The development of the Xpert MTB/RIF (Xpert) was a major step forward for improving tuberculosis (TB) and rifampin (RIF) diagnosis globally. However, Xpert sensitivity is imperfect in smear-negative and HIV-associated TB and some limitations also remain in the determination of RIF-resistance status. The Xpert Ultra (Ultra) has been developed as the next-generation assay to overcome these limitations.
This was a prospective multicenter diagnostic accuracy study in adults with signs/symptoms of pulmonary TB. Xpert and Ultra were performed from the same specimen and accuracy determined with four cultures as the reference standard for TB detection (two MGIT tubes + two LJ slants, performed on two specimens obtained on separate days) and phenotypic drug-susceptibility testing for RIF resistance detection.
1,520 patients were enrolled in 10 sites across 8 countries. Sensitivity of the Ultra was 5% higher than that of Xpert (95%CI +2.7, +7.8) but specificity was 3.2% lower (95%CI -2.1, -4.7). Sensitivity-increases were higher among smear-negative patients (+17%, 95%CI +10, +25) and among HIV-infected patients (+12%, 95%CI +4.9, +21). Specificity-decreases were higher in patients with a history of TB (-5.4%, 95%CI -9.1, -3.1) than in patients with no history of TB (-2.4%, 95%CI -4.0, -1.3). Reclassifying ‘trace calls’ (the semi-quantitative category of the Ultra assay that corresponds to the lowest bacillary burden) as ‘TB-negative’-either in all cases or in those with a history- mitigates some of the specificity losses (Specificity –1.0%/-1.9% if trace reclassified for all cases/cases with history) while maintaining some of the sensitivity gains over Xpert (Sensitivity +7.6%/+15%). Ultra classified more patients correctly as RIF-resistant (+1.1%, 95%CI -2.0, +4.6) and RIF-sensitive (+2.6%, 95%CI +0.2, +5.2) overall because the Xpert missed TB in patients with very paucibacillary disease entirely.
Ultra has higher sensitivity than Xpert in smear-negative and HIV-infected patients and improved accuracy for RIF detection. However, as a result of the increased sensitivity, Ultra also detects TB DNA in some patients with prior TB disease, possibly due to persistence of non-viable bacilli, leading to reduced specificity. Similar results can be expected for other upcoming next-generation molecular TB assays. A discussion of resulting implementation challenges and the willingness to trade off specificity for increased sensitivity in different settings is urgently needed.