title: Impact of replacing smear microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a stepped-wedge cluster-randomized trial.
abstract: BACKGROUND
  Abundant evidence on Xpert MTB/RIF accuracy for diagnosing tuberculosis (TB) and rifampicin resistance has been produced, yet there are few data on the population benefit of its programmatic use. We assessed whether the implementation of Xpert MTB/RIF in routine conditions would (1) increase the notification rate of laboratory-confirmed pulmonary TB to the national notification system and (2) reduce the time to TB treatment initiation (primary endpoints).
  
  
  RESULTS
  We conducted a stepped-wedge cluster-randomized trial from 4 February to 4 October 2012 in 14 primary care laboratories in two Brazilian cities. Diagnostic specimens were included for 11,705 baseline (smear microscopy) and 12,522 intervention (Xpert MTB/RIF) patients presumed to have TB. Single-sputum-sample Xpert MTB/RIF replaced two-sputum-sample smear microscopy for routine diagnosis of pulmonary TB. In total, 1,137 (9.7%) tests in the baseline arm and 1,777 (14.2%) in the intervention arm were positive (p<0.001), resulting in an increased bacteriologically confirmed notification rate of 59% (95% CI = 31%, 88%). However, the overall notification rate did not increase (15%, 95% CI =  -6%, 37%), and we observed no change in the notification rate for those without a test result (-3%, 95% CI = -37%, 30%). Median time to treatment decreased from 11.4 d (interquartile range [IQR] = 8.5-14.5) to 8.1 d (IQR = 5.4-9.3) (p = 0.04), although not among confirmed cases (median 7.5 [IQR = 4.9-10.0] versus 7.3 [IQR = 3.4-9.0], p = 0.51). Prevalence of rifampicin resistance detected by Xpert was 3.3% (95% CI = 2.4%, 4.3%) among new patients and 7.4% (95% CI = 4.3%, 11.7%) among retreatment patients, with a 98% (95% CI = 87%, 99%) positive predictive value compared to phenotypic drug susceptibility testing. Missing data in the information systems may have biased our primary endpoints. However, sensitivity analyses assessing the effects of missing data did not affect our results.
  
  
  CONCLUSIONS
  Replacing smear microscopy with Xpert MTB/RIF in Brazil increased confirmation of pulmonary TB. An additional benefit was the accurate detection of rifampicin resistance. However, no increase on overall notification rates was observed, possibly because of high rates of empirical TB treatment.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01363765. Please see later in the article for the Editors' Summary.
authors.affiliation: Rio de Janeiro Municipal Health Secretariat, Rio de Janeiro, Brazil; Programa de Pós-graduação em Clínica Médica, Rio de Janeiro Federal University, Rio de Janeiro, Brazil.
authors.forename: Betina
authors.initials: B
authors.lastname: Durovni
authors.affiliation: Rio de Janeiro Municipal Health Secretariat, Rio de Janeiro, Brazil; Programa de Pós-graduação em Doenças Infecciosas, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Brazil.
authors.forename: Valeria
authors.initials: V
authors.lastname: Saraceni
authors.affiliation: KNCV Tuberculosis Foundation, The Hague, The Netherlands; Department of Global Health, Academic Medical Center and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: van den Hof
authors.affiliation: Programa de Pós-graduação em Clínica Médica, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Montreal Chest Institute, McGill University, Montreal, Canada.
authors.forename: Anete
authors.initials: A
authors.lastname: Trajman
authors.affiliation: Programa de Pós-graduação em Doenças Infecciosas, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Brazil; Amazonas State University, Manaus, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cordeiro-Santos
authors.affiliation: Rio de Janeiro Municipal Health Secretariat, Rio de Janeiro, Brazil; Oswaldo Cruz Foundation, Instituto de Pesquisa Evandro Chagas, Rio de Janeiro, Brazil.
authors.forename: Solange
authors.initials: S
authors.lastname: Cavalcante
authors.affiliation: Global Health Strategies, Rio de Janeiro, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Menezes
authors.affiliation: KNCV Tuberculosis Foundation, The Hague, The Netherlands; Department of Global Health, Academic Medical Center and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Cobelens
mesh_terms: D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D001938:Brazil; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D016133:Polymerase Chain Reaction; D012293:Rifampin / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D014376:Tuberculosis / Q000175:diagnosis* / Q000188:drug therapy; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin