
      CountriesEstimated cases
      Cases estimated by countries to be fully reported by 1st quarter 2019.


      N
      Estimated coverage
      Countries’ estimate of the national coverage of the aDSM project on new drugs.


      %
      Cases enrolled NMale

      N (%)
      Cases treated with Bdq

      N (%)
      Cases treated with Dlm

      N (%)
      Cases treated with Bdq-Dlm or Dlm-Bdq consecutively N (%)Cases treated with Bdq-Dlm in combination N (%)
      EUROPE
      Belgium36032 (67)3 (100)0 (0)0 (0)0 (0)
      Belarus
      2 centres.
      113802717 (63)20 (74)7 (26)0 (0)0 (0)
      Italy
      6 centres.
      29802717 (63)20 (74)6 (25)0 (0)1 (4)
      Latvia301003018 (60)20 (40)3 (10)1 (3)6 (20)
      Lithuania170100Data uploading
      MacedoniaNo cases100
      Netherlands
      2 centres.
      610065 (83)3 (50)0 (0)1 (17)2 (33)
      Portugal110011 (100)0 (0)1 (100)0 (0)0 (0)
      Russian Federation
      2 centres.
      257100
      In the 2 Oblasts reporting.
      14087 (62)135 (96)2 (1)1 (0.7)2 (1)
      SerbiaNo cases100
      Slovakia110010 (0)1 (100)0 (0)0 (0)0 (0)
      Spain
      6 centres.
      910010 (0)1 (100)0 (0)0 (0)0 (0)
      Sweden1610052 (40)4 (80)0 (0)1 (20)
      Case with Dlm for 4 days only, not concomitant with Bdq.
      0 (0)
      United Kingdom42042 (50)4 (100)0 (0)0 (0)0 (0)
      AFRICA
      Niger211001313 (100)10 (77)0 (0)0 (0)3 (23)
      Sudan510022 (100)2 (100)0 (0)0 (0)0 (0)
      LATIN AMERICA
      Argentina1110030 (0)3 (100)0 (0)0 (0)0 (0)
      Brazil331002622 (85)26 (100)0 (0)0 (0)0 (0)
      ColombiaNo cases100
      Mexico
      2 centres.
      810043 (75)1 (25)1 (25)0 (0)2 (50)
      ParaguayNo cases100
      Peru3080Data uploading
      ASIA
      China
      1 centre.
      5100
      In the Province reporting.
      Data uploading
      India15100
      In the State reporting.
      105 (50)9 (90)0 (0)1 (10)0 (0)
      Malaysia
      1 centre.
      8100Data uploading
      United Arab EmiratesNo cases
      OCEANIA
      Australia6100
      In the State reporting.
      64 (67)6 (100)0 (0)0 (0)0 (0)
      TOTAL 27781Range 20%–100%309200 (65)268 (87)20 (7)5 (2)16 (5)
      a Cases estimated by countries to be fully reported by 1st quarter 2019.
      b Countries’ estimate of the national coverage of the aDSM project on new drugs.
      c In the 2 Oblasts reporting.
      d In the Province reporting.
      e In the State reporting.
      f 2 centres.
      g 6 centres.
      h 1 centre.
      i Case with Dlm for 4 days only, not concomitant with Bdq.
      This resulted in 100% coverage for the majority of the countries, while in some of them the actual coverage was lower. In the Russian Federation 2 Regions (Moscow and Arkhangelsk Oblasts) are represented with 100% coverage, as well as the Victoria State in Australia and the Zhejiang Province in China.
      A total of 309 cases were fully reported from January 2016 to January 2019 (65% males; 268 treated with bedaquiline, 20 with delamanid and 21 with the two drugs prescribed in combination or consecutively) out of the estimated 781 cases the participating countries committed to report in the first quarter 2019.
      The recruitment process in all continents was long and time-consuming, although the support and enthusiasm of the participating colleagues allowed for resolution of any existing problems. Several countries (including Sub-Saharan Africa) were asked to participate, but some centres decided to decline as the project is on a voluntary basis and the activity is perceived as ‘difficult’ ‘or time-consuming’ without provision for additional resources.
      During the ‘interim analysis’, planned in the second quarter 2019, AEs will be analysed separately both per drug (bedaquiline, delamanid, linezolid, fluoroquinolones, clofazimine, etc.) and per ‘severity’ status.
      To our knowledge, this is the first published evidence of a global aDSM project in the literature.

      Conflict of interest statement

      No competing interest declared.

      Funding sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      Approval was not required.

      Acknowledgements

      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.

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