TY - JOUR
T1 - Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance
T2 - a prospective multicentre diagnostic accuracy study
AU - study team
AU - Dorman, Susan E.
AU - Schumacher, Samuel G.
AU - Alland, David
AU - Nabeta, Pamela
AU - Armstrong, Derek T.
AU - King, Bonnie
AU - Hall, Sandra L.
AU - Chakravorty, Soumitesh
AU - Cirillo, Daniela M.
AU - Tukvadze, Nestani
AU - Bablishvili, Nino
AU - Stevens, Wendy
AU - Scott, Lesley
AU - Rodrigues, Camilla
AU - Kazi, Mubin I.
AU - Joloba, Moses
AU - Nakiyingi, Lydia
AU - Nicol, Mark P.
AU - Ghebrekristos, Yonas
AU - Anyango, Irene
AU - Murithi, Wilfred
AU - Dietze, Reynaldo
AU - Lyrio Peres, Renata
AU - Skrahina, Alena
AU - Auchynka, Vera
AU - Chopra, Kamal Kishore
AU - Hanif, Mahmud
AU - Liu, Xin
AU - Yuan, Xing
AU - Boehme, Catharina C.
AU - Ellner, Jerrold J.
AU - Denkinger, Claudia M.
AU - Dorman, Susan E.
AU - Schumacher, Samuel G.
AU - Alland, David
AU - Nabeta, Pamela
AU - Armstrong, Derek T.
AU - King, Bonnie
AU - Hall, Sandra L.
AU - Chakravorty, Soumitesh
AU - Tukvadze, Nestani
AU - Bablishvili, Nino
AU - Rodrigues, Camilla
AU - Kazi, Mubin I.
AU - Joloba, Moses
AU - Nakiyingi, Lydia
AU - Ghebrekristos, Yonas
AU - Anyango, Irene
AU - Murithi, Wilfred
AU - Manabe, Yukari C.
N1 - Funding Information:
SGS, PN, CMD, and CCB are employed by FIND. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritised tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics and related products for treatment of tuberculosis and other diseases. These agreements strictly define FIND's independence and neutrality vis-a-vis the companies whose products get evaluated and describe roles and responsibilities. DA reports grants from Johns Hopkins University School of Medicine and Cepheid during the conduct of the study; grants from National Institutes of Health (NIH), the Foundation for Innovative New Diagnostics, and the Henry Jackson Foundation outside the submitted work; and US and European patents within the Rutgers University Molecular Beacon Patent Pool for non-competitive co-amplification methods, assays for short sequence variants, wavelength-shifting probes and primers, nucleic acid detection probes having non-fret fluorescence quenching and kits and assays including such probes, homogeneous multiplex screening assays and kits, and PCR primers and probes for M tuberculosis. WS is a board member of the Contract Laboratory Service, the African Society for Laboratory Medicine, the Antimicrobial Drug Resistance Group, the World Bank/Presidential Project (for mines), the Task Team for Correctional Services, and the National HIV and Tuberculosis Drug Resistance Working Group. WS declares consultancy paid to institution from the Bill & Melinda Gates Foundation Grand Challenges Canada, consultancy from WHO (EID, CD4, drug resistance, POC, Xpert TB), consultancy paid to institution from Clinton Foundation (Point-of-Care), personal fees from National Health Laboratory Service, joint staff with University of the Witwatersrand, expert testimony for grant funders (NIH, US Centers for Disease Control and Prevention [CDC], Global Fund), grants from NIH, CDC, the Global Fund, Clinton Foundation, Bill & Melinda Gates Foundation, PATH, Grand Challenges Canada, London School of Hygiene & Tropical Medicine, South African Medical Research Council, and the UK Medical Research Council, expert training, teaching development, and speaker fees paid to institution from FIND, and conference speaker fees paid to institution from Cepheid, outside the submitted work. LS reports having a patent USP 8709712 issued. SC now works for Cepheid and has a patent pending for some of the primers and probes used in the assay kit. All other authors declare no competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Funding Information:
We thank study participants, without whom this work would not have been possible, and the clinical and laboratory teams at the participating trial sites. We thank Kate Shearer for review of the analysis plan and statistical code—since FIND was involved in the development of the Xpert and Xpert Ultra assays, key sections of statistical code were completely re-written and re-run by Shearer, as an independent statistician, to ensure an independent analysis. We thank Martin Jones, Marie Simmons, Bob Kwiatkowski, Pam Johnson, and David Persing from Cepheid for their support during assay development and with logistics for the study. We thank Nora Champouillon from FIND for facilitating the project. This work was supported by grants from the Government of Netherlands (DSO/GA-523/10) for assay development; and grants from the Government of Australia (70957), the Bill & Melinda Gates Foundation (OPP1105925), the UK aid from the UK Government (204074-101); and by the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, USA (contract #HHSN2722000900050C and K24AI104830 (SED)) for clinical evaluation. Wendy Stevens and Lesley Scott were supported by funding received from the South African Medical Research Council with funds received from the South African National Department of Health, and the UK Medical Research Council, with funds received from the UK Government's Newton Fund under the UK/South Africa Newton Fund #015NEWTON TB. Investigational cartridges, Xpert MTB/RIF cartridges, and GeneXpert instruments were generously donated by Cepheid. Cepheid personnel had no role in study design, implementation, analysis, manuscript writing, or decision to submit the study findings for publication.
Publisher Copyright:
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Background The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation. We compared the diagnostic performance of Xpert Ultra with that of Xpert for detection of tuberculosis and rifampicin resistance. Methods In this prospective, multicentre, diagnostic accuracy study, we recruited adults with pulmonary tuberculosis symptoms presenting at primary health-care centres and hospitals in eight countries (South Africa, Uganda, Kenya, India, China, Georgia, Belarus, and Brazil). Participants were allocated to the case detection group if no drugs had been taken for tuberculosis in the past 6 months or to the multidrug-resistance risk group if drugs for tuberculosis had been taken in the past 6 months, but drug resistance was suspected. Demographic information, medical history, chest imaging results, and HIV test results were recorded at enrolment, and each participant gave at least three sputum specimen on 2 separate days. Xpert and Xpert Ultra diagnostic performance in the same sputum specimen was compared with culture tests and drug susceptibility testing as reference standards. The primary objectives were to estimate and compare the sensitivity of Xpert Ultra test with that of Xpert for detection of smear-negative tuberculosis and rifampicin resistance and to estimate and compare Xpert Ultra and Xpert specificities for detection of rifampicin resistance. Study participants in the case detection group were included in all analyses, whereas participants in the multidrug-resistance risk group were only included in analyses of rifampicin-resistance detection. Findings Between Feb 18, and Dec 24, 2016, we enrolled 2368 participants for sputum sampling. 248 participants were excluded from the analysis, and 1753 participants were distributed to the case detection group (n=1439) and the multidrug-resistance risk group (n=314). Sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for the 137 participants with smear-negative and culture-positive sputum (difference of 17%, 95% CI 10 to 24); 90% and 77%, respectively, for the 115 HIV-positive participants with culture-positive sputum (13%, 6·4 to 21); and 88% and 83%, respectively, across all 462 participants with culture-positive sputum (5·4%, 3·3 to 8·0). Specificities of Xpert Ultra and Xpert for case detection were 96% and 98% (−2·7%, −3·9 to −1·7) overall, and 93% and 98% for patients with a history of tuberculosis. Xpert Ultra and Xpert performed similarly in detecting rifampicin resistance. Interpretation For tuberculosis case detection, sensitivity of Xpert Ultra was superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. However, this increase in sensitivity came at the expense of a decrease in specificity. Funding Government of Netherlands, Government of Australia, Bill & Melinda Gates Foundation, Government of the UK, and the National Institute of Allergy and Infectious Diseases.
AB - Background The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation. We compared the diagnostic performance of Xpert Ultra with that of Xpert for detection of tuberculosis and rifampicin resistance. Methods In this prospective, multicentre, diagnostic accuracy study, we recruited adults with pulmonary tuberculosis symptoms presenting at primary health-care centres and hospitals in eight countries (South Africa, Uganda, Kenya, India, China, Georgia, Belarus, and Brazil). Participants were allocated to the case detection group if no drugs had been taken for tuberculosis in the past 6 months or to the multidrug-resistance risk group if drugs for tuberculosis had been taken in the past 6 months, but drug resistance was suspected. Demographic information, medical history, chest imaging results, and HIV test results were recorded at enrolment, and each participant gave at least three sputum specimen on 2 separate days. Xpert and Xpert Ultra diagnostic performance in the same sputum specimen was compared with culture tests and drug susceptibility testing as reference standards. The primary objectives were to estimate and compare the sensitivity of Xpert Ultra test with that of Xpert for detection of smear-negative tuberculosis and rifampicin resistance and to estimate and compare Xpert Ultra and Xpert specificities for detection of rifampicin resistance. Study participants in the case detection group were included in all analyses, whereas participants in the multidrug-resistance risk group were only included in analyses of rifampicin-resistance detection. Findings Between Feb 18, and Dec 24, 2016, we enrolled 2368 participants for sputum sampling. 248 participants were excluded from the analysis, and 1753 participants were distributed to the case detection group (n=1439) and the multidrug-resistance risk group (n=314). Sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for the 137 participants with smear-negative and culture-positive sputum (difference of 17%, 95% CI 10 to 24); 90% and 77%, respectively, for the 115 HIV-positive participants with culture-positive sputum (13%, 6·4 to 21); and 88% and 83%, respectively, across all 462 participants with culture-positive sputum (5·4%, 3·3 to 8·0). Specificities of Xpert Ultra and Xpert for case detection were 96% and 98% (−2·7%, −3·9 to −1·7) overall, and 93% and 98% for patients with a history of tuberculosis. Xpert Ultra and Xpert performed similarly in detecting rifampicin resistance. Interpretation For tuberculosis case detection, sensitivity of Xpert Ultra was superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. However, this increase in sensitivity came at the expense of a decrease in specificity. Funding Government of Netherlands, Government of Australia, Bill & Melinda Gates Foundation, Government of the UK, and the National Institute of Allergy and Infectious Diseases.
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U2 - 10.1016/S1473-3099(17)30691-6
DO - 10.1016/S1473-3099(17)30691-6
M3 - Article
C2 - 29198911
AN - SCOPUS:85035313153
SN - 1473-3099
VL - 18
SP - 76
EP - 84
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 1
ER -