Design and protocol for a cluster randomised trial of enhanced diagnostics for tuberculosis screening among people living with HIV in hospital in Malawi (CASTLE study)
Rachael M Burke, Saulos Nyirenda, Hussein H Twabi, Marriott Nliwasa, Elizabeth Joekes, Naomi Walker, Rose Nyirenda, Ankur Gupta-Wright, Katherine Fielding, Peter MacPherson, Elizabeth L Corbett, Rachael M Burke, Saulos Nyirenda, Hussein H Twabi, Marriott Nliwasa, Elizabeth Joekes, Naomi Walker, Rose Nyirenda, Ankur Gupta-Wright, Katherine Fielding, Peter MacPherson, Elizabeth L Corbett
Abstract
Background: People living with HIV (PLHIV) have a high risk of death if hospitalised in low-income countries. Tuberculosis has long been the leading cause of admission and death, in part due to suboptimal diagnostics. Two promising new diagnostic tools are digital chest Xray with computer-aided diagnosis (DCXR-CAD) and urine testing with Fujifilm SILVAMP LAM (FujiLAM). Neither test has been rigorously evaluated among inpatients. Test characteristics may be complementary, with FujiLAM especially sensitive for disseminated tuberculosis and DCXR-CAD especially sensitive for pulmonary tuberculosis, making combined interventions of interest.
Design and methods: An exploratory unblinded, single site, two-arm cluster randomised controlled trial, with day of admission as the unit of randomisation. A third, smaller, integrated cohort arm (4:4:1 random allocation) contributes to understanding case-mix, but not trial outcomes. Participants are adults living with HIV not currently on TB treatment. The intervention (DCXR-CAD plus urine FujiLAM plus usual care) is compared to usual care alone. The primary outcome is proportion of participants started on tuberculosis treatment by day 56, with secondary outcomes of mortality (time to event) measured to to 56 days from enrolment, proportions with undiagnosed tuberculosis at death or hospital discharge and comparing proportions with enrolment-day tuberculosis treatment initiation.
Discussion: Both DCXR-CAD and FujiLAM have potential clinical utility and may have complementary diagnostic performance. To our knowledge, this is the first randomised trial to evaluate these tests among hospitalised PLHIV.
Conflict of interest statement
The authors have declared that no competing interests exist.
References
- Ford N, Shubber Z, Meintjes G, Grinsztejn B, Eholie S, Mills EJ, et al.. Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis. Lancet HIV. 2015;2: e438–444. doi: 10.1016/S2352-3018(15)00137-X
- Burke RM, Henrion MYR, Mallewa J, Masamba L, Kalua T, Khundi M, et al.. Incidence of HIV-positive admission and inpatient mortality in Malawi [2012–2019]: a population cohort study. AIDS. 2021. doi: 10.1097/QAD.0000000000003006
- Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, et al.. TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis. J Int AIDS Soc. 2016;19. doi: 10.7448/IAS.19.1.20714
- Gupta RK, Lucas SB, Fielding KL, Lawn SD. Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis. AIDS. 2015;29: 1987–2002. doi: 10.1097/QAD.0000000000000802
- Peter JG, Zijenah LS, Chanda D, Clowes P, Lesosky M, Gina P, et al.. 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. Lancet. 2016;387: 1187–1197. doi: 10.1016/S0140-6736(15)01092-2
- Gupta-Wright A, Corbett EL, van Oosterhout JJ, Wilson D, Grint D, Alufandika-Moyo M, et al.. 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. The Lancet. 2018;392: 292–301. doi: 10.1016/S0140-6736(18)31267-4
- Lawn SD, Kerkhoff AD, Burton R, Schutz C, Boulle A, Vogt M, et al.. Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort. BMC Med. 2017;15: 67. doi: 10.1186/s12916-017-0822-8
- Qin ZZ, Sander MS, Rai B, Titahong CN, Sudrungrot S, Laah SN, et al.. Using artificial intelligence to read chest radiographs for tuberculosis detection: A multi-site evaluation of the diagnostic accuracy of three deep learning systems. Sci Rep. 2019;9: 1–10.
- Pande T, Cohen C, Pai M, Ahmad Khan F. Computer-aided detection of pulmonary tuberculosis on digital chest radiographs: a systematic review. Int J Tuberc Lung Dis. 2016;20: 1226–1230. doi: 10.5588/ijtld.15.0926
- Broger T, Sossen B, du Toit E, Kerkhoff AD, Schutz C, Reipold EI, et al.. Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy study. The Lancet Infectious Diseases. 2019;19: 852–861. doi: 10.1016/S1473-3099(19)30001-5
- Broger T, Nicol MP, Székely R, Bjerrum S, Sossen B, Schutz C, et al.. Diagnostic accuracy of a novel tuberculosis point-of-care urine lipoarabinomannan assay for people living with HIV: A meta-analysis of individual in- and outpatient data. PLOS Medicine. 2020;17: e1003113. doi: 10.1371/journal.pmed.1003113
- MacPherson P, Webb EL, Lalloo DG, Nliwasa M, Maheswaran H, Joekes E, et al.. Design and protocol for a pragmatic randomised study to optimise screening, prevention and care for tuberculosis and HIV in Malawi (PROSPECT Study). Wellcome Open Res. 2018;3: 61. doi: 10.12688/wellcomeopenres.14598.3
- Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al.. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346: e7586. doi: 10.1136/bmj.e7586
- Karat AS, Omar T, von Gottberg A, Tlali M, Chihota VN, Churchyard GJ, et al.. Autopsy Prevalence of Tuberculosis and Other Potentially Treatable Infections among Adults with Advanced HIV Enrolled in Out-Patient Care in South Africa. PLoS One. 2016;11. doi: 10.1371/journal.pone.0166158
- Bates M, Mudenda V, Shibemba A, Kaluwaji J, Tembo J, Kabwe M, et al.. Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study. Lancet Infect Dis. 2015;15: 544–551. doi: 10.1016/S1473-3099(15)70058-7
- UNAIDS, Country Factsheet Malawi. [accessed 16 Dec 2021].
- Bresges C, Wilson D, Fielding K, Corbett EL, Del-Greco F, Grint D, et al.. Early Empirical Tuberculosis Treatment in HIV-Positive Patients Admitted to Hospital in South Africa: An Observational Cohort Study. Open Forum Infectious Diseases. 2021;8. doi: 10.1093/ofid/ofab162
Source: PubMed