Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial

BMC Infectious Diseases, Sep 2016

Background HIV-associated tuberculosis (TB) co-infection remains an enormous burden to international public health. Post-mortem studies have highlighted the high proportion of HIV-positive adults admitted to hospital with TB. Determine TB-LAM and Xpert MTB/RIF assays can substantially increase diagnostic yield of TB within one day of hospital admission. However, it remains unclear if this approach can impact clinical outcomes. The STAMP trial aims to test the hypothesis that the implementation a urine-based screening strategy for TB can reduce all cause-mortality among HIV-positive patients admitted to hospital when compared to current, sputum-based screening. Methods The trial is a pragmatic, individually randomised, multi-country (Malawi and South Africa) clinical trial with two study arms (1:1 recruitment). Unselected HIV-positive patients admitted to medical wards, irrespective of presentation, meeting the inclusion criteria and giving consent will be randomized to screening for TB using either: (i) ‘standard of care’- testing of sputum using the Xpert MTB/RIF assay (Xpert) or (ii) ‘intervention’- testing of sputum using Xpert and testing of urine using (a) Determine TB-LAM lateral-flow assay and (b) Xpert following concentration of urine by centrifugation. Patients will be excluded if they have received TB treatment in the previous 12 months, if they have received isoniazid preventive therapy in the last 6 months, if they are aged <18 years or they live outside the pre-specified geographical area. Results will be provided to the responsible medical team as soon as available to inform decisions regarding TB treatment. Both the study and routine medical team will be masked to study arm allocation. 1300 patients will be enrolled per arm (equal numbers at the two trial sites). The primary endpoint is all-cause mortality at 56 days. An economic analysis will be conducted to project long-term outcomes for shorter-term trial data, including cost-effectiveness. Discussion This pragmatic trial assesses an intervention to reduce the high mortality caused by HIV-associated TB, which could feasibly be scaled up in high-burden settings if shown to be efficacious and cost-effective. We discuss the challenges of designing a trial to assess the impact on mortality of laboratory-based TB screening interventions given frequent initiation of empirical treatment and a failure of several previous clinical trials to demonstrate an impact on clinical outcomes. We also elaborate on the practical and ethical issues of ‘testing a test’ in general. Trial registration ISRCTN Registry (ISRCTN71603869) prospectively registered 08 May 2015; the South African National Controlled Trials Registry (DOH-27-1015-5185) prospectively registered October 2015.

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Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial

Gupta-Wright et al. BMC Infectious Diseases Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial Ankur Gupta-Wright 0 1 Katherine L. Fielding Joep J. van Oosterhout Douglas K. Wilson Elizabeth L. Corbett 0 1 Clare Flach Krishna P. Reddy Rochelle P. Walensky Jurgens A. Peters 1 Melanie Alufandika-Moyo Stephen D. Lawn 1 0 Malawi-Liverpool-Wellcome Trust Clinical Research Program, University of Malawi College of Medicine , Blantyre , Malawi 1 Department of Clinical Research, London School of Hygiene & Tropical Medicine , London , UK Background: HIV-associated tuberculosis (TB) co-infection remains an enormous burden to international public health. Post-mortem studies have highlighted the high proportion of HIV-positive adults admitted to hospital with TB. Determine TB-LAM and Xpert MTB/RIF assays can substantially increase diagnostic yield of TB within one day of hospital admission. However, it remains unclear if this approach can impact clinical outcomes. The STAMP trial aims to test the hypothesis that the implementation a urine-based screening strategy for TB can reduce all causemortality among HIV-positive patients admitted to hospital when compared to current, sputum-based screening. Methods: The trial is a pragmatic, individually randomised, multi-country (Malawi and South Africa) clinical trial with two study arms (1:1 recruitment). Unselected HIV-positive patients admitted to medical wards, irrespective of presentation, meeting the inclusion criteria and giving consent will be randomized to screening for TB using either: (i) 'standard of care'- testing of sputum using the Xpert MTB/RIF assay (Xpert) or (ii) 'intervention'- testing of sputum using Xpert and testing of urine using (a) Determine TB-LAM lateral-flow assay and (b) Xpert following concentration of urine by centrifugation. Patients will be excluded if they have received TB treatment in the previous 12 months, if they have received isoniazid preventive therapy in the last 6 months, if they are aged <18 years or they live outside the pre-specified geographical area. Results will be provided to the responsible medical team as soon as available to inform decisions regarding TB treatment. Both the study and routine medical team will be masked to study arm allocation. 1300 patients will be enrolled per arm (equal numbers at the two trial sites). The primary endpoint is all-cause mortality at 56 days. An economic analysis will be conducted to project long-term outcomes for shorter-term trial data, including cost-effectiveness. (Continued on next page) - (Continued from previous page) Discussion: This pragmatic trial assesses an intervention to reduce the high mortality caused by HIV-associated TB, which could feasibly be scaled up in high-burden settings if shown to be efficacious and cost-effective. We discuss the challenges of designing a trial to assess the impact on mortality of laboratory-based TB screening interventions given frequent initiation of empirical treatment and a failure of several previous clinical trials to demonstrate an impact on clinical outcomes. We also elaborate on the practical and ethical issues of ‘testing a test’ in general. Trial registration: ISRCTN Registry (ISRCTN71603869) prospectively registered 08 May 2015; the South African National Controlled Trials Registry (DOH-27-1015-5185) prospectively registered October 2015. Background HIV-associated TB remains an enormous burden to international public health, even in regions with high coverage of antiretroviral therapy (ART). Globally, in 2014, there were an estimated 0.4 million TB related deaths in people living with HIV, which accounts for approximately one-quarter of TB deaths and one-third of HIV deaths [ 1 ]. This burden disproportionately affects sub-Saharan Africa where TB is a common cause of hospital admission and mortality among HIV-positive patients admitted to hospital [ 2 ]. Diagnosis of TB in people living with HIV remains challenging due to non-specific clinical features, early dissemination beyond the lungs and relatively low mycobacterial burden within sputum samples [ 3–5 ]. A metaanalysis of post-mortem studies in adult HIV-positive patients dying in hospitals in sub-Saharan Africa reported that between 32 and 67 % (pooled summary estimate 43 %) had evidence of TB at post-mortem [ 6 ]. TB was disseminated in almost 90 % of patients, and remained undiagnosed at the time of death in almost one-half of TB cases, reflecting a failure of current sputum and clinical based diagnosis of TB, and presenting a strong rationale for routine systematic screening of HIVpositive hospital admissions. New diagnostic tools have been high on the TB research agenda for the past decade, and are recognised as crucial to the World Health Organization’s (WHO) End TB Strategy [ 7 ]. The Xpert MTB/RIF rapid molecular assay (Xpert, C (...truncated)


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Ankur Gupta-Wright, Katherine Fielding, Joep van Oosterhout, Douglas Wilson, Elizabeth Corbett, Clare Flach, Krishna Reddy, Rochelle Walensky, Jurgens Peters, Melanie Alufandika-Moyo, Stephen Lawn. Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial, BMC Infectious Diseases, 2016, pp. 501, 16, DOI: 10.1186/s12879-016-1837-z