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Introduction: Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome.

Aim: We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB.

Methods: In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002–14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries.

Results: A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6–0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2–1.5), male sex (OR: 1.3; 95% CI: 1.1–1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1–1.4), positive HIV status (OR: 3.3; 95% CI: 1.6–6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5–2.2).

Conclusions: This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.


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  1. World Health Organization (WHO). Global Tuberculosis Report 2017. Geneva: WHO; 2017. Available from: http://www.who.int/tb/publications/global_report/en/
  2. Hollo V, Beauté J, Ködmön C, van der Werf MJ. Tuberculosis notification rate decreases faster in residents of native origin than in residents of foreign origin in the EU/EEA, 2010 to 2015. Euro Surveill. 2017;22(12):30486.  https://doi.org/10.2807/1560-7917.ES.2017.22.12.30486  PMID: 28367798 
  3. European Centre for Disease Prevention and Control (ECDC) / WHO Regional Office for Europe (WHO/Europe). Tuberculosis surveillance and monitoring in Europe 2017. Stockholm: ECDC; 2017. Available from: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/ecdc-tuberculosis-surveillance-monitoring-Europe-2017.pdf
  4. van der Werf MJ, Ködmön C, Hollo V, Sandgren A, Zucs P. Drug resistance among tuberculosis cases in the European Union and European Economic Area, 2007 to 2012. Euro Surveill. 2014;19(10):20733.  https://doi.org/10.2807/1560-7917.ES2014.19.10.20733  PMID: 24650865 
  5. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000;4(9):796-806. PMID: 10985648 
  6. Stagg HR, Lipman MC, McHugh TD, Jenkins HE. Isoniazid-resistant tuberculosis: a cause for concern? Int J Tuberc Lung Dis. 2017;21(2):129-39.  https://doi.org/10.5588/ijtld.16.0716  PMID: 28234075 
  7. Jenkins HE, Zignol M, Cohen T. Quantifying the burden and trends of isoniazid resistant tuberculosis, 1994-2009. PLoS One. 2011;6(7):e22927.  https://doi.org/10.1371/journal.pone.0022927  PMID: 21829557 
  8. Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17(2):223-34.  https://doi.org/10.1016/S1473-3099(16)30407-8  PMID: 27865891 
  9. Law S, Benedetti A, Oxlade O, Schwartzman K, Menzies D. Comparing cost-effectiveness of standardised tuberculosis treatments given varying drug resistance. Eur Respir J. 2014;43(2):566-81.  https://doi.org/10.1183/09031936.00005613  PMID: 23766335 
  10. Cattamanchi A, Dantes RB, Metcalfe JZ, Jarlsberg LG, Grinsdale J, Kawamura LM, et al. Clinical characteristics and treatment outcomes of patients with isoniazid-monoresistant tuberculosis. Clin Infect Dis. 2009;48(2):179-85.  https://doi.org/10.1086/595689  PMID: 19086909 
  11. Jacobson KR, Theron D, Victor TC, Streicher EM, Warren RM, Murray MB. Treatment outcomes of isoniazid-resistant tuberculosis patients, Western Cape Province, South Africa. Clin Infect Dis. 2011;53(4):369-72.  https://doi.org/10.1093/cid/cir406  PMID: 21810750 
  12. Bang D, Andersen PH, Andersen AB, Thomsen VO. Isoniazid-resistant tuberculosis in Denmark: mutations, transmission and treatment outcome. J Infect. 2010;60(6):452-7.  https://doi.org/10.1016/j.jinf.2010.03.017  PMID: 20347869 
  13. Garcia-Prats AJ, du Plessis L, Draper HR, Burger A, Seddon JA, Zimri K, et al. Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children. Int J Tuberc Lung Dis. 2016;20(11):1469-76.  https://doi.org/10.5588/ijtld.16.0293  PMID: 27776587 
  14. Yuen CM, Jenkins HE, Rodriguez CA, Keshavjee S, Becerra MC. Global and Regional Burden of Isoniazid-Resistant Tuberculosis. Pediatrics. 2015;136(1):e50-9.  https://doi.org/10.1542/peds.2015-0172  PMID: 26034243 
  15. Karo B, Krause G, Hollo V, van der Werf MJ, Castell S, Hamouda O, et al. Impact of HIV infection on treatment outcome of tuberculosis in Europe. AIDS. 2016;30(7):1089-98.  https://doi.org/10.1097/QAD.0000000000001016  PMID: 26752278 
  16. Stagg HR, Harris RJ, Hatherell HA, Obach D, Zhao H, Tsuchiya N, et al. What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis. Thorax. 2016;71(10):940-9.  https://doi.org/10.1136/thoraxjnl-2015-208262  PMID: 27298314 
  17. Fregonese F, Ahuja SD, Akkerman OW, Arakaki-Sanchez D, Ayakaka I, Baghaei P, et al. Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med. 2018;6(4):265-75.  https://doi.org/10.1016/S2213-2600(18)30078-X  PMID: 29595509 
  18. World Health Organization (WHO). WHO treatment guidelines for isoniazid-resistant tuberculosis - supplement to the WHO treatment guidelines for drug-resistant tuberculosis. Geneva: WHO; 2018. Available from: http://www.who.int/tb/publications/2018/WHO_guidelines_isoniazid_resistant_TB/en/
  19. European Commission. Commission Regulation No 2119/98/EC of 24 September 1998 on setting up a network for the epidemiological surveillance and control of communicable diseases in the Community. Official Journal of the European Union. Luxembourg: Publications Office of the European Union. 3.10.1998:L 268/1. Available from: https://eur-lex.europa.eu/resource.html?uri=cellar:293fab95-972a-4d0c-ba28-45d9055fe1a3.0008.02/DOC_1&format=PDF
  20. Menzies D, Benedetti A, Paydar A, Royce S, Madhukar P, Burman W, et al. Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med. 2009;6(9):e1000150.  https://doi.org/10.1371/journal.pmed.1000150  PMID: 20101802 
  21. Fox L, Kramer MR, Haim I, Priess R, Metvachuk A, Shitrit D. Comparison of isoniazid monoresistant tuberculosis with drug-susceptible tuberculosis and multidrug-resistant tuberculosis. Eur J Clin Microbiol Infect Dis. 2011;30(7):863-7.  https://doi.org/10.1007/s10096-011-1167-4  PMID: 21431989 
  22. Villegas L, Otero L, Sterling TR, Huaman MA, Van der Stuyft P, Gotuzzo E, et al. Prevalence, Risk Factors, and Treatment Outcomes of Isoniazid- and Rifampicin-Mono-Resistant Pulmonary Tuberculosis in Lima, Peru. PLoS One. 2016;11(4):e0152933.  https://doi.org/10.1371/journal.pone.0152933  PMID: 27045684 
  23. Báez-Saldaña R, Delgado-Sánchez G, García-García L, Cruz-Hervert LP, Montesinos-Castillo M, Ferreyra-Reyes L, et al. Isoniazid Mono-Resistant Tuberculosis: Impact on Treatment Outcome and Survival of Pulmonary Tuberculosis Patients in Southern Mexico 1995-2010. PLoS One. 2016;11(12):e0168955.  https://doi.org/10.1371/journal.pone.0168955  PMID: 28030600 
  24. Gegia M, Cohen T, Kalandadze I, Vashakidze L, Furin J. Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007-2009. Int J Tuberc Lung Dis. 2012;16(6):812-6.  https://doi.org/10.5588/ijtld.11.0637  PMID: 22507372 
  25. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167(4):603-62.  https://doi.org/10.1164/rccm.167.4.603  PMID: 12588714 
  26. National Institute for Health and Care Excellence (NICE). Tuberculosis. London: NICE. [Accessed 13 Nov 2018: ]. Available from: https://www.nice.org.uk/guidance/ng33/chapter/Recommendations#managing-active-tb-in-all-age-groups
  27. Waitt CJ, Squire SB. A systematic review of risk factors for death in adults during and after tuberculosis treatment. Int J Tuberc Lung Dis. 2011;15(7):871-85.  https://doi.org/10.5588/ijtld.10.0352  PMID: 21496360 
  28. Karo B, Hauer B, Hollo V, van der Werf MJ, Fiebig L, Haas W. Tuberculosis treatment outcome in the European Union and European Economic Area: an analysis of surveillance data from 2002-2011. Euro Surveill. 2015;20(49):30087.  https://doi.org/10.2807/1560-7917.ES.2015.20.49.30087  PMID: 26676247 
  29. Wang TY, Lin SM, Shie SS, Chou PC, Huang CD, Chung FT, et al. Clinical characteristics and treatment outcomes of patients with low- and high-concentration isoniazid-monoresistant tuberculosis. PLoS One. 2014;9(1):e86316.  https://doi.org/10.1371/journal.pone.0086316  PMID: 24466020 
  30. Huyen MN, Cobelens FG, Buu TN, Lan NT, Dung NH, Kremer K, et al. Epidemiology of isoniazid resistance mutations and their effect on tuberculosis treatment outcomes. Antimicrob Agents Chemother. 2013;57(8):3620-7.  https://doi.org/10.1128/AAC.00077-13  PMID: 23689727 
  31. Lönnroth K, Migliori GB, Abubakar I, D’Ambrosio L, de Vries G, Diel R, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;45(4):928-52.  https://doi.org/10.1183/09031936.00214014  PMID: 25792630 

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