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Evaluation of Xpert MTB/RIF Assay for the Rapid Identification of TB and Rifampin Resistance in HIV Infected & HIV uninfected Pulmonary TB suspects: ACTG 5295/TBTC 34.

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  1. Evaluation of Xpert MTB/RIF Assay for the Rapid Identification of TB and Rifampin Resistance in HIV Infected & HIV uninfected Pulmonary TB suspects: ACTG 5295/TBTC 34 AF Luetkemeyer, C Firnhaber, MA Kendall, X Wu, D Benator, GH Mazurek, B Metchock, P Johnson, S Swindells, I Sanne, DV Havlir, B Grinsztejn, D Alland, on behalf of the ACTG A5295/TBTC 34 Study teams

  2. Disclosures • Instruments, cartridges and research grant support from Cepheid • Funding from NIH AIDS Clinical Trials Group (ACTG) and the CDC Tuberculosis Trials Consortium (TBTC)

  3. Background • GeneXpert MTB/RIF: automated real time PCR that diagnoses M. tuberculosis & identifies rifampin resistance in < 2 hours • Performance in high TB prevalence settings well characterized • Sensitivity of 1 Xpert: AFB+ 98-99% , AFB- ~60-70% • Specificity: 98-99% • Limited data for use in lower TB prevalence regions and in HIV coinfection

  4. Study Aims • Determine sensitivity and specificity of Xpert MTB/RIF assay overall and by AFB smear status • Evaluate Xpert performance by: • low TB prevalence (US) vs. higher TB prevalence (Brazil and South Africa) • HIV-infected vs. HIV-uninfected • Evaluate by Xpert performance for RIF resistance detection • Performance in setting of non-tuberculosis mycobacterial growth

  5. Study population • Pulmonary TB suspects • AFB+ sputum within 7 days of entry, or • Clinical suspicion of TB as evidenced by decision to send sputum for AFB smear/culture in addition to cough, fever, night sweats, or weight loss • TB treatment < 48 hours • Regions by TB prevalence • Low prevalence (US: target enrollment ≥ 70%) • Higher prevalence (Brazil & South Africa) • HIV-infected and uninfected • All participants underwent HIV testing

  6. Methods • 2 sputum samples for Xpert MTB/RIF testing (G4 cartridges) • Method of sputum collection (induced or expectorated) and processing (unprocessed orsedimented) prior to Xpert testing determined by local standard of care and not assigned by study • Xpert conducted within 7 days of sputum collection • Xpert testing at 2 central labs in US (Emory, UCSF) and at 1 lab in Rio de Janeiro, Brazil and 1 in Johannesburg, South Africa • All labs participated in external XpertQuality Assurance program • Xpert results compared to 2 sputum specimens, each evaluated with AFB smear, liquid and solid mycobacterial culture • Rifampin resistance by proportions method on Middlebrook agar • rpoB sequencing conducted on a specimen from each participant with ≥1 culture with TB growth

  7. Results • 720 of 994 participants had results for 2 AFB smears, 2 liquid and solid media mycobacterial cultures, and 2 Xpert available at time of analysis

  8. Results

  9. Sensitivity of 1 Xpert • No significant impact of region on sensitivity in AFB-/TB culture+

  10. Specificity of 1 Xpert • No significant impact of region on specificity

  11. Xpert Performance in HIV infection • HIV status did not significantly impact sensitivity or specificity

  12. Xpert in setting of NonTuberculosis Mycobacteria(NTM) Growth

  13. Discordance between Xpert & Culture • All discordance occurred in AFB smear negative specimens • 10 with Xpert TB+/ TB Culture negative:

  14. Xpert TB Negative /TB culture + • Of the 15 with 1stXpert TB negative, 2ndXpertwas TB+ in 3 out of 15 • 20% incremental yield of 2ndXpert test • In AFB-/TB culture+: • Sensitivity of 2 Xperts: 69.2% (27/39) • Sensitivity of 1 Xpert: 61.5% (24/39)

  15. Rifampin susceptibility • 3 Rifampin resistant specimens by culture-based DST: Xpert detected 3 out of 3 • Specificity: 98.8% (81/82) • One participant: Xpert RIF resistant / Culture RIF sensitive • 2 Xpert tests: 1 RIF resistant, 1 RIF sensitive • rpoB sequencing: wild type • NPV: 100% • PPV: 75% (n=4)

  16. Conclusions • Excellent performance for detection of TB including in low prevalence settings • Sensitivity AFB+100%, AFB- 61.5% • Specificity 98.9% overall, 99.3% in low prevalence • Performance not significantly impacted by region nor HIV status • Xpert detected 3 of 3 specimens rifampin resistant specimens by culture • Data support use of Xpert MTB/RIF in low prevalence settings and in HIV infection

  17. Acknowledgements • Study participants • Support from NIH, CDC, & Cepheid • ACTG 5295 Team • Tuberculosis Trials Consortium (TBTC) S34 Team • CDC Tuberculosis Lab • Participating ACTG & TBTC sites & site investigators

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