Adverse drug reactions of first-line antitubercular drugs: A retrospective study on characteristics, management, factors, and impacts

Abstract

Objective: To elucidate the characteristics, management strategies, risk factors, and clinical impacts associated with adverse drug reactions (ADRs) induced by first-line antitubercular drugs to enhance tuberculosis (TB) management.

Methods: A retrospective cohort study was conducted by retrieving drug-susceptible TB records among adult patients who received TB treatment from 2018 to 2021 at 10 public health clinics in Sarawak, Malaysia. Only the initial TB treatment and occurrence of specific ADRs within the study period were considered. Regression analysis was performed to identify the risk factors associated with both overall ADRs and individual types of ADRs.

Results: Among 2 953 cases, 705 (23.9%) developed ADRs. Cutaneous reactions were the most prevalent (47.1%), followed by hepatotoxicity (32.8%) and gastrointestinal disturbances (29.8%). Six out of seven types of ADRs investigated occurred within the intensive phase, mostly manifesting at approximately 2 weeks of initiation. Hepatotoxicity resulted in the majority (85.3%) of treatment discontinuations, while vision problems led to treatment modifications in half of the cases. Risk factors for all ADRs included age ≥60 years, females, illicit drug use, and comorbidities such as HIV-positive, diabetes, and chronic liver disease. Alcohol consumption was independently associated with hepatotoxicity. ADRs caused around one-third of interruptions exceeding 2 weeks (33.0%) and subsequently necessitated treatment restarts (34.5%).

Conclusions: Understanding these various aspects contributes to improving the overall management of ADRs in TB treatment. Close ADR monitoring and reporting are essential to strengthen ADR management.

Keywords

Adverse events / Cutaneous reactions / Hepatotoxicity / Gastrointestinal disturbances / Risk factors / Tuberculosis

References

[1] Prabhu R, Singh V. The history of tuberculosis: Past, present, and future. Adv Microbiol 2019; 9(11): 931-942.

[2] World Health Organization. Global tuberculosis report. Geneva: World Health Organization; 2023.

[3] American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000; 161(4): 1376-1395.

[4] Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Executive summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016; 63(7): 853-867.

[5] World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-susceptible tuberculosis treatment. Geneva: World Health Organization; 2022.

[6] Prasad R, Singh A, Gupta N. Adverse drug reactions in tuberculosis and management. Indian J Tuberc 2019; 66(4): 520-532.

[7] Oh AL, Makmor-Bakry M, Islahudin F, Wong IC. Prevalence and predictive factors of tuberculosis treatment interruption in the Asia region: A systematic review and meta-analysis. BMJ Glob Health 2023; 8: e010592.

[8] Zegeye A, Dessie G, Wagnew F, Gebrie A, Islam SMS, Tesfaye B, et al. Prevalence and determinants of anti-tuberculosis treatment non-adherence in Ethiopia: A systematic review and meta-analysis. PLoS One 2019; 14(1): e0210422.

[9] World Health Organization. Tuberculosis incidence (per 100 000 population). World Health Organization Data. [Online]. Available from: https://data.who.int/indicators/i/C288D13. [Accessed on 2 April 2024].

[10] Tuberculosis data 2018-2021. Kuching: Tuberculosis and Leprosy Disease Control Section, Infectious Disease Control Branch, Sarawak State Health Department; 2023.

[11] Ho YH, Lim CT, Albart SA, Schee JP, Yong MC, Looi I. Characteristics of patients with tuberculosis and the associated factors with TB-related mortality in a rural setting in Sarawak, Malaysia: A single-centre study. Med J Malaysia 2023; 78(1): 1-6.

[12] Oh AL, Makmor-Bakry M, Islahudin F, Ting CY, Chan SK, Tie ST. Characteristics, predictors and consequences of tuberculosis treatment interruption: A multicentre retrospective cohort study. Trop Med Int Health 2024; 29(5): 434-445.

[13] Ministry of Health Malaysia. Clinical practice guidelines: Management of tuberculosis. 4th ed. Putrajaya: Malaysian Health Technology Assessment Section (MaHTAS), Medical Development Division, Ministry of Health Malaysia; 2021.

[14] World Health Organization. Definitions and reporting framework for tuberculosis–2013 revision: Updated December 2014 and January 2020. Geneva: World Health Organization; 2013.

[15] Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49(12): 1373-1379.

[16] Iseman MD. Tuberculosis therapy: Past, present and future. Eur Respir J 2002; 20(36 Suppl): 87S.

[17] Fei CM, Zainal H, Ali IAH. Evaluation of adverse reactions induced by anti-tuberculosis drugs in Hospital Pulau Pinang. Malays J Med Sci 2018; 25(5): 103-114.

[18] Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003; 167(11): 1472-1477.

[19] Tahaoğlu K, Ataç G, Sevim T, Tärün T, Yazicioğlu O, Horzum G, et al. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis 2001; 5(1): 65-69.

[20] Singh KP, Carvalho ACC, Centis R, D'Ambrosio L, Migliori GB, Mpagama SG, et al. Clinical standards for the management of adverse effects during treatment for TB. Int J Tuberc Lung Dis 2023; 27(7): 506519.

[21] Rizk HG, Lee JA, Liu YF, Endriukaitis L, Isaac JL, Bullington WM. Drug-induced ototoxicity: A comprehensive review and reference guide. Pharmacotherapy 2020; 40(12): 1265-1275.

[22] World Health Organization. The use of the WHO-UMC system for standardised case causality assessment. Uppsala: The Uppsala Monitoring Centre; 2013.

[23] Damasceno GS, Guaraldo L, Engstrom EM, Filha MMT, Santos RS, Vasconcelos AGG, et al. Adverse reactions to antituberculosis drugs in Manguinhos, Rio de Janeiro, Brazil. Clinics 2013; 68(3): 329-337.

[24] Teleman MD, Chee CB, Earnest A, Wang YT. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Int J Tuberc Lung Dis 2002; 6(8): 699-705.

[25] Siddiqui AN, Khayyam KU, Sharma M. Effect of diabetes mellitus on tuberculosis treatment outcome and adverse reactions in patients receiving directly observed treatment strategy in India: A prospective study. Biomed Res Int 2016: 7273935. doi:10.1155/2016/7273935.

[26] Breen RA, Miller RF, Gorsuch T, Smith CJ, Schwenk A, Holmes W, et al. Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection. Thorax 2006; 61(9): 791-794.

[27] Song JH, Yoon SY, Park TY, Heo EY, Kim DK, Chung HS, et al. The clinical impact of drug-induced hepatotoxicity on anti-tuberculosis therapy: A case control study. Respir Res 2019; 20: 283.

[28] Riccardi N, Canetti D, Rodari P, Besozzi G, Saderi L, Dettori M, et al. Tuberculosis and pharmacological interactions: A narrative review. Curr Res Pharmacol Drug Discov 2021; 2: 100007.

[29] Common Terminology Criteria for Adverse Events v4. 0 (CTCAE). U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute; 2009.