Evaluation of the Xpert MTB Host Response assay for the triage of patients with presumed pulmonary tuberculosis: a prospective diagnostic accuracy study in Viet Nam, India, the Philippines, Uganda, and South Africa

Background Non-sputum-based triage tests for tuberculosis are a priority for ending tuberculosis. We aimed to evaluate the diagnostic accuracy of the late-prototype Xpert MTB Host Response (Xpert HR) blood-based assay. Methods We conducted a prospective diagnostic accuracy study among outpatients with presumed tuberculosis in outpatient clinics in Viet Nam, India, the Philippines, Uganda, and South Africa. Eligible participants were aged 18 years or older and reported cough lasting at least 2 weeks. We excluded those receiving tuberculosis treatment in the preceding 12 months and those who were unwilling to consent. Xpert HR was performed on capillary or venous blood. Reference standard testing included sputum Xpert MTB/RIF Ultra and mycobacterial culture. We performed receiver operating characteristic (ROC) analysis to identify the optimal cutoff value for the Xpert HR to achieve the target sensitivity of 90% or more while maximising specificity, then calculated diagnostic accuracy using this cutoff value. This study was prospectively registered with ClinicalTrials.gov, NCT04923958. Findings Between July 13, 2021, and Aug 15, 2022, 2046 adults with at least 2 weeks of cough were identified, of whom 1499 adults (686 [458%] females and 813 [542%] males) had valid Xpert HR and reference standard results. 329 (219%) had microbiologically confirmed tuberculosis. Xpert HR had an area under the ROC curve of 089 (95% CI 086-091). The optimal cutoff value was less than or equal to -125, giving a sensitivity of 903% (95% CI 865-933; 297 of 329) and a specificity of 626% (95% CI 597-653; 732 of 1170). Sensitivity was similar across countries, by sex, and by subgroups, although specificity was lower in people living with HIV (451%, 95% CI 378-526) than in those not living with HIV (659%, 628-688; difference of 208%, 95% CI 130-286; p<00001). Xpert HR had high negative predictive value (958%, 95% CI 941-971), but positive predictive value was only 401% (95% CI 368-441). Using the Xpert HR as a triage test would have reduced confirmatory sputum testing by 573% (95% CI 542-604). Interpretation Xpert HR did not meet WHO minimum specificity targets for a non-sputum-based triage test for pulmonary tuberculosis. Despite promise as a rule-out test that could reduce confirmatory sputum testing, further cost-effectiveness modelling and data on acceptability and usability are needed to inform policy recommendations.