The WHO-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 multicenter study (June 2017-March 2021), in nine sub-Saharan African countries enrolling adults with confirmed pulmonary tuberculosis by Xpert MTB/RIF or Ultra. Xpert MTB/XDR results were compared to a WHO-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 by detecting 606/637 isoniazid-resistant (95%; CI 94–97), 22/33 fluoroquinolones-resistant (67%; CI 48–81) and 159/279 ethionamide-resistant (57%; CI 51–63) samples. The assay reliably detected most common resistance-conferring mutations such as katG S315T, fabG1 C-15T and gyrAA90V 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 programs.
Massou et al. (Thu,) studied this question.