Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy study

Abstract

Background: Most tuberculosis-related deaths in people with HIV could be prevented with earlier diagnosis and treatment. The only commercially available tuberculosis point-of-care test (Alere Determine TB LAM Ag [AlereLAM]) has suboptimal sensitivity, which restricts its use in clinical practice. The novel Fujifilm SILVAMP TB LAM (FujiLAM) assay has been developed to improve the sensitivity of AlereLAM. We assessed the diagnostic accuracy of the FujiLAM assay for the detection of tuberculosis in hospital inpatients with HIV compared with the AlereLAM assay.

Methods: For this diagnostic accuracy study, we assessed biobanked urine samples obtained from the FIND Specimen Bank and the University of Cape Town Biobank, which had been collected from hospital inpatients (aged ≥18 years) with HIV during three independent prospective cohort studies done at two South African hospitals. Urine samples were tested using FujiLAM and AlereLAM assays. The conduct and reporting of each test was done blind to other test results. The primary objective was to assess the diagnostic accuracy of FujiLAM compared with AlereLAM, against microbiological and composite reference standards (including clinical diagnoses).

Findings: Between April 18, 2018, and May 3, 2018, urine samples from 968 hospital inpatients with HIV were evaluated. The prevalence of microbiologically-confirmed tuberculosis was 62% and the median CD4 count was 86 cells per μL. Using the microbiological reference standard, the estimated sensitivity of FujiLAM was 70·4% (95% CI 53·0 to 83·1) compared with 42·3% (31·7 to 51·8) for AlereLAM (difference 28·1%) and the estimated specificity of FujiLAM was 90·8% (86·0 to 94·4) and 95·0% (87·7-98·8) for AlereLAM (difference -4·2%). Against the composite reference standard, the specificity of both assays was higher (95·7% [92·0 to 98·0] for FujiLAM vs 98·2% [95·7 to 99·6] for AlereLAM; difference -2·5%), but the sensitivity of both assays was lower (64·9% [50·1 to 76·7] for FujiLAM vs 38·2% [28·1 to 47·3] for AlereLAM; difference 26·7%).

Interpretation: In comparison to AlereLAM, FujiLAM offers superior diagnostic sensitivity, while maintaining specificity, and could transform rapid point-of-care tuberculosis diagnosis for hospital inpatients with HIV. The applicability of FujiLAM for settings of intended use requires prospective assessment.

Funding: Global Health Innovative Technology Fund, UK Department for International Development, Dutch Ministry of Foreign Affairs, Bill & Melinda Gates Foundation, German Federal Ministry of Education and Research, Australian Department of Foreign Affairs and Trade, Wellcome Trust, Department of Science and Technology and National Research Foundation of South Africa, and South African Medical Research Council.

Figure 1

Fujifilm SILVAMP TB LAM test device, procedure, and principle One antibody binds to tetra-arabinoside and hexa-arabinoside structures in the arabinan domain of lipoarabinomannan and the other antibody targets MTX-Man capping motifs of lipoarabinomannan (MTX-Man refers to mannose caps further modified with a 5-methylthio-D-xylofuranose residue)., , Au=gold. C=control line. MTX-LAM=5-methylthio-D-xylofuranose-lipoarabinomannan. T=test line.

Figure 2

Study flow diagram Details of patients are provided in the appendix. CRS=composite reference standard. MRS=microbiological reference standard.

Figure 3

Sensitivity and specificity of FujiLAM versus AlereLAM against MRS and CRS Sensitivity and specificity of FujiLAM and AlereLAM assays for all cohorts combined (A), by cohort (B), and by CD4 count (C). Sensitivity and specificity estimates for (A) and (C) were based on analysis using a bivariate random-effects model. AlereLAM=Alere Determine TB LAM Ag assay. CRS=composite reference standard. FP=false positive. FN=false negative. FujiLAM=Fujifilm SILVAMP TB LAM assay. MRS=microbiological reference standard. TP=true positive. TN=true negative.

Figure 4

Diagnostic yields for cohort 2 Number of microbiologically confirmed tuberculosis diagnoses in all patients (A), and patients with CD4 counts of equal to or less than 100 cells per μL (B), detected by each diagnostic test on samples obtained within 24 h of hospital admission. Numbers represent the number of tuberculosis cases diagnosed by a given assay or assays. Tuberculosis cases missed includes diagnoses made by positive mycobacterial culture on any specimen collected at any point during patient admission or diagnoses made on the basis of Xpert testing of any specimen collected after the first 24 h of hospital admission. AlereLAM=Alere Determine TB LAM Ag assay. FujiLAM=Fujifilm SILVAMP TB LAM assay.