Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil

Five sites from four different regions in Brazil were included: inpatient services at Hospital Sanatorio Partenon-Secretaria Estadual de Saúde do Rio Grande do Sul (HU-SES-RGS), Hospital Messejana – Secretaria Estadual do Ceará (HM-SES-CE), Instituto Estadual Ary Parreiras – Secretaria Estadual do Rio de Janeiro (IETAP-SES-RJ), outpatient services at Instituto Clemente Ferreira – Secretaria Estadual de São Paulo (ICF-SES-SP) and, Centro de Referência Hélio Fraga – Fundação Oswaldo Cruz – Rio de Janeiro (CRPHF-Fiocruz-RJ).

Eligible participants were any patients aged 18 years and older with cough for 3 weeks or more and, in accordance with national guidance [22], with the presence of at least one of the following social-clinical conditions defining them as pDR TB at triage as follows: (a) suspected re-treatment failure or previous treatment default; (b) HIV seropositive subjects, c) close contact with smear positive MDR-TB cases, (d) homeless or e) hospitalization in TB reference centers. All participants gave written Informed Consent. Subjects were excluded if they: (a) had DST results (drug resistant or drug sensitive) from another laboratory that had been used by an attending physician to start anti-TB treatment at triage; (b) had no laboratory assessment of the drug sensitivity confirmation of M. tuberculosis; (c) were harboring environmental mycobacteria and, (d) had no clinical and/or laboratory results available in the medical records.

Local study staff was comprised by one of each of the following: a attending physician, a nurse, and a laboratory technician that belonged to the professional staff of the Health Unit. During the study period, the survey was carried out by the study staff on all presumed drug resistant TB that fulfilled the eligibility criteria and was attended consecutively in five Health Units. Prospectively, routinely collected clinical data were extracted onto a Study Form from patient registers and clinical records. Patient registers contained information on all included patients listed in consecutive order with name, age, sex, address, phone number, type of patients (previous treatment classification) and date of diagnosis (when available). Also, it was collected from medical records, clinical data, socio-demographics, previous treatment failures or defaults, HIV status and hospitalization. Clinical samples collected in Health Units were sent to a local laboratory using standard practice. Laboratories issued results according to routine procedures. All clinical samples from these 5 sites were sent to the local Mycobacterial Laboratory for smear microscopy, culture, drug susceptibility testing and identification at species level. Participants were assigned to have their samples submitted to the following routine bacteriological tests: BACTEC™ MGIT 960™ Mycobacterial Detection System (MGIT960) or Lowenstein-Jensen (LJ)/Ogawa Kudo (OK) and Proportion Method (PM), according to the Brazilian Tuberculosis National Guidelines [22]. Tests were performed according to laboratory routine and the techniques used are all fully described [23]. Clinical and radiological improvement was judged by the attending physicians at each site. TB patients received anti-TB treatment and clinical follow-up from the attending physician as routinely planned in the local algorithm. In summary, routine clinical procedures were not affected by this study. Every 2 months, data monitoring research team checked all clinical and laboratory data collected.

Drug resistant (DR-TB) cases were defined as those harboring M. tb isolates resistant to one or more drugs and multidrug resistant (MDR-TB) cases as resistant to at least Rifampin-RIF and Isoniazid-INH. Drug sensitive (DS-TB) cases were defined as those harboring M.tb isolates susceptible to all first-line anti-TB drugs (RMP, INH, Ethambutol-EMB, Pyrazinamid-PZA and Streptomycin-SM). Empirical treatment was defined when at triage physicians started TB treatment regimen before DST results were available. Appropriate anti-TB treatment was defined accordingly to the regimen prescribed by the attending physician (matching DST results). Interim treatment outcomes were evaluated after 6 months of enrollment using available data from medical records. Retreatment cases were grouped according to the outcome of previous treatment: cured, completed, defaulted or failed. A patient was defined as cured when tested smear-negative at treatment completion or, at least in one of the previous test.

A completed treatment was defined as patients who completed treatment but without smear microscopy proof of cure. Persons who had treatment interruption for two consecutive months or more were grouped as defaulted. Those who remained smear-positive when tested five or 6 months after initiation of their previous treatment were defined as treatment failures. Clinical or radiological improvement and/or culture conversion were considered favorable TB treatment responses. Death from any cause and default were unfavorable. Transferred care cases which had no outcome data were all excluded.

A standard form was created in order to collect data regarding to the following timing: triage (screening visit), sputum collection, DST result released by laboratory, DST results seen by the physician and, initiation or change of TB treatment regimen after DST results. The primary endpoint was time from triage to initiation or change of TB treatment regimen because of the DST result. The secondary endpoint was the proportion of favorable treatment outcomes according to the initial empirical treatment regimen prescribed as follows: with first line drug regimen (RIF + INH + EMB + PZA) or with second line drug regimen (ethionamide, levofloxacin, amikacyn/capreomicyin, clofazimine).

We compared socio-demographic and clinical characteristics between included and excluded patients. Also, we identified the factors associated with drug resistance. Exploratory analysis was carried out through dichotomous outcomes based on the calculation proportion for all the different groups. For continuous outcomes, median and interquartiles were used. Sample distribution of time periods from triage to DST results and to initiate or change TB treatment were compared. Fisher’s Exact Test with mid-p correction for comparisons between proportions was used, as well as the Mann-Whitney Test to compare differences in morbidity. All analyses were performed using SPSS software (version 17).