Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study

Abstract

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.

Figure 1

Specimen laboratory testing, participant flow, and exclusions from analysis eligibility Eligible participants were asked to provide four sputum specimens (sputum 1–4) on 2 separate days. Xpert MTB/RIF Ultra assay (Xpert Ultra) on the first of sputum specimen was the index test, and Xpert MTB/RIF assay on the first sputum specimen was the comparator test. When possible, a fourth sputum specimen was obtained for additional solid and liquid cultures in cases with Xpert and Xpert Ultra discrepant results on sputum specimen 1. Sputum 4 results were only used for secondary analyses. NALC-NaOH=N-acetyl-L-cysteine and sodium hydroxide. MGIT=mycobacteria growth indicator tube. *Some reasons for exclusion overlap.

Figure 2

Specificity estimates of Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculosis case detection in patients with a tuberculosis treatment history and for different approaches to handling an initial Xpert Ultra trace-positive result The curves show specificity in participants with tuberculosis history as a function of the time since completion of treatment for the previous tuberculosis episode within 10 years of enrolment (50 cases with treatment more than 10 years earlier were omitted; recoding these 50 cases to be at 10 years did not lead to any noticeable changes in the findings). The results of the Xpert Ultra conditional trace results approach are not shown but would have been directly below the curve for the Ultra without trace. Curves were created using running-line least squares (mean) smoothers with a bandwidth of 0·8.