The "first in class" product for low complexity automated NAATs for detection of resistance to INH and second-line anti-TB drugs is the Xpert MTB/XDR Assay (Cepheid, Sunnyvale, USA). This test uses a cartridge designed for the GeneXpert instrument to detect resistance to INH, FQs, ETO and second-line injectable drugs (AMK, kanamycin and capreomycin). However, unlike Xpert MTB/RIF and Xpert MTB/RIF Ultra, which are performed on a GeneXpert instrument that can detect 6 colours, the new test requires a 10-colour GeneXpert instrument. There is an option to combine the 6 and 10-colour systems through a common computer. A bioequivalence study of Xpert MTB/RIF and Xpert MTB/RIF Ultra on the 6- and 10-colour system will be reviewed by WHO later in 2021 and guidance will then be provided.
The low complexity automated NAAT is intended for use as a follow-on test in specimens determined to be MTBC-positive; it offers the chance to improve access to rapid DST in intermediate and even peripheral laboratories. The Xpert MTB/XDR test provides results in less than 90 minutes, leading to faster time to results than the current standard of care (i.e. LPAs or culture-based phenotypic DST). This NAAT requires the same infrastructure and training of technicians as the other Xpert tests.
The overall pooled sensitivity for detection of INH resistance was 94% (95% CI: 89-97%) and specificity was 98% (95% CI: 95-99%) (Table 3.3). Overall pooled sensitivity for detection of FQ resistance was 93% (95% CI: 88-96%) and specificity was 98% (95% CI: 94-99%) (Table 3.4). Thus, Xpert MTB/XDR could be used as a reflex test to complement existing technologies that only test for RIF resistance, allowing the rapid and accurate detection of resistance to INH and FQ in cases of RIF-susceptible TB, and of resistance to FQ, INH, ETO and AMK in cases of RR-TB. The package insert includes the use of the test on culture isolates; performance based on the FIND study - see Web Annex 4.15 in (5)¹⁶ - confirms this potential use case. However, the primary purpose of this test is to achieve rapid and early detection of resistance, and recommendations are for use directly on clinical specimens. Appendix 2 provides an information sheet summarizing this test.
WHO recommends the use of low complexity automated NAATs for detection of resistance to INH and second-line anti-TB drugs in the following situations (5):
- In people with bacteriologically confirmed pulmonary TB, low complexity automated NAATs in sputum may be used for initial detection of resistance to INH and FQs, rather than culture-based phenotypic DST.
- In people with bacteriologically confirmed pulmonary TB and resistance to RIF, low complexity automated NAATs in sputum may be used for initial detection of resistance to ETO, rather than DNA sequencing of the inhA promoter.
- In people with bacteriologically confirmed pulmonary TB and resistance to RIF, low complexity automated NAATs in sputum may be used for initial detection of resistance to AMK, rather than culture-based phenotypic DST.
Notes:
- These recommendations are based on the evidence of diagnostic accuracy in sputum of adults with bacteriologically confirmed pulmonary TB, with or without RIF resistance.
- The recommendations are extrapolated for adolescents and children based on the generalization of data from adults.
- The recommendations apply to People with HIV (studies included a varying proportion of such people). Data stratified by HIV status were not available.
- The recommendations are extrapolated to people with extrapulmonary TB and testing of non-sputum samples was considered appropriate, which affects the certainty. The panel did not evaluate test accuracy in non-sputum samples directly, including in children. However, extrapolation was considered appropriate given that WHO recommendations exist for similar technologies for use on non-sputum samples (e.g. Xpert MTB/RIF and Xpert Ultra).