title: Evaluation of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in a high HIV prevalence setting.
abstract: BACKGROUND
  Xpert MTB/RIF is a novel automated molecular diagnostic recently endorsed by the World Health Organization. However, performance-related data from high HIV prevalence settings are limited.
  
  
  OBJECTIVE
  The impact of sample-related factors on performance and the significance of Xpert MTB/RIF-positive culture-negative discordance remain unclear.
  
  
  METHODS
  Xpert MTB/RIF was evaluated using single archived spot-sputum samples from 496 South African patients with suspected TB. Mycobacterium tuberculosis culture positivity and phenotypic resistance to rifampicin served as reference standards.
  
  
  RESULTS
  Overall, Xpert MTB/RIF detected 95% (95% confidence interval [CI], 88-98%; 89 of 94) of smear-positive culture-positive cases and the specificity was 94% (91-96%; 320 of 339). The sensitivity in smear-negative cases was 55% (35-73%; 12 of 22) when the analysis was restricted to 1 ml of unprocessed sputum and culture time-to-positivity of less than or equal to 28 days. Compared with smear microscopy (n=94), Xpert MTB/RIF detected an additional 17 cases (n=111) representing an 18% (11-27%; 111 vs. 94) relative increase in the rapid TB case detection rate. Moreover, compared with smear microscopy, the inclusion of Xpert MTB/RIF-positive culture-negative TB cases (ruled-in by an alternative diagnostic method) resulted in the detection of a further 16 cases (n=127), thus significantly increasing the rapid TB case detection rate to 35% (95% CI, 26-45%; 94 to 111 vs. 94 to 127; P<0.01), the overall specificity to 99.1% (97-100%; 320 of 323; P<0.001), and sensitivity in smear-negative TB to 60% (P=0.12). Performance strongly correlated with smear status and culture time-to-positivity. In patients infected with HIV compared with patients uninfected with HIV Xpert MTB/RIF showed a trend to reduced sensitivity (P=0.09) and significantly reduced negative predictive value (P=0.01). The negative predictive value for rifampicin resistance was 99.4%.
  
  
  CONCLUSIONS
  XpertMTB/RIF outperformed smear microscopy, established a diagnosis in a significant proportion of patients with smear-negative TB, detected many highly likely TB cases missed by culture, and accurately ruled out rifampicin-resistant TB. Sample-specific factors had limited impact on performance. Performance in patients infected with HIV, especially those with advanced immunosuppression, warrants further study.
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Grant
authors.initials: G
authors.lastname: Theron
authors.forename: Jonny
authors.initials: J
authors.lastname: Peter
authors.forename: Richard
authors.initials: R
authors.lastname: van Zyl-Smit
authors.forename: Hridesh
authors.initials: H
authors.lastname: Mishra
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Streicher
authors.forename: Samuel
authors.initials: S
authors.lastname: Murray
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.forename: Andrew
authors.initials: A
authors.lastname: Whitelaw
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.forename: Surendra
authors.initials: S
authors.lastname: Sharma
authors.forename: Madhukar
authors.initials: M
authors.lastname: Pai
authors.forename: Robin
authors.initials: R
authors.lastname: Warren
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D012321:DNA-Directed RNA Polymerases; D024881:Drug Resistance, Bacterial; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D015995:Prevalence; D012293:Rifampin / Q000494:pharmacology; D012680:Sensitivity and Specificity; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis; D014397:Tuberculosis, Pulmonary / Q000150:complications* / Q000175:diagnosis*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; C505805:rpoB protein, Mycobacterium tuberculosis; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin