Evaluation of the Xpert MTB Host Response assay for the triage of patients [TB0108]

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A triage test with a minimum sensitivity of 90% and specificity of 70%, meeting predefined operational targets, could help reduce underdiagnosis and misdiagnosis of tuberculosis, decrease delays in starting treatment, and lower the cost and infrastructure demands of current gold-standard sputum-based tests in high-burden settings. 

Sweeney and colleagues validated a three-gene host blood signature, utilizing blood mRNA to measure markers associated with the host inflammatory response, which can differentiate tuberculosis disease from other conditions. This signature has been developed into an automated, blood-based quantitative PCR test on the GeneXpert platform, generating a TB Score based on the cycle threshold of expressed genes. Early studies from stored samples and interim results from a multisite study suggest that this test may achieve the WHO's target product profile minimum accuracy threshold for a tuberculosis triage test.

We aimed to prospectively evaluate the diagnostic accuracy of the late-prototype Xpert MTB Host Response (Xpert HR; Cepheid, Sunnyvale, CA, USA) assay, a pioneering host RNA transcriptomic signature-based test, against a microbiological reference standard as a triage test for pulmonary tuberculosis. We also compared its performance with WHO target product profiles.

This prospective diagnostic accuracy study was conducted among outpatients presumed to have tuberculosis, across clinics in five countries: Vietnam, India, the Philippines, Uganda, and South Africa, as part of the Rapid Research in Diagnostics Development (R2D2) TB Network.

The primary outcome was the diagnostic accuracy of Xpert HR, measured against a microbiological reference standard defined by any positive (very low grade or higher) sputum Xpert Ultra result, two positive (trace or higher) sputum Xpert Ultra results, or any positive culture result in liquid (MGIT) or solid media.

The results of this five-country diagnostic accuracy study suggest that the Xpert HR late-prototype is the first blood-based tuberculosis assay to approximate the WHO's minimum diagnostic accuracy targets for a tuberculosis triage test (minimum sensitivity of 90% and specificity of 70%). When optimized for sensitivity at 90% or higher, the test achieved a specificity of 62.6% (95% CI 59.7–65.3) against the microbiological reference standard and 69.4% (66.8–71.9) against the sputum Xpert Ultra reference standard. Accuracy was generally consistent across subgroups and settings, except for approximately 20% lower specificity in individuals with HIV compared to those without HIV, and the need for a different cutoff to maintain similar performance in the Philippines.

Xpert HR also demonstrated a high negative predictive value across countries and subgroups, reducing the number of people requiring confirmatory sputum tuberculosis testing by more than 50%. This positions it as a potentially useful rule-out or triage test for pulmonary tuberculosis. There is a pressing need for non-sputum-based triage tests to enhance tuberculosis case-finding while reducing the number of confirmatory tests needed.

According to our findings, using Xpert HR as a triage test for facility-based case finding would have reduced confirmatory tests by over half while missing only 10% of individuals with pulmonary tuberculosis (assuming a 10% prevalence). Lower tuberculosis prevalence would result in even greater reductions in confirmatory testing. While the current cost of the Xpert HR assay is unknown, it is likely to exceed the WHO-recommended target of US$2 per test. Cost-effectiveness modeling will be crucial to establish viable use cases and cost thresholds for Xpert HR as a triage test based on the diagnostic accuracy reported.

Source: Gupta-Wright, Ankur, Huy Ha, Shima Abdulgadar, Rebecca Crowder, Jerusha Emmanuel, Job Mukwatamundu, Danaida Marcelo et al. "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." The Lancet Global Health 12, no. 2 (2024): e226-e234.

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