Paucibacillary tuberculosis drives the low positive predictive value of Xpert MTB/RIF Ultra for rifampicin resistance detection in low-prevalence settings

Abstract

Background Xpert MTB/RIF Ultra (Ultra) aimed to improve the specificity in identifying rifampicin-resistant tuberculosis (RR-TB), compared to Xpert MTB/RIF. Methods In a nationwide study in Rwanda, patients diagnosed with RR-TB by Ultra between December 2021 and January 2024 underwent repeat Ultra testing, complemented by rpoB gene sequencing and phenotypic drug-susceptibility testing (pDST), serving as reference tests. Results Of 129 patients initially diagnosed with RR-TB by Ultra, only 41 (32%) had concordant rifampicin results upon repeat Ultra testing. The remaining 88 patients (68%) had unconfirmed resistance on repeat Ultra. Reference testing was available for 40 (98%) of 41 confirmed cases, all verified as true RR-TB. Among 88 unconfirmed cases, reference testing was available for 61 (69%), with seven (11%) confirmed as true RR-TB, while 54 (89%) were found to have rifampicin-susceptible TB. Notably, 89% of 55 patients with very low bacillary loads on their initial Ultra had false RR-TB results, a significantly higher risk of false resistance compared to other bacillary load categories combined (risk ratio: 8.20; 95% CI: 3.56-18.85; p<0.001). Consequently, 53% (54/101) of initial RR patients with available reference testing received unnecessary RR-TB treatment. Conclusions Ultra represents a valuable tool for rapid RR-TB detection, however, in low prevalence settings its low positive predictive value for RR detection is largely driven by samples with very low bacillary loads. As programs expand active case-finding and early detection of asymptomatic disease, the proportion of TB detected with very low bacillary load will increase. Diagnostic algorithms require adjustments to prevent unnecessary RR-TB treatment.