Mishra H, Reeve BWP, Palmer Z, et al. - In an HIV-endemic setting where previous tuberculosis is frequent and current test performance is suboptimal, the performance of Xpert MTB/RIF Ultra (Ultra) vs Xpert MTB/RIF (Xpert) was examined. Sputum samples were obtained from patients in South Africa for this two-cohort diagnostic accuracy study examining the accuracy of Ultra and Xpert against a single culture reference standard.  In the first cohort (cohort A), adults (aged ≥ 18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa were recruited and provided three sputum samples, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤ 2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), random allocation (1:1) of decontaminated sediments, after processing, was done for testing with Ultra or Xpert. From Feb 6, 2016, to Feb 2, 2018, 302 people were recruited into cohort A; the head-to-head analyses of Ultra and Xpert involved 239 people. For cohort B, 352 samples were eligible for inclusion in analyses and were randomly assigned to Ultra (n = 173) or Xpert (n = 179). Outcomes suggest that relative to Xpert, ultra produced more non-actionable results and had diminished specificity in a setting with a high burden of previous tuberculosis. In patients with recent previous tuberculosis, indeterminate results for rifampicin resistance and negative culture results were observed in a quarter of Ultra-positive samples, indicating the probability of unsuccessful results for additional drug-resistance testing. Data gained seem to have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings.