Globally, isoniazid-resistant, rifampicin-susceptible TB (Hres-TB) is the most common form of drug-resistant TB. It was estimated that the prevalence of Hres-TB is 7.4% among new cases and 11.4% in previously treated TB patients.1 Hres-TB has been associated with poor treatment outcomes: a meta-analysis revealed that treatment failure, relapse rates and acquired drug resistance were respectively 10.9, 1.8 and 5.1 times higher in Hres-TB than in drug-susceptible TB (DS-TB).2 In most low- and middle-income countries, access to drug susceptibility testing (DST) remains limited. Although Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA) testing is widely available, it only includes resistance testing for rifampicin (RIF, R). Thus, many patients with undiagnosed Hres-TB receive first-line treatment, increasing the possibility of acquiring additional resistance, possibly leading to the emergence of multidrug-resistant TB (MDR-TB).3–7
We conducted a retrospective cohort study in 90 patients with Hres-TB and 134 patients with DS-TB from two TB reference centres in Brazil and Mexico (63 cases from Brazil and 161 cases from Mexico), from January 2014 to December 2019. In the Hres-TB group, 43 patients with monoresistance to isoniazid (INH, H) and 47 with polyresistance (resistance to INH plus another drug(s) other than RIF) were included: 24 were resistant to streptomycin, 11 to pyrazinamide (PZA, Z), 4 to ethambutol (EMB, E), 7 to PZA and streptomycin, and 1 to PZA and EMB (including 7 M. bovis isolates). The aim of this study was 1) to identify factors associated with Hres-TB, 2) to compare the treatment outcomes between Hres-TB and DS-TB, and 3) to evaluate the impact of regimens containing fluoroquinolones. The study was approved by the Research Ethics Committees of Hospital de Clínicas de Porto Alegre, RS, Brazil, and Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
Patients aged ≥16 years with pulmonary or extrapulmonary TB were included in the study. Demographic data, and information about previous TB, comorbidities, TB symptoms, chest-X ray (CXR), TB treatment and outcomes (cure, lost to follow-up, death) were collected. In Brazil and Mexico, DS-TB cases are treated with 2 months of HRZE/4 months of HR (continuation phase drugs are provided daily in Brazil, while in Mexico this is three times per week). In Brazil, Hres-TB cases are treated with 2 months of RZE and levofloxacin (Lfx) or 7 months of RELfx (preferred), or 9 months of HRZE. In Mexico, the preferred regimen is LfxHRZE when Hres-TB is identified before first-line anti-TB treatment is started; if diagnosed after, the inclusion and effectiveness of Lfx were assessed to determine its necessity and benefits. If it is determined that the addition of Lfx would not provide significant advantages, the treatment regimen was continued with HRZE for a duration of 6 to 9 months. Data analysis was performed using IBM SPSS Statistics, v22.0 (IBM Corporation, Armonk, NY, USA). Data were presented as number of cases, mean ± standard deviation (SD), or median with interquartile ranges (IQRs). Categorical comparisons were performed using χ2 test with the Yates’s correction if indicated, Fisher’s exact test or Pearson χ2. Continuous variables were compared using the t-test, Wilcoxon test or analysis of variance.
The demographic and clinical characteristics of Hres-TB and DS-TB cases are shown in the Table. There were no statistically significant differences between the groups. The cured, lost to follow-up and death rates were also not different when comparing cases with INH monoresistance, polyresistance and DS-TB (P > 0.05 for all). In the Hres-TB group, 69 patients were from Mexico and 21 from Brazil. The Brazilian cohort was younger than the Mexican group (39.0 ± 13.0 vs. 47.9 ± 16.8 years; P = 0.027). HIV infection was more frequent among the Brazilians than Mexicans (n = 15, 71.4% vs. n = 6, 10.7%; P < 0.0001). Diabetes was more common in the Mexicans than in Brazilians (n = 20, 36.4% vs. n = 1, 4.8%; P = 0.014). Previous TB treatment was more frequent among Brazilian patients than Mexicans (n = 8, 38.1% vs. n = 2, 3.8%; P < 0.0001). Although genotyping and subspecies identification was not systematically performed at both sites, 40% of INH-resistant isolates in Mexico were due to inhA mutation.
Table.
Demographic, epidemiological, and clinical characteristics of Hres-TB and DS-TB cases
| Variables | Hres-TB (n = 90) n/N (%) |
DS-TB (n = 134) n/N (%) |
P-value |
|---|---|---|---|
| Age, years, mean ± SD | 45.9 ± 16.3 | 44.9 ± 16.5 | 0.655 |
| Males | 66/90 (73.3) | 95/134 (70.9) | 0.805 |
| White race | 15/42 (71.4) | 31/21 (73.8) | 0.999 |
| Smoking | 34/75 (45.3) | 61/134 (45.5) | 0.979 |
| Alcohol abuse | 30/74 (40.5) | 46/134 (34.3) | 0.459 |
| Drug use | 15/74 (20.3) | 26/134 (19.4) | 0.999 |
| HIV | 21/77 (27.3) | 39/134 (29.1) | 0.900 |
| Diabetes | 21/76 (27.6) | 35/134 (26.1) | 0.940 |
| Symptoms | |||
| Cough | 17/21 (81.0) | 33/42 (78.6) | 0.999 |
| Weight loss | 13/21 (61.9) | 24/42 (57.1) | 0.928 |
| Night sweats | 5/21 (23.8) | 21/42 (50.0) | 0.086 |
| Dyspnoea | 8/21 (38.1) | 11/42 (26.2) | 0.497 |
| Chest pain | 7/21 (33.3) | 8/42 (19.0) | 0.347 |
| Fever | 13/21 (61.9) | 29/42 (69.0) | 0.777 |
| Haemoptysis | 0/21 (0) | 2/42 (4.8) | 0.548 |
| Previous TB | 10/73 (13.7) | 20/134 (14.9) | 0.974 |
| Previous treatment dropout | 5/8 (62.5) | 9/14 (64.3) | 0.999 |
| Chest X-ray | |||
| Cavitary lesions | 4/77 (5.2) | 14/123 (11.4) | 0.217 |
| Bilateral pulmonary involvement with cavitary lesions | 12/77 (15.6) | 16/123 (13.0) | 0.763 |
| Bilateral pulmonary involvement, no cavitation | 30/77 (39.0) | 57/123 (46.3) | 0.380 |
| Non-cavitary, non-bilateral pulmonary involvement | 26/77 (33.8) | 30/123 (24.4) | 0.202 |
| Normal | 4/77 (5.2) | 5/123 (4.1) | 0.736 |
| Treatment outcomes | |||
| Cure | 56/77 (72.7) | 53/77 (68.8) | 0.723 |
| Lost to follow-up | 7/77 (9.1) | 12/77 (15.6) | 0.327 |
| Death | 13/77 (16.9) | 12/77 (15.6) | 0.999 |
Hres-TB = isoniazid-resistant TB; DS-TB = drug-susceptible TB; SD = standard deviation.
Among Hres-TB patients, we did not have information on the treatment regimen used in 12 patients. Among the remaining 78 patients, 35 used 6–9 months of HRZE, 30 used regimens containing fluoroquinolones (FQs) (28 Lfx, 2 moxifloxacin, 2 cases received second-line injectables in addition to an FQ due to severe disease and M. bovis isolation), and only 13 used HRZE/HR. Patients treated with FQ-containing regimens had significantly higher cure rates than the patients treated with HRZE (n = 26, 89.7% vs. n = 30, 63.8%; P = 0.027). Loss to follow-up rates were lower among those on FQ regimens compared to those on HRZE (n = 0 vs. n = 7, 14.9%; P = 0.040). Death rates were not statistically different in the two groups (n = 3, 10.3% for FQ regimens vs. n = 9, 19.1% for HRZE; P = 0.354).
Since 2018, WHO guidelines for the treatment of Hres-TB recommend the use of a 6-month regimen with REZ plus Lfx.8–10 Hres-TB cases previously were treated with a 6-month HRZE, which had an acceptable success rate; however, prolonged use of PZA and the risk of relapse were a concern.11 The WHO’s decision was based on an individual-level patient meta-analysis comparing 251 patients in 15 observational studies who received an FQ plus RZE and 1,350 patients with no FQ.8 Patients on FQ had significantly higher odds of treatment success, with no difference in mortality, compared with patients using non-FQ regimens. In the present study, although based on a smaller sample size, we observed similar results. Some studies showed conflicting results regarding the use of FQ regimens for treating Hres-TB.12–14 In a high-income setting, Stagg et al. reported that a 12-month RHZE regimen (with short-duration PZA) was effective independently of FQ addition.12 In a recent multicentre retrospective cohort with 318 patients with Hres-TB, the authors concluded that the addition of FQ was not associated with positive treatment outcomes, except in the group of patients using a combination regimen of 2-months’ REZ and 7–10 months’ RE.14
This study had some limitations. First, it is a retrospective cohort study and some data are missing, including detailed information on the treatment used and outcomes for some patients. Second, due to the observational nature of the study design, we cannot exclude the risk of selection bias and confounding factors. On the other hand, this study included patients from two TB centres in two countries, bringing more evidence on the benefits of using regimens with FQ for the treatment of Hres-TB.
In conclusion, there are still a large number of patients with Hres-TB who are not identified early. DST, not just for RIF, should be available to all individuals with TB, to allow for a timely decision on the best treatment regimen. In addition, the use of FQ-containing regimens should be further evaluated in randomised clinical trials.
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