Monitoring the Cardiotoxic Effects of Bedaquiline in Older Children and Adolescents with Multiple and Extensive Drug Resistance

The objective: to evaluate expanded monitoring of cardiovascular disorders in older children and adolescents with multiple drug resistant tuberculosis receiving bedaquiline (Bq) as a part of anti-tuberculosis therapy.

Subjects and Methods: A cohort retrospective-prospective study (2015-2021) was conducted, which included 36 patients aged 13-17 years old who received Bq. The prospective part included 19 patients (Main Group), they underwent extended monitoring (EM) of cardiotoxic reactions; this extended monitoring program was developed in Central Tuberculosis Research Institute. The retrospective part included 17 patients (Control Group), in whom cardiotoxic reactions were assessed using standard monitoring recommended by the Russian Society of Phthisiologists at that time. The relationship between the studied risk factor (monitoring by standard ECG) and the outcome (Bq discontinuation) was assessed using the Pearson χ² test.

Results. Prolongation of the QTc interval > 0.440 ms was noted in 17.6% of cases in Control Group and it was regarded as a cardiotoxic effect of Bq, the drug was discontinued. In Main Group, prolongation was noted in 47.3% of cases which was considered a functional disorder of the cardiovascular system according to EM, the drug was not discontinued, χ² = 3.896; p = 0.049. EM can be used in older children and adolescents with multiple drug resistant respiratory tuberculosis, which will make it possible to safely include Bq to chemotherapy regimens.

1. Borisov S.E., Filippov A.V., Ivanova D.A., Ivanushkina T.N., Litvinova N.V., Garmash Yu.Yu. Efficacy and safety of chemotherapy regimens containing bedaquiline in respiratory tuberculosis patients: immediate and final results. Tuberculosis and Lung Diseases, 2019, vol. 97, no. 5, pp. 28-40. (In Russ.) http://doi.org/10.21292/2075-1230-2019-97-5-28-40

2. Vasilyeva I.A., Bagdasaryan T.R., Balasanyants G.S. et al. Federalnye klinicheskiye rekomendatsii po diagnostike i lecheniyu tuberkuleza organov dykhaniya s mnozhestvennoy i shirokoy lekarstennoy ustoichivostyu vozbuditelya. [Federal clinical guidelines for diagnosis and treatment of respiratory tuberculosis with multiple and extensive drug resistance]. 3rd ed., Moscow, 2015, 68 p. Available: https://roftb. ru/netcat_files/doks2015/3final. pdf Accessed October 14, 2023

3. Gorlischev V.P., Kalinin L.A., Mikhalskiy A.I., Shkolnikova M.A., Shkolnikov V.L. Method for correcting the electrocardiographic interval considering the heart rate. Problemy Upravleniya, 2016, no. 6, pp. 65-70. (In Russ.)

4. Klinicheskie rekomendatsii. Tuberkulez u detey. [Clinical guidelines on tuberculosis in children]. ROF Publ., 2022, 111 p. Available: https://cr.minzdrav.gov.ru/recomend/507_2. Accessed October 14, 2023

5. Lebedev D.S., Mikhaylov E.N., Neminuschiy N.M. et al. Ventricular arrhythmias. Ventricular tachycardias and sudden cardiac death. 2020 Clinical guidelines. Rossiysky Kardiologicheskiy Journal, 2021, vol. 26, no. 7, pp. 128-189. (In Russ.) https://doi.org/10.15829/1560-4071-2021- 4600

6. Makarov L.M. EKG v pediatrii. [ECG in pediatrics]. 3rd edition, Moscow, 2013, 696 p. doi:10.13140/RG.2.1.4117.1049

7. Myshkova E.P., Petrenko T.I., Kolpakova T.A. Comparative analysis of efficacy and safety of various anti-tuberculosis therapy regimens in patients with MDR/XDR tuberculosis. Tuberculosis and Lung Diseases, 2022, vol. 100, no. 5, pp. 35-42. (In Russ.) https://doi.org/10.21292/2075-1230-2022-100-11-48-55

8. Ostroumova O.D., Goloborodova I.V. Drug-induced long QT interval: prevalence, risk factors, treatment and prevention. Consilium Medicum, 2019, vol. 21, no. 5, pp. 62-67. (In Russ.) https://doi.org/10.26442/207517 53.2019.5.190415

9. Stavitskaya N.V., Felker I.G., Zhukova E.M., Tlif A.I., Doctorova N.P., Kudlay D.A. The multivariate analysis of the results of bedaquiline use in the therapy of MDR/XDR pulmonary tuberculosis. Tuberculosis and Lung Diseases, 2020, vol. 98, no. 7, pp. 56-62. (In Russ.) https://doi.org/10.21292/2075-1230-2020-98-7-56-62

10. Starshinova A.A., Nazarenko M.M., Belyaeva E.N., Kudlay D.A., Pavlova M.V., Yablonskiy P.K. Efficacy of treatment with bedaquiline of tuberculosis patients with multiple and extensive drug resistance. Tuberculosis and Lung Diseases, 2022, vol. 100, no. 5, pp. 56-63. (In Russ.) https://doi.org/10.21292/2075-1230-2022-100-5-56-63

11. Diacon A. H., Pym A., Grobusch M. P., et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline // The New England Journal of Medicine. – 2014. – Vol. 371, № 8. – p. 723-732. https://doi.org/10.1056/NEJMoa1313865

12. Global tuberculosis report 2021. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO.

13. Gubkina M.F, Khokhlova J.Y, Yukhimenko N.V, Petrakova I.Y. Prolonged use of bedaquiline in the treatment for MDR-TB in a child // IDCases. – 2021. – Vol. 26. – P: 01311. https://doi.org/10.1016/j.idcr.2021.e01311.

14. Lachenal N., Hewison C., Mitnick C., Lomtadze N., Coutisson S., Osso E., et al. Setting up pharmacovigilance based on available endTB Project data for bedaquiline // The International Journal of Tuberculosis and Lung Disease. – 2020. – Vol. 24, № 10. – P. 1087-1094. https://doi.org/10.5588/ijtld.20.0115.

15. Salle P., Rey J.L., Bernasconi P., et al. Torsades de pointe. Aapropos of 60 cases // Ann Cardiol Angerol. – 1985. – Vol. 34, № 4. – P. 341–8.

16. WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and adolescents. Geneva: World Health Organization; 2022. License: CC BY-NC-SA 3.0 IGO. Available at: http://apps.who.int/iris. [Accessed: 13.01.2023]

17. Zhiyi L., Nafees A., Parvaneh B., et al. Drug-associated adverse events in the treatment of multidrugresistant tuberculosis: an individual patient data meta-analysis // The Lancet Respiratory Medicine. – 2020. – Vol. 8, № 4. – P. 383-394. https://doi.org/10.1016/S2213-2600 (20) 30047-3