Impact of the change in the antitubercular regimen from three to four drugs on cure and frequency of adverse reactions in tuberculosis patients from Brazil: A retrospective cohort study

Autoři: María B. Arriaga aff001;  Ninfa M. C. Torres aff001;  Nelia C. N. Araujo aff001;  Simone C. C. Caldas aff002;  Bruno B. Andrade aff002;  Eduardo M. Netto aff001
Působiště autorů: Universidade Federal da Bahia, Salvador, Brazil aff001;  Instituto Brasileiro de Investigação da Tuberculose, Salvador, Brazil aff002;  Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil aff003;  Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador, Brazil aff004;  Universidad Militar Nueva Granada, Bogotá, Colombia aff005;  Curso de Medicina, Faculdade de Tecnologia e Ciências (FTC), Salvador, Brazil aff006;  Curso de Medicina, Universidade Salvador (UNIFACS), Salvador, Brazil aff007;  Escola Bahiana de Medicina e Saúde Pública, Salvador, Brazil aff008
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article



The Ministry of Health in Brazil included ethambutol in the intensive phase of sensible tuberculosis (TB) treatment in March 2010, due to the increasing drug resistance, and implemented the fixed dose combination in the TB treatment guidelines.


A retrospective cohort study was performed to determine the impact of change from three to four drugs schemes on the TB cure and frequency of adverse drug reactions (ADRs) in TB patients. To answer this question, we used data from 730 randomly selected patients who received anti-TB treatment between January 2007 and December 2014 in a reference center from Salvador, Brazil.


TB patients who received the RHEZ regimen (n = 365) developed ADRs more frequently than those treated with the RHZ (n = 365) (86 [23.6%] vs. 55 [15.1%]; p = 0.01). This difference in ADR incidence was even higher in patients above 30 years-old (64 [74.4%] vs. 36 [65.5%]; p = 0.01). The overall number of ADR episodes was greater in patients from the RHEZ group than in the group that received RHZ (170 [61.4%] vs. 107 [38.6%]; p = 0.03). Multivariable logistic regression analysis adjusted for age, alcohol use and diabetes demonstrated that patients receiving the RHEZ regimen had increased odds of developing ADRs than those undertaking the RHZ scheme (odds ratio [OR]: 1.61, 95% confidence interval [CI]: 1.10–2.35; p = 0.015). The overall cure rate was similar between the distinct treatment groups.


The patients treated with the four-drug regimen exhibited increased risk of ADRs compared to those who received the three-drug regimen, and especially in patients older than 30 years of age.

Klíčová slova:

Adverse reactions – Antibiotic resistance – Brazil – Drug therapy – Extensively drug-resistant tuberculosis – Isoniazid – Tuberculosis – Tuberculosis diagnosis and management


1. World Health Organization Global Tuberculosis Programme G. Global Tuberculosis Report 2016. Geneva; 2016.

2. International Union Against Tuberculosis and Lung Diseases (IUATLD), WHO Tuberculosis Programme. The promise and reality of fixed-dose combinations with rifampicin. Int Union Against Tuberc Lung Dis. 1994;69: 219–220.

3. World Health Organization Global Tuberculosis Programme G. Treatment of Tuberculosis Guidelines for National Programmes [Internet]. 2003 [cited 19 Sep 2016]. Available:

4. World Health Organization / International Union Against Tuberculosis and Lung Disease Global Project on Anti-tuberculosis Drug Resistance Surveillence 1994–1997. Anti-Tuberculosis Drug Resistance in the World Report No. 1. Geneva; 1997.

5. World Health Organization Global Tuberculosis Programme G. Global Tuberculosis Report 2009. Geneva; 2009.

6. Nacional P, Inqu II. Nota técnica sobre as mudanças no tratamento da tuberculose no Brasil para adultos e adolescentes. 2009.

7. BRASIL M da S do. Nota técnica sobre as mudanças no tratamento da tuberculose no Brasil para adultos e adolescentes [Internet]. 2009 p. 5.

8. Vieira DEO, Gomes M. Efeitos adversos no tratamento da tuberculose: experiência em serviço ambulatorial de um hospital-escola na cidade de São Paulo. J Bras Pneumol. 2008;34: 1049–1055. doi: 10.1590/s1806-37132008001200010 19180340

9. Schaberg T, Rebhan K, Lode H. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J. 1996;9: 2026–2030. doi: 10.1183/09031936.96.09102026 8902462.

10. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf. 2006;5: 231–249. [PubMed: doi: 10.1517/14740338.5.2.231 16503745].

11. Marra F, Marra C a, Bruchet N, Richardson K, Moadebi S, Elwood RK, et al. Adverse drug reactions associated with first-line anti-tuberculosis drug regimens. Int J Tuberc Lung Dis. 2007;11: 868–875. [PubMed: 17705952].

12. Slatery E. Neglected or Non-compliant? Assessing the difficulties of tuberculosis patients in Salvador-BA, Brazil. Indep Study Proj Collect. 2014; 1–45. Available:

13. Nacional P, Devep T. Mudanças no tratamento da tuberculose no Brasil [Internet]. [cited 27 Jul 2016]. Available:çasnoTratamentodaTuberculose—apresentaçãoparaareuniãodemultiplicadores.pdf

14. DATASUS—SIM—Sistema de Informação sobre Mortalidade [Internet]. [cited 28 Nov 2016]. Available:

15. SINAN—Sistema de Informação de Agravos de Notificação [Internet]. [cited 28 Nov 2016]. Available:

16. Diretoria de Vigilância Epidemiológica. Boletim Epidemiológico Avanços no Diagnóstico da Tuberculose [Internet]. Brasília; 2015. pp. 1–4. Available:

17. Sullivan KM, Dean A. OPENEPI: A Web-based epidemiologic and statistical calculator for Public Health. 2009;124: 471–474. doi: 10.1177/003335490912400320 19445426

18. World Health Organization—Geneva. Safety Monitoring of Medicinal Products [Internet]. 2012 [cited 25 Sep 2016]. Available:

19. World Health Organization—Geneva. The WHO Adverse Reaction Terminology–WHO-ART [Internet]. 2015 [cited 18 Sep 2016]. Available:

20. Naranjo et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 239–245. doi: 10.1038/clpt.1981.154 7249508

21. World Health Organization. WHOPAR TB158 [Internet]. [cited 26 Nov 2016]. Available:

22. World Health Organization. WHOPAR TB168 [Internet]. [cited 26 Nov 2016]. Available:

23. World Health Organization. WHO List of Prequalified Medicinal Products [Internet]. [cited 11 Nov 2016]. Available:

24. National Institute for Health and Care Excellence. Tuberculosis [Internet]. United Kingdom; 2016 [cited 25 Sep 2016] pp. 1–178. Available:

25. 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: 853–867. doi: 10.1093/cid/ciw566 27621353

26. Khade Amitkumar Anandrao and Vishal Janu Gothal K. Incidence and comparative analysis of adverse drug reactions in DOTS. Int J Pharm Sci Res. 2013;4: 3641–3644. doi: 10.13040/IJPSR.0975-8232.4(9).3641–44

27. Nazir A, Imam SF, Shabbir I, Saleem S. Adverse Drug Reactions of First Line Anti-tuberculosis Drugs used in DOTS Implemented Setting in Lahore. Pak J Med Res. 2015;54: 101–105. Available:

28. Maciel ELN, Guidoni LM, Favero JL, Hadad DJ, Molino LP, Jonhson JL, et al. Adverse effects of the new tuberculosis treatment regimen recommended by the Brazilian Ministry of Health. J Bras Pneumol. 36: 232–238. [PubMed: doi: 10.1590/s1806-37132010000200012 20485945 ].

29. Chung-Delgado K, Revilla-Montag A, Guillen-Bravo S, Velez-Segovia E, Soria-Montoya A, Nuñez-Garbin A, et al. Factors associated with anti-tuberculosis medication adverse effects: A case-control study in Lima, Peru. PLoS One. 2011;6: 1–6. doi: 10.1371/journal.pone.0027610 22110689

30. Zhang T, Du J, Yin X, Xue F, Liu Y, Li R, et al. Adverse Events in Treating Smear-Positive Tuberculosis Patients in China. Int J Environ Res Public Health. 2015;13: 1–11. [PubMed: doi: 10.3390/ijerph13010086 26729141].

31. IBGE:: Instituto Brasileiro de Geografia e Estatística. Projeção da populacão do Brasil pelo sexo e idade: 2000–2060 [Internet]. [cited 25 Sep 2016]. Available:

32. Gaspar RS, Nunes N, Nunes M, Rodrigues VP. Temporal analysis of reported cases of tuberculosis and of tuberculosis-HIV co-infection in Brazil between 2002 and 2012. J Bras Pneumol. 2016;42: 416–422. doi: 10.1590/S1806-37562016000000054 28117471

33. Shin HJ, Kwon YS. Treatment of drug susceptible pulmonary tuberculosis. Tuberc Respir Dis (Seoul). 2015;78: 161–167. doi: 10.4046/trd.2015.78.3.161 26175767

34. Sadiq S, Khajuria V, Tandon VR, Mahajan A, Singh JB. Adverse Drug Reaction Profile in Patients on Anti-tubercular Treatment Alone and in Combination with Highly Active Antiretroviral Therapy. J Clin diagnostic Res. 2015;9: FC01–FC04. [PubMed: 4625257]. doi: 10.7860/JCDR/2015/13452.6652.

35. Resende LSO, Dos Santos-Neto ET. Risk factors associated with adverse reactions to antituberculosis drugs. J Bras Pneumol. 2015;41: 77–89. doi: 10.1590/S1806-37132015000100010 25750677.

36. Sahu R, Singh K, Subodh S. Adverse Drug Reactions to Anti-TB Drugs: Pharmacogenomics Perspective for Identification of Host Genetic Markers. Curr Drug Metab. 2015;16: 538–552. doi: 10.2174/1389200216666150812123725 26264201

37. Zeng J, Xie L, Luo H, Xie J. The epigenetic modifications of genes associated with tuberculosis susceptibility and implications for Epi-drugs. Crit Rev Eukaryot Gene Expr. 2015;25: 349–362. doi: 10.1615/critreveukaryotgeneexpr.2015014334 26559095

38. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ. 2001;79: 61–68. [PubMed: 11217670]. S0042-96862001000100012 [pii]

39. Mitchison DA. Infectivity of patients with pulmonary tuberculosis during chemotherapy. Eur Respir J. 1990; 385–386. 2114306

40. Gallardo Carmen R, Rigau Comas D, Valderrama Rodríguez A, Roqué i Figuls M, Parker Lucy A, Caylà J, et al. Fixed-dose combinations of drugs versus single drug formulations for treating pulmonary tuberculosis. Cochrane Database Syst Rev. 2016; 1–147 [PubMed: 27186634] doi: 10.1002/14651858.CD012199

41. Albanna AS, Smith BM, Cowan D, Menzies D. Fixed-dose combination antituberculosis therapy: a systematic review and meta-analysis. Eur Respir J. 2013;42: 721–732. [PubMed: doi: 10.1183/09031936.00180612 23314904].

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