To test or not? Xpert MTB/RIF as an alternative to smear microscopy to guide line probe assay testing for drug-resistant tuberculosis

Background: Xpert MTB/RIF (Xpert) revolutionised tuberculosis (TB) diagnosis, however, laboratory decision making on whether widely-used reflex drug susceptibility assays (MTBDRplus, MTBDRsl) are done on specimens is often based on smear microscopy status. Method: We performed receiver operator characteristic (ROC) curve analyses using sputum bacterial load measures [smear microscopy grade, Xpert semi-quantitation category and minimum cycle threshold (CTmin) values] for the classification of likely non-actionable (not resistant or susceptible) line probe assays results. We evaluated the actionable-to-non-actionable result ratio and pay-offs with missed isoniazid and fluoroquinolone resistance compared to if LPAs were done universally. Findings: Smear-negatives were more likely than smear-positives to generate a non-actionable MTBDRplus [23% (133/559) vs. 4% (15/381)] or MTBDRsl [39% (220/559) vs. 12% (47/381)] result, however, excluding smear-negatives would result in missed rapid diagnoses [e.g., only 51% (273/537) of LPA-diagnosable isoniazid resistance detected if smear-negatives omitted]. Within smear-negatives, testing ; [≥]medium specimens had a high ratio of actionable-to-non-actionable results (12.8 or a 4-fold improvement vs. test all for MTBDRplus, 4.5 or 3-fold improvement for MTBDRsl), which would capture 64% (168/264) and 77% (34/44) of LPA-detectable resistance. If CTmin were used, greater resolution and higher ratios offset against fewer missed resistant cases were obtained. Conclusion: Routinely-generated Xpert quantitative information permits identification of smear-negatives in whom the ratio of actionable-to-non-actionable LPA results may prove acceptably high to laboratories depending on their local contexts. Xpert CTmin or, if unavailable, semiquantitation category should be used to guide reflex DST; permitting the rational expansion of direct DST to certain paucibacillary specimens.