Multidrug-resistant tuberculosis: Successes, challenges, and the road ahead
Tuberculosis (TB) is a leading cause of infection-related mortality globally and imposes a significant burden on morbidity among survivors. While progress has been achieved toward the World Health Organization’s End TB goal, it has been slower than anticipated and, in part, reversed by the impact of the severe acute respiratory syndrome coronavirus 2 pandemic. Multidrug-resistant TB (MDR-TB) presents a formidable challenge, characterized by catastrophic costs, reduced treatment success rates, and increased loss to follow-up, leading to its perpetuation in local communities and the risk of onward transmission. Given this, the need to reshape services and refine management in a cost-effective manner is of paramount importance, particularly in developing countries where the majority of cases reside. In this short piece, we discuss the economic impact of MDR-TB and how this impact can be mitigated through several methods, including decentralized models of care.
Akalu, T.Y., Clements, A.C.A., Wolde, H.F., & Alene, K.A. (2023). Economic burden of multidrug-resistant tuberculosis on patients and households: A global systematic review and meta-analysis. Scientific Reports, 13(1):22361. https://doi.org/10.1038/s41598-023-47094-9
Alene, K.A., Clements, A.C.A., McBryde, E.S., Jaramillo, E., Lönnroth, K., Shaweno, D., et al. (2018). Mental health disorders, social stressors and health-related quality of life in patients with multidrug-resistant tuberculosis: A systematic review and meta-analysis. Journal of Infection, 77(5):357-367. https://doi.org/10.1016/j.jinf.2018.07.007
Assebe, L.F., Reda, H.L., Wubeneh, A.D., Lerebo, W.T., & Lambert, S.M. (2015). The effect of isoniazid preventive therapy on incidence of tuberculosis among HIV-infected clients under pre-ART care, Jimma, Ethiopia: A retrospective cohort study. BMC Public Health, 15:346. https://doi.org/10.1186/s12889-015-1719-0
Assefa, D.G., Dememew, Z.G., Zeleke, E.D., Manyazewal, T., & Bedru, A. (2024). Financial burden of tuberculosis diagnosis and treatment for patients in Ethiopia: A systematic review and meta-analysis. BMC Public Health, 24(1):260. https://doi.org/10.1186/s12889-024-17713-9
Bu, Q., Qiang, R., Fang, L., Peng, X., Zhang, H., & Cheng, H. (2023). Global trends in the incidence rates of MDR and XDR tuberculosis: Findings from the global burden of disease study 2019. Frontiers in Pharmacology, 14:1156249. https://doi.org/10.3389/fphar.2023.1156249
Carter, D.J., Glaziou, P., Lonnroth, K., Siroka, A., Floyd, K., Weil, D., et al. (2018). The impact of social protection and poverty elimination on global tuberculosis incidence: A statistical modelling analysis of sustainable development Goal 1. Lancet Global Health, 6(5):514-522. https://doi.org/10.1016/S2214-109X(18)30195-5
Cates, L., Crudu, V., Codreanu, A., Ciobanu, N., Fosburgh, H., Cohen, T., et al. (2021). Laboratory costs of diagnosing TB in a high multidrug-resistant TB setting. The International Journal of Tuberculosis and Lung Disease, 25(3):228-230. https://doi.org/10.5588/ijtld.20.0586
Chen, Y., Zhiang, Y., Wu, Z., Xu, B., Chen, J., Sha, W., et al.(2022). Impact of Financial Support on Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Population-based, Retrospective cohort Study in China. PREPRINT (Version 1). Research Square https://doi.org/10.21203/rs.3.rs-2192240/v1
Cox, H., & Furin, J. (2021). The incalculable costs of tuberculosis. The Lancet Global Health, 9(10):1337-1338. https://doi.org/10.1016/S2214-109X(21)00345-4
European Centre for Disease Prevention and Control. (2023). Tuberculosis: Annual Epidemiological Report for 2020. Available from: https://www.ecdc.europa.eu/ en/publications-data/tuberculosis-surveillance-and-monitoring-europe-2023-2021-data [Last accessed on 2024 Apr 04].
Falzon, D., Zignol, M., Bastard, M., Floyd, K., & Kasaeva, T. (2023). The impact of the COVID-19 pandemic on the global tuberculosis epidemic. Frontiers in Immunology, 29(14):1234785. https://doi.org/10.3389/fimmu.2023.1234785
Ferreira, M.R.L., Bonfim, R.O., Bossonario, P.A., Maurin, V.P., Valença, A.B.M., Abreu, P.D., et al. (2023). Social protection as a right of people affected by tuberculosis: A scoping review and conceptual framework. Infectious Diseases of Poverty, 12(1):103. https://doi.org/10.1186/s40249-023-01157-1
Fitzpatrick, C., & Floyd, K. (2012). A systematic review of the cost and cost effectiveness of treatment for multidrug-resistant tuberculosis. Pharmacoeconomics, 30(1):63-80. https://doi.org/10.2165/11595340-000000000-00000
Ghazy, R.M., El Saeh, H.M., Abdulaziz, S., Hammouda, E.A., Elzorkany, A.M., Khidr, H., et al. (2022). A systematic review and meta-analysis of the catastrophic costs incurred by tuberculosis patients. Scientific Reports, 12(1):558. https://doi.org/10.1038/s41598-021-04345-x
Grobler, L., Nagpal, S., Sudarsanam, T.D., & Sinclair, D. (2016). Nutritional supplements for people being treated for active tuberculosis. Cochrane Database of Systematic Reviews, 2016(6):CD006086. https://doi.org/10.1002/14651858.CD006086.pub4
Gunther, G., Guglielmetti, L., Leu, C., Lange, C., & van Leth, F. (2023). Availability and costs of medicines for the treatment of tuberculosis in Europe. Clinical Microbiology and Infection, 29(1):77-84. https://doi.org/10.1016/j.cmi.2022.07.026
Gupta, A., Juneja, S., Babawale, V., Rustam Majidovich, N., Ndjeka, N., Thi Mai Nguyen, P., et al. (2024). Global adoption of 6-month drug-resistant TB regimens: Projected uptake by 2026. PLoS One, 19(1):e0296448. https://doi.org/10.1371/journal.pone.0296448
Ikram, A., Ali, A., Abbasi, S.H., Ashraf, N., Wali, S., Salman, M., et al. (2020). Is Tuberculosis Treatment Truly Free? A study to identify key factors contributing to the catastrophic cost of TB care in Pakistan. Journal of Tuberculosis Research, 8(4):181-198. https://doi.org/10.4236/jtr.2020.84017
Iradukunda, A., Ndayishimiye, G.P., Sinarinzi, D., Odjidja, EN., Ntakaburimvo, N., Nshimirimana, I., et al. (2021). Key factors influencing multidrug-resistant tuberculosis in patients under anti-tuberculosis treatment in two centres in Burundi: A mixed effect modelling study. BMC Public Health, 21;2142. https://doi.org/10.1186/s12889-021-12233-2
Ismail, N.A., Omar, S.V., Moultrie, H., Bhyat, Z., Conradie, F., Enwerem, M., et al. (2022). Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to Bedaquiline in patients treated for rifampicin-resistant tuberculosis: A cross-sectional and longitudinal study. The Lancet Infectious Diseases, 22(4):496-506. https://doi.org/10.1016/S1473-3099(21)00470-9
Jang, J.G., & Chung, J.H. (2020). Diagnosis and treatment of multidrug-resistant tuberculosis. Yeungnam University Journal of Medicine, 37(4):277-285. https://doi.org/10.12701/yujm.2020.00626
Jiang, Y., Chen, J., Ying, M., Liu, L., Li, M., Lu, S., et al. (2023). Factors associated with loss to follow-up before and after treatment initiation among patients with tuberculosis: A 5-year observation in China, Frontiers in Medicine (Lausanne), 10:1136094. https://doi.org/10.3389/fmed.2023.1136094
Labuda, S.M., Seaworth, B., Dasgupta, S., & Goswami, N.D. (2024). Bedaquiline, pretomanid, and linezolid with or without Moxifloxacin for tuberculosis. The Lancet Respiratory Medicine, 12(2):e5-e6. https://doi.org/10.1016/S2213-2600(23)00426-5
Laurence, Y.V., Griffiths, U.K., & Vassall, A., (2015). Costs to health services and the patient of treating tuberculosis: A systematic literature review. Pharmacoeconomics, 33(9):939-955. https://doi.org/10.1007/s40273-015-0279-6
Makamure, B., Makumbirofa, S., Bandason, T., Leccese, P., Mutetwa, R., Robertson, V., et al. (2017). A suggested algorithm for detection of multi drug-resistant tuberculosis in Zimbabwe. The Journal of Infection in Developing Countries, 11(8):611-618. https://doi.org/10.3855/jidc.8009
Maleche-Obimbo, E., Odhiambo, M.A., Njeri, L., Mburu, M., Jaoko, W., Were, F., et al. (2022). Magnitude and factors associated with post-tuberculosis lung disease in low- and middle-income countries: A systematic review and meta-analysis. PLoS Global Public Health, 2(12):e0000805. https://doi.org/10.1371/journal.pgph.0000805
Meghji, J., Gregorius, S., Madan, J., Chitimbe, F., Thomson, R., Rylance, J., et al. (2021). The long term effect of pulmonary tuberculosis on income and employment in a low income, urban setting. Thorax, 76(4):387-395. https://doi.org/10.1136/thoraxjnl-2020-215338
Menzies, N.A., Allwood, B.W., Dean, A.S., Dodd, P.J., Houben, R.M.G.J., James, L.P., et al. (2023). Global burden of disease due to rifampicin-resistant tuberculosis: A mathematical modeling analysis. Nature Communications, 14(1):6182. https://doi.org/10.1038/s41467-023-41937-9
Molla, K.A., Reta, M.A., & Ayene, Y.Y. (2022). Prevalence of multidrug-resistant tuberculosis in East Africa: A systematic review and meta-analysis. PLoS One, 17(6):e0270272. https://doi.org/10.1371/journal.pone.0270272
Molla, Y., Jerene, D., Jemal, I., Nigussie, G., Kebede, T., Kassie, Y., et al. (2017). The experience of scaling up a decentralized, ambulatory model of care for management of multidrug-resistant tuberculosis in two regions of Ethiopia. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 7:28-33. https://doi.o10.1016/j.jctube.2017.03.001
Monedero, I., & Caminero, J.A. (2013). Common errors in multidrug-resistant tuberculosis management. Expert Review of Respiratory Medicine, 8(1):15-23. https://doi.org/10.1586/17476348.2014.856758
Mulder, C., Rupert, S., Setiawan, E., Mambetova, E., Edo, P., Sugiharto, J., et al. (2022). Budgetary impact of using BPaL for treating extensively drug-resistant tuberculosis. BMJ Global Health, 7(1):e007182. https://doi.org/10.1136/bmjgh-2021-007182
Nyang’wa, B.T., Berry, C., Kazounis, E., Motta, I., Parpieva, N., Tigay, Z., et al. (2022). A 24-week, All-oral regimen for Rifampin-Resistant Tuberculosis. The New England Journal of Medicine, 387(25):2331-2343. https://doi.org/10.1056/NEJMoa2117166
Oliosi, J.G.N., Reis-Santos, B., Locatelli, R.L., Sales, C.M.M., da Silva Filho, W.G., da Silva, K.C., et al. (2019). Effect of the Bolsa Familia Programme on the outcome of tuberculosis treatment: A prospective cohort study. The Lancet Global Health, 7(2):219-226. https://doi.org/10.1016/S2214-109X(18)30478-9
Onorato, L., Gentile, V., Russo, A., Di Caprio, G., Alessio, L., Chiodini, P., et al. (2021). Standard versus high dose of rifampicin in the treatment of pulmonary tuberculosis: A systematic review and meta-analysis. Clinical Microbiology and Infection, 27(6):830-837. https://doi.org/10.1016/j.cmi.2021.03.031
Ou, Z.J., Yu, D.F., Liang, Y.H., He, W.Q., Li, Y.Z., Meng, Y.X., et al. (2021). Trends in burden of multidrug-resistant tuberculosis in countries, regions, and worldwide from 1990 to 2017: Results from the Global Burden of Disease study. Infectious Diseases of Poverty, 10(1):24. https://doi.orgg/10.1186/s40249-021-00803-w
Riccardi, N., Canetti, D., Martini, M., Diaw, M.M., DI Biagio, A., Codecasa, L., et al. (2020). The evolution of a neglected disease: Tuberculosis discoveries in the centuries. Journal of Preventive Medicine and Hygiene, 61(1):E9-E12. https://doi.org/10.15167/2421-4248/jpmh2020.61.1s1.1353
Rockwood, N., Du Bruyn, E., Morris, T., & Wilkinson, R.J. (2016). Assessment of treatment response in tuberculosis. Expert Review of Respiratory Medicine, 10(6):643-654. https://doi.org/10.1586/17476348.2016.1166960
Saderi, L., Cabibbe, A.M., Puci, M., Di Lorenzo, B., Centis, R., Pontali, E., et al. (2023). A systematic review of the costs of diagnosis for multidrug-resistant/extensively drug-resistant TB in different settings. The International Union Against Tuberculosis and Lung Disease, 27(5):348-356. https://doi.org/10.5588/ijtld.22.0657
Seijger, C., Hoefsloor, W., Bergsma-de Guchteneire, I., Te Brake, L., van Ingen, J., Kuipers, S., et al. (2019). High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre. PLoS One, 14(3):e0213718. https://doi.org/10.1371/journal.pone.0213718
Sinha, P., Jacobson, K.R., Horsburgh, C.R. Jr., & Acuña- Villaorduña, C. (2023). At long last: Short, all-oral regimes for multidrug-resistant Tuberculosis in the United States. Open Forum Infectious Diseases, 10(4):ofad177. https://doi.org/10.1093/ofid/ofad177
Stop TB Partnership. (2023). Stop TB’s Global Drug Facility Announces Historic Price Reductions up to 55% for Bedaquiline, a Life-Saving Drug to Treat Drug-Resistant TB. Geneva: Stop TB Partnership. Available from: https://www. stoptb.org/news/stop-tbs-global-drug-facility-announces-historic-price-reductions-to-55-bedaquiline-life-saving [Last accessed on 2024 Jan 24].
Storla, D.G., Yimer, S., & Bjune, G.A. (2008). A systematic review of delay in the diagnosis and treatment of tuberculosis. BMC Public Health, 8:15. https://doi.org/10.1186/1471-2458-8-15
Subbaraman, R., de Mondesert, L., Musiimenta, A., Pai, M., Mayer, K.H., Thomas, B.E., et al. (2018). Digital adherence technologies for the management of tuberculosis therapy: Mapping the landscape and research priorities. BMJ Global Health, 3(5):e001018. https://doi.org/10.1136/bmjgh-2018-001018
Sultana, Z.Z., Ul Hoque, F., Beyene, J., Akhlak-Ul-Islam, M., Khan, M.H.R., Ahmed, S., et al. (2021). HIV infection and multidrug resistant tuberculosis: A systematic review and meta-analysis. BMC Infectious Diseases, 21(1):51. https://doi.org/10.1186/s12879-020-05749-2
Suppli, C.H., Norman, A., Folkvardsen, D.B., Gissel, T.N., Weinreich, U.M., Koch, A., et al. (2022). First outbreak of multidrug-resistant tuberculosis (MDR-TB) in Denmark involving six Danish-born cases. International Journal of Infectious Diseases, 117:258-263. https://doi.org/10.1016/j.ijid.2022.02.017
Tanimura, T., Jaramillo, E., Weil, D., Raviglione, M., & Lönnroth, K. (2014). Financial burden for tuberculosis patients in low- and middle-income countries: A systematic review. European Respiratory Journal, 43(6):1763-1775. https://doi.org/10.1183/09031936.00193413
United Nations. (2018). High Level Meeting on the Fight Against Tuberculosis. New York, USA: United Nations Publications. Available from: https://cdn.who.int/ media/docs/default-source/documents/tuberculosis/ pol i t i cal-declarat ion-un-general - assembly-tb-tuberculosis77cd7a27-7e8d-4fbb-9729-a5dbd505798f. pdf?sfvrsn=4f4090dc_1&download=true [Last accessed on 2024 Jan 26].
Van den Hof, S., Collins, D., Hafidz, F., Beyene, D., Tursynbayeva, A., & Tiemersma, E. (2016). The socioeconomic impact of multidrug resistant tuberculosis on patients: rEsults from Ethiopia, Indonesia and Kazakhstan. BMC Infectious Diseases, 16(1):470. https://doi.org/10.1186/s12879-016-1802-x
Van Rie, A., Walker, T., de Jong, B., Rupasinghe, P., Rivière, E., Dartois, V., et al. (2022). Balancing access to BPaLM regimens and risk of resistance. Lancet Infectious Diseases, 22(10):1411-1412. https://doi.org/10.1016/S1473-3099(22)00543-6
World Health Organization. (2014). Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis. Available from: https://www. ncbi.nlm.nih.gov/books/NBK247432 [Last accessed on 2024 Jan 25].
World Health Organization. (2015). The End TB Strategy. Available from: https://who-htm-tb-2015.19-eng.pdf [Last accessed on 2024 Jan 20].
World Health Organization. (2021). Global Tuberculosis Report 2021. Available from: https://iris.who.int/bitstream/han dle/10665/346387/9789240037021-eng.pdf?sequence=1 [Last accessed on 2024 Jan 20].
World Health Organization. (2021). WHO Consolidated Guidelines on Tuberculosis. Module 3: Diagnosis - Rapid Diagnostics for Tuberculosis Detection, 2021 Update. Available from: https://iris.who.int/bitstream/han dle/10665/376221/9789240089488-eng.pdf?sequence=1 [Last accessed on 2024 Jan 20].
World Health Organization. (2021). WHO Global Lists of High Burden Countries for Tuberculosis (TB), TB/HIV and Multidrug/Rifampicin-Resistant TB (MDR/RR-TB), 2021- 2025: Background Document. Available from: https://www. who.int/news/item/17-06-2021-who-releases-new-global-lists-of-high-burden-countries-for-tb-hiv-associated-tb-and-drug-resistant-tb [Last accessd on 2024 Jan 24].
World Health Organization. (2022). WHO Consolidated Guidelines on Tuberculosis: Module 4: Treatment-drug Resistant Tuberculosis Treatment, 2022 Update. Available from: https://www.ncbi.nlm.nih.gov/books/NBK588557 [Last accessed on 2024 Jan 30].
World Health Organization. (2023). Global Tuberculosis Report 2023. Available from: https://cdn.who.int/media/ docs/default-source/hq-tuberculosis/global-tuberculosis-report-2023/top-findings-and-messages-in-the-2023- report.pdf?sfvrsn=2d4dd1bd_18&download=true [Last accessed on 2024 Jan 20].
Xi, Y., Zhang, W., Qiao, R.J., & Tang, J. (2022). Risk factors for multidrug-resistant tuberculosis: A worldwide systematic review and meta-analysis. PLoS One, 17(6):e0270003. https://doi.org/10.1371/journal.pone.0270003
Yadav, R.N., Verma, A.K., & Kaushik, G., (2022). Laboratory cost analysis of conventional and newer molecular tests for diagnosis of presumptive multidrug-resistant tuberculosis patients. Journal of Global Infectious Diseases, 14(3):93-98. https://doi.org/10.4103/jgid.jgid_309_21
Yang, T., Chen, T., Che, Y., Chen, Q., & Bo, D. (2020). Factors associated with catastrophic total costs due to tuberculosis under a designated hospital service model: A cross-sectional study in China. BMC Public Health, 20(1):1009. https://doi.org/10.1186/s12889-020-09136-z
Yu, M.C., Chiang, C.T., Lee, J.J., Chien, S.T., Lin, C.J., Lee, S.W., et al. (2018). Treatment outcomes of multidrug-resistant tuberculosis in Taiwan: Tackling loss to follow-up. Clinical Infectious Diseases, 67(2):202-210. https://doi.org/10.1093/cid/ciy066
Zijenah, L.S. (2018). The World Health Organization Recommended TB Diagnostic Tools. Available from: https:// www.the/world/health/organization/recommended/tb/ diagnostic/tools/intechopen [Last accessed on 2024 Feb 22].