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Clinical evaluation of the Xpert MTB/XDR assay for rapid detection of isoniazid, fluoroquinolone, ethionamide and second-line drug resistance: A cross-sectional multicentre diagnostic accuracy study

Background The WHO End TB Strategy requires universal drug susceptibility testing and treatment of all people with tuberculosis. However, available second-line diagnostic tools are cumbersome and require sophisticated laboratory infrastructure, and ultimately less than half of those with drug-resistant tuberculosis receive appropriate treatment. Xpert MTB/XDR was developed to help overcome these limitations. Methods We assessed the diagnostic accuracy of sputum-based Xpert MTB/XDR for isoniazid, fluoroquinolone, ethionamide and second-line injectable resistance detection in adults with an Xpert MTB/RIF or Ultra Mycobacterium tuberculosis-positive result against a composite reference standard of phenotypic drug-susceptibility testing and whole genome sequencing (NCT03728725). Participants with pulmonary tuberculosis symptoms and [≥]1 risk factor for drug resistance were consecutively enrolled between four clinical sites in India, Moldova and South Africa. Findings Between 31 July 2019 and 21 March 2020, we enrolled 710 patients, of which 611 (86.1%) had results from index and composite reference standard tests and were included in analysis. The sensitivity of Xpert MTB/XDR was 94% for isoniazid, 95% for fluoroquinolones, 54% for ethionamide, 73% for amikacin, 86% for kanamycin, and 61% for capreomycin resistance detection. Specificity was 98-100% for all drugs. Performance was equivalent to line-probe assays. The non-determinate rate of Xpert MTB/XDR was 2.96%. Interpretation This first prospective, multicentre clinical study of the Xpert MTB/XDR assay demonstrated high diagnostic test accuracy, meeting target product profile criteria for a next-generation drug susceptibility test. Funding German Federal Ministry of Education and Research through KfW, Dutch Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and Trade.