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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Conclusion: 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.

Fig 1. Study flow diagram.

IBIT: Brazilian Institute for Tuberculosis Investigation (Reference Health Center); RHZ: Rifampicin (600mg), Isoniazid (400mg) and Pyrazinamide (2000mg). Dose to patients >45kg; RHEZ: Rifampicin (150mg), Isoniazid (75mg), Ethambutol (275mg) and Pyrazinamide (400mg) (fixed dose combination-FDC).

Fig 2. Distribution of ADRs in TB patients.

(A) Frequency of ADRs in patients with RHZ and RHEZ anti- TB regime. (B) Outcomes treatment were compared between patients with RHZ and RHEZ anti-TB treatment. The significant p values are shown. (C) ADRs frequencies of anti-TB treatment groups with RHZ and RHEZ are shown. (D) ADRs distribution for systems were compared between patients with RHZ and RHEZ anti-TB treatment. The significant p-values are shown. Others: Hepatic, ocular, circulatory and respiratory system.

Fig 3. MDR-TB cases and crude and odds ratio for adverse drug reaction in tuberculosis patients.

(A) Total number of MDR-TB cases shown per year in Brazil, Salvador and IBIT (B) A multivariable regression model adjusted for RHEZ-FDC treatment, age ≥ 30 years, alcohol consumption and diabetes. The odds associated with the covariates used in the model adjustment are displayed in Table 3. OR = Odds ratio; CI = confidence intervals.