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      Novel FujiLAM assay to detect tuberculosis in HIV-positive ambulatory patients in four African countries: a diagnostic accuracy study

      , PhD a , * , , MSc a , , MBChB c , , APGDCR e , , MD f , , MPH g , , MMed h , , MSc d , , MBBS g , , MSc a , , DPSN g , , MSc i , , MPH j , , MPH k , , MPH l , , MSc m , , MPH n , , MD o , , MD p , , MD e , , MD e , , PhD c , , BSc b , , MSc q , , PhD r , , MD i , , PhD s , , PhD t , , PhD u
      The Lancet. Global Health
      The Author(s). Published by Elsevier Ltd.

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          Development of rapid biomarker-based tests that can diagnose tuberculosis using non-sputum samples is a priority for tuberculosis control. We aimed to compare the diagnostic accuracy of the novel Fujifilm SILVAMP TB LAM (FujiLAM) assay with the WHO-recommended Alere Determine TB-LAM Ag test (AlereLAM) using urine samples from HIV-positive patients.


          We did a diagnostic accuracy study at five outpatient public health facilities in Uganda, Kenya, Mozambique, and South Africa. Eligible patients were ambulatory HIV-positive individuals (aged ≥15 years) with symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (CD4 count <200 cells per μL, or HIV clinical stage 3 or 4; group 2). All participants underwent clinical examination, chest x-ray, and blood sampling, and were requested to provide a fresh urine sample, and two sputum samples. FujiLAM and AlereLAM urine assays, Xpert MTB/RIF Ultra assay on sputum or urine, sputum culture for Mycobacterium tuberculosis, and CD4 count were systematically carried out for all patients. Sensitivity and specificity of FujiLAM and AlereLAM were evaluated against microbiological and composite reference standards.


          Between Aug 24, 2020 and Sept 21, 2021, 1575 patients (823 [52·3%] women) were included in the study: 1031 patients in group 1 and 544 patients in group 2. Tuberculosis was microbiologically confirmed in 96 (9·4%) of 1022 patients in group 1 and 18 (3·3%) of 542 patients in group 2. Using the microbiological reference standard, FujiLAM sensitivity was 60% (95% CI 51–69) and AlereLAM sensitivity was 40% (31–49; p<0·001). Among patients with CD4 counts of less than 200 cells per μL, FujiLAM sensitivity was 69% (57–79) and AlereLAM sensitivity was 52% (40–64; p=0·0218). Among patients with CD4 counts of 200 cells per μL or higher, FujiLAM sensitivity was 47% (34–61) and AlereLAM sensitivity was 24% (14–38; p=0·0116). Using the microbiological reference standard, FujiLAM specificity was 87% (95% CI 85–89) and AlereLAM specificity was 86% (95 CI 84–88; p=0·941). FujiLAM sensitivity varied by lot number from 48% (34–62) to 76% (57–89) and specificity from 77% (72–81) to 98% (93–99).


          Next-generation, higher sensitivity urine-lipoarabinomannan assays are potentially promising tests that allow rapid tuberculosis diagnosis at the point of care for HIV-positive patients. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use.


          ANRS and Médecins Sans Frontières.

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          Most cited references25

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          Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial.

          HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality.
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            Is Open Access

            Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial

            Summary Background Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes. Methods We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869. Findings Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per μL (IQR 79–436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] −2·8%, 95% CI −5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per μL (aRD −7·1%, 95% CI −13·7 to −0·4; p=0.036), severe anaemia (−9·0%, −16·6 to −1·3; p=0·021), and patients with clinically suspected tuberculosis (−5·7%, −10·9 to −0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups. Interpretation Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. Funding Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust.
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              Is Open Access

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

              Summary 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.

                Author and article information

                Lancet Glob Health
                Lancet Glob Health
                The Lancet. Global Health
                The Author(s). Published by Elsevier Ltd.
                13 December 2022
                January 2023
                13 December 2022
                : 11
                : 1
                : e126-e135
                [a ]Department of Field Epidemiology, Epicentre, Paris, France
                [b ]Department of Research, Epicentre, Paris, France
                [c ]Department of Medicine, Epicentre, Mbarara, Uganda
                [d ]Laboratory of Mycobacteriology, Epicentre, Mbarara, Uganda
                [e ]Department of Medicine, Médecins Sans Frontières, Nairobi, Kenya
                [f ]Department of Medicine, Médecins Sans Frontières, Maputo, Mozambique
                [g ]Department of Medicine, Médecins Sans Frontières, Eshowe, South Africa
                [h ]Department of Medicine, Mbarara Regional Referral Hospital, Mbarara, Uganda
                [i ]Southern African Medical Unit, Médecins Sans Frontières, Cape Town, South Africa
                [j ]Department of Medicine, Médecins Sans Frontières, Paris, France
                [k ]National Tuberculosis and Leprosy Control Services, Ministry of Health, Kampala, Uganda
                [l ]Department of Health Services, Ministry of Health, Homa Bay, Kenya
                [m ]National Tuberculosis and Leprosy Control Services, Ministry of Health, Nairobi, Kenya
                [n ]KwaZulu-Natal Department of Health, Durban, South Africa
                [o ]King Cetswayo District Office, Department of Health, Eshowe, South Africa
                [p ]National STI, HIV/AIDS Control Program, Ministry of Health, Maputo, Mozambique
                [q ]Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium
                [r ]Department of Innovation and New Technology, Elizabeth Glaser Pediatric AIDS Foundation, Geneva, Switzerland
                [s ]Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
                [t ]Institute for Global Health, University College London, London, UK
                [u ]Université de Montpellier, TransVIHMI, INSERM, IRD, Montpellier, France
                Author notes
                [* ]Correspondence to: Dr Helena Huerga, Department of Field Epidemiology, Epicentre, Paris 75019, France
                © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

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