title: Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study.
abstract: BACKGROUND
  The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) can detect tuberculosis and its multidrug-resistant form with very high sensitivity and specificity in controlled studies, but no performance data exist from district and subdistrict health facilities in tuberculosis-endemic countries. We aimed to assess operational feasibility, accuracy, and effectiveness of implementation in such settings.
  
  
  METHODS
  We assessed adults (≥18 years) with suspected tuberculosis or multidrug-resistant tuberculosis consecutively presenting with cough lasting at least 2 weeks to urban health centres in South Africa, Peru, and India, drug-resistance screening facilities in Azerbaijan and the Philippines, and an emergency room in Uganda. Patients were excluded from the main analyses if their second sputum sample was collected more than 1 week after the first sample, or if no valid reference standard or MTB/RIF test was available. We compared one-off direct MTB/RIF testing in nine microscopy laboratories adjacent to study sites with 2-3 sputum smears and 1-3 cultures, dependent on site, and drug-susceptibility testing. We assessed indicators of robustness including indeterminate rate and between-site performance, and compared time to detection, reporting, and treatment, and patient dropouts for the techniques used.
  
  
  RESULTS
  We enrolled 6648 participants between Aug 11, 2009, and June 26, 2010. One-off MTB/RIF testing detected 933 (90·3%) of 1033 culture-confirmed cases of tuberculosis, compared with 699 (67·1%) of 1041 for microscopy. MTB/RIF test sensitivity was 76·9% in smear-negative, culture-positive patients (296 of 385 samples), and 99·0% specific (2846 of 2876 non-tuberculosis samples). MTB/RIF test sensitivity for rifampicin resistance was 94·4% (236 of 250) and specificity was 98·3% (796 of 810). Unlike microscopy, MTB/RIF test sensitivity was not significantly lower in patients with HIV co-infection. Median time to detection of tuberculosis for the MTB/RIF test was 0 days (IQR 0-1), compared with 1 day (0-1) for microscopy, 30 days (23-43) for solid culture, and 16 days (13-21) for liquid culture. Median time to detection of resistance was 20 days (10-26) for line-probe assay and 106 days (30-124) for conventional drug-susceptibility testing. Use of the MTB/RIF test reduced median time to treatment for smear-negative tuberculosis from 56 days (39-81) to 5 days (2-8). The indeterminate rate of MTB/RIF testing was 2·4% (126 of 5321 samples) compared with 4·6% (441 of 9690) for cultures.
  
  
  CONCLUSIONS
  The MTB/RIF test can effectively be used in low-resource settings to simplify patients' access to early and accurate diagnosis, thereby potentially decreasing morbidity associated with diagnostic delay, dropout and mistreatment.
  
  
  BACKGROUND
  Foundation for Innovative New Diagnostics, Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership (TA2007.40200.009), Wellcome Trust (085251/B/08/Z), and UK Department for International Development.
authors.affiliation: Foundation for Innovative New Diagnostics, Geneva, Switzerland. catharina.boehme@finddiagnostics.org
authors.forename: Catharina C
authors.initials: CC
authors.lastname: Boehme
authors.forename: Mark P
authors.initials: MP
authors.lastname: Nicol
authors.forename: Pamela
authors.initials: P
authors.lastname: Nabeta
authors.forename: Joy S
authors.initials: JS
authors.lastname: Michael
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gotuzzo
authors.forename: Rasim
authors.initials: R
authors.lastname: Tahirli
authors.forename: Ma Tarcela
authors.initials: MT
authors.lastname: Gler
authors.forename: Robert
authors.initials: R
authors.lastname: Blakemore
authors.forename: William
authors.initials: W
authors.lastname: Worodria
authors.forename: Christen
authors.initials: C
authors.lastname: Gray
authors.forename: Laurence
authors.initials: L
authors.lastname: Huang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Caceres
authors.forename: Rafail
authors.initials: R
authors.lastname: Mehdiyev
authors.forename: Lawrence
authors.initials: L
authors.lastname: Raymond
authors.forename: Andrew
authors.initials: A
authors.lastname: Whitelaw
authors.forename: Kalaiselvan
authors.initials: K
authors.lastname: Sagadevan
authors.forename: Heather
authors.initials: H
authors.lastname: Alexander
authors.forename: Heidi
authors.initials: H
authors.lastname: Albert
authors.forename: Frank
authors.initials: F
authors.lastname: Cobelens
authors.forename: Helen
authors.initials: H
authors.lastname: Cox
authors.forename: David
authors.initials: D
authors.lastname: Alland
authors.forename: Mark D
authors.initials: MD
authors.lastname: Perkins
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000904:Antibiotics, Antitubercular / Q000494:pharmacology* / Q000627:therapeutic use; D001431:Bacteriological Techniques; D003906:Developing Countries; D024881:Drug Resistance, Bacterial; D005260:Female; D018023:HIV Seronegativity; D006679:HIV Seropositivity / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D012293:Rifampin / Q000494:pharmacology* / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D013183:Sputum / Q000382:microbiology*; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis* / Q000188:drug therapy / Q000821:virology; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis* / Q000188:drug therapy / Q000821:virology; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin