Expanding LAM’s use case: A new rapid urine assay for diagnosing tuberculosis with high sensitivity in HIV-positive and -negative South African and Ugandan outpatients, including in people with sputum-scarce tuberculosis

Abstract

<title>Abstract</title> <underline> <italic>Introduction:</italic> </underline> <italic/> Non-sputum tuberculosis (TB) tests are a global priority. Next-generation urine lipoarabinomannan (LAM) diagnostics with utility beyond only people with advanced immunosuppression are urgently needed. <underline> <italic>Methods:</italic> </underline> <italic/> We performed a two-centre diagnostic accuracy study to evaluate the performance of Biopromic TB LAM assay (BP-LAM assay) and the lateral flow Determine TB LAM Ag test (LF-LAM) on stored urine from 629 adults with presumptive pulmonary TB (315 with TB, 314 without) from primary care in South Africa and Uganda. Diagnostic accuracy was assessed against an extended sputum microbiological reference standard (eMRS) and sputum induction done if people could not expectorate. <underline> <italic>Results:</italic> </underline> BP-LAM assay had higher sensitivity than LF-LAM [95% confidence interval (CI) 63% (58, 69) vs. 22% (18, 27); p&lt;0.001] and similar specificities [93% (90, 96) vs. 89% (85, 92)], respectively. BP-LAM assay sensitivity did not differ in HIV-positive vs. -negative people [67% (58, 76) vs. 62% (55, 69)] nor its accuracy affected by CD4 counts. The design-locked version of BP-LAM assay had improved specificity compared to its prototype-version. BP-LAM assay diagnosed TB in people who could not expectorate sputum resulting in similar diagnostic yield amongst those tested (DYT) to Xpert MTB/RIF Ultra and culture (64% vs. 61-55%) in a scenario where sputum induction was unavailable. BP-LAM assay false-negatives had, compared to true-positives, less severe disease,and more previous TB. False-positive results were, vs. true-negatives, more likely to be non-tuberculous mycobacteria (NTM)-positive [19% (4/21) vs. 4% (12/293)]. <underline> <italic>Conclusions:</italic> </underline> BP-LAM assay has higher sensitivity than LF-LAM, including in HIV-negative people. BP-LAM assay holds promise and warrants further evaluation, especially in groups where non-sputum tests are a priority. <underline> <italic>Funding:</italic> </underline> <italic/> The Global Health Technology Fund (GHIT) programs RFP-TRP-2018-001 and RFP-PD-2020-002, SAMRC (MRC-RFA-IFSP-01-2013), EDCTP2 (RIA2018D-2509, PreFIT; RIA2018D-2493, SeroSelectTB; RIA2020I-3305, CAGE-TB; TMA2020CDF-3209, RADIANT).