Performance evaluation of the Xpert MTB/XDR test for the detection of drug resistance to Mycobacterium tuberculosis among people diagnosed with tuberculosis in South Africa

Background: Tuberculosis (TB) remains a significant public health concern in South Africa, with high incidence rates and a growing burden of drug-resistant TB. This study aimed to assess the diagnostic performance of the Xpert MTB/XDR test, a novel molecular assay, for detecting drug resistance in TB patients using archived sputum sediments. Methods: The study involved a comprehensive analysis of 322 samples collected from presumptive TB patients between 2016 - 2019 across South Africa, previously characterized by phenotypic and genotypic methods. The Xpert MTB/XDR test was evaluated for its ability to detect resistance to isoniazid (INH), ethionamide (ETH), fluoroquinolones (FLQ), and second-line injectable drugs (SLID) compared to phenotypic drug susceptibility testing (pDST) and whole-genome sequencing (WGS). The Xpert MTB/RIF Ultra and G4 tests were performed to determine agreement with this test for TB detection. Findings: The Xpert MTB/XDR test performance showed excellent sensitivity and specificity for detecting Mycobacterium tuberculosis ( M. tuberculosis ), with a sensitivity of 98.3% and specificity of 100% compared to culture. The sensitivities using a composite reference standard, pDST and sequencing, were over 90% for INH, FLQ, AMK, KAN, and CAP resistance, meeting the WHO target product profile criteria for this class. A lower sensitivity of 65.9% for ETH resistance was observed, driven by the limited targets covered by the assay. Interpretation: The Xpert MTB/XDR test offers a promising solution for the rapid detection of drug-resistant TB in South Africa. It could significantly enhance TB control efforts in this setting and contribute to improved patient care and management. ### Competing Interest Statement The sponsor was involved in the design, conduct and execution of the clinical study, and assisted in monitoring and collection of data. The sponsor participated in the interpretation of the data and preparation of the manuscript. GL and XL are Cepheid employees. ### Funding Statement The study sponsor (Cepheid) provided the investigational product, funding and administrative and logistical support to this study site. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of the Witwatersrand, Johannesburg Human Research Ethics Committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors