Multicentre field evaluation of Xpert MTB/XDR in sub-Saharan Africa

The World Health Organization-endorsed Xpert MTB/XDR assay provides a rapid method to detect resistance to isoniazid, fluoroquinolones, injectables aminoglycosides and ethionamide, yet evaluation of its performance, particularly in endemic settings, remains limited.

We conducted a prospective multicentre study (June 2017 to March 2021) in nine sub-Saharan African countries, enrolling adults with pulmonary tuberculosis confirmed by Xpert MTB/RIF or Ultra. Xpert MTB/XDR results were compared to a World Health Organization-endorsed targeted next-generation sequencing reference used on the same sputum, with discordance resolved using whole genome sequencing and phenotypic drug-susceptibility testing when available. Diagnostic accuracy for each drug was calculated, also accounting for genotypic heteroresistance detection.

Among 1238 included patients, Xpert MTB/XDR demonstrated high specificity (≥98%) across all drugs yet showed variable sensitivity, detecting 606 out of 637 isoniazid-resistant (95%, 95% CI 94-97%), 22 out of 33 fluoroquinolones-resistant (67%, 95% CI 48-81%) and 159 out of 279 ethionamide-resistant (57%, 95% CI 51-63%) samples. The assay reliably detected most common resistance-conferring mutations, such as katG_S315T, fabG1_C-15T, and gyrA_A90V and D94G, yet failed to detect low-frequency heteroresistance (≤10-35%) and off-target mutations, mostly for ethionamide. Amikacin resistance was rare (0.2%). Sensitivity for fluoroquinolones was higher (78%) among rifampicin-resistant samples, highlighting its utility as a reflex test in rifampicin-resistant patients.

Xpert MTB/XDR offers rapid diagnosis of resistance with high specificity. While limitations in detecting low-frequency and off-target variants affect its sensitivity, most frequent, fixed in-target mutations are readily detected. Future studies should evaluate strategies to integrate Xpert MTB/XDR with other diagnostic approaches in national tuberculosis programmes.