Incidence rate and time to serious adverse events among rifampicin resistant tuberculosis patients in Georgia treated with new and repurposed anti-tuberculosis drugs, 2016-2018
Considering the complexity of second-line anti-tuberculosis (TB) treatment regimens, the management of drug-resistant TB (DR-TB) in Georgia remains a major challenge. Since the introduction of new and repurposed anti-TB medications, the implementation of active TB Drug Safety Monitoring (aDSM) was a critical program component to help establish safety and manage all treatment related Serious Adverse Events (SAEs). In our study, we aimed to describe the occurrence, characteristics and timing of SAE among patients with Rifampicin Resistant and Multi-Drug Resistant TB (RR/MDR-TB) receiving new and/or repurposed anti-TB medications (bedaquiline, delamanid, linezolid, clofazimine, imipenem) during the period of 2016-2018 in Georgia and identify predictors of SAE. The data were obtained from the medical charts, electronic database and standardized aDSM reports During 2016-2018 period in total 970 people with RR/MDR-TB were notified in Georgia and 388 of them received new and/or repurposed TB drugs as part of their treatment regimen and all were included into the study. The results showed a total of 73 SAEs registered among 49 (12.6%) patients receiving new and/or repurposed drugs. The overall SAE incidence rate per 100 person-months was 1.16. The severity of the majority of the SAEs (46.6%) was grade III and 21.9% were grade IV. The most common SAE reported was hepatotoxicity, with an incidence of 0.26 per 100 person-month (n=16, 21.9%) followed by cardiotoxicity with an incidence of 0.16 per 100 person-month (n=10, 13.7%). Median time to SAE occurrence was 183 days (IQR 84 – 334) after treatment initiation. Resistance profile was the only predictor associated with occurrence of a SAEs. There was increased hazard of SAEs among patients with XDR-TB (adjusted HR=2.18, 95% CI: 1.12-4.23). Our findings on SAEs among patients treated with new or repurposed anti-TB drugs are echoing the findings available in the literature. They highlight the need for close monitoring of patients and underlines the importance of the aDSM during the whole treatment. Safety profile of the medications and combinations used are yet to be established and larger datasets comprised of patients receiving same treatment regimens need to be utilized.
WHO. Global tuberculosis report 2019. Geneva: World Health Organization; 2019:1–297. Available from: https://www.who.int/tb/publications/global_report/en/
WHO Regional Office for Europe/European Centre for Disease Prevention and Control. Tuberculosis surveillance and monitoring in Europe 2019-2017 data. Copenhagen: WHO Regional Office for Europe. 2019.
Diel R, Vandeputte J, De Vries G, et al. Costs of tuberculosis disease in the European Union: A systematic analysis and cost calculation. Eur Respir J 2014;43:554-65.
Falzon D, Gandhi N, Migliori GB, et al. Resistance to fluoroquinolones and second-line injectable drugs: Impact on multidrug-resistant TB outcomes. Eur Respir J 2013;42:156-68.
Migliori GB, Tiberi S, Zumla A, et al. MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network. Int J Infect Dis 2020;92S:S15-25.
Awofeso N. Anti-tuberculosis medication side-effects constitute major factor for poor adherence to tuberculosis treatment. Bull World Health Organ 2008;86:B-D.
WHO. Active tuberculosis drug-safety monitoring and management. Geneva: World Health Organization; 2015. Available from: https://www.who.int/tb/publications/aDSM/en/
Akkerman O, Aleksa A, Alffenaar JW, et al. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study. Int J Infect Dis 2019;83:72–6.
Borisov S, Danila E, Maryandyshev A, et al. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: First global report. Eur Respir J 2019;54:1901522.
WHO. Tuberculosis data. Accessed on: 2019 Nov 22. Available from: https://www.who.int/tb/data/en/
Arora S, Kalishman SG, Thornton KA, et al. Project ECHO: A telementoring network model for continuing professional development. J Contin Educ Health Prof 2017;37:239–44.
WHO. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization; 2015. Available from: https://apps.who.int/iris/bitstream/handle/10665/130918/9789241548809_eng.pdf?sequence=1&isAllowed=y
U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases. Division of AIDS table for grading the severity of adult and pediatric adverse events. Corrected Version 2.1. Available from: https://rsc.niaid.nih.gov/clinical-research-sites/table-grading-severity-adult-pediatric-adverse-events-changes-highlighted
R Core Team. A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2018.
Hewison C, Bastard M, Khachatryan N, et al. Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia. Int J Tuberc Lung Dis 2018;22:766-72.
Mbuagbaw L, Guglielmetti L, Hewison C, et al. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg Infect Dis 2019;25:936-43.
Lorent N, Sebatunzi O, Mukeshimana G, et al. Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: A prospective cohort study. PLoS One 2011;6:e19566.
Van der Walt M, Lancaster J, Odendaal R, et al. Serious treatment related adverse drug reactions amongst anti-retroviral naïve MDR-TB patients. PLoS One 2013;8:e58817.
Schnippel K, Firnhaber C, Berhanu R, et al. Adverse drug reactions during drug-resistant TB treatment in high HIV prevalence settings: a systematic review and meta-analysis. J Antimicrob Chemother 2017;72:1871-9.
Borisov SE, Dheda K, Enwerem M, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017;49:1700387.
Kalandarova L, Tillashaikhov M, Parpieva N, et al. Treatment outcomes and adverse reactions in patients with multidrug-resistant tuberculosis managed by ambulatory or hospitalized care from 2010-2011 in Tashkent, Uzbekistan. Public Heal Panor 2016;02:21–9.
WHO. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2020. Available from: https://apps.who.int/iris/handle/10665/332397
Hwang TJ, Wares DF, Jafarov A, et al. Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: a meta-analysis. Int J Tuberc Lung Dis 2013;17:1257-66.
Walker IF, Khanal S, Hicks JP, et al. Implementation of a psychosocial support package for people receiving treatment for multidrug-resistant tuberculosis in Nepal: A feasibility and acceptability study. PLoS One 2018;13:e0201163.
Huque R, Elsey H, Fieroze F, et al. “Death is a better option than being treated like this”: a prevalence survey and qualitative study of depression among multi-drug resistant tuberculosis in-patients. BMC Public Health 2020;20:848.
- Abstract views: 179
- PDF: 95
- Supplementary: 25