title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  ISRCTN Registry ( ISRCTN71603869 ) prospectively registered 08 May 2015; the South African National Controlled Trials Registry (DOH-27-1015-5185) prospectively registered October 2015.
authors.affiliation: Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK. ankurgw@outlook.com.|Malawi-Liverpool-Wellcome Trust Clinical Research Program, University of Malawi College of Medicine, Blantyre, Malawi. ankurgw@outlook.com.
authors.forename: Ankur
authors.identifier: 0000-0002-5150-2970
authors.initials: A
authors.lastname: Gupta-Wright
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.|University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Fielding
authors.affiliation: Dignitas International, Zomba, Malawi.|Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.affiliation: Department of Internal Medicine, Edendale Hospital, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Wilson
authors.affiliation: Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK.|Malawi-Liverpool-Wellcome Trust Clinical Research Program, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Corbett
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Flach
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.|Harvard University Center for AIDS Research, Harvard Medical School, Boston, MA, USA.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Reddy
authors.affiliation: Divisions of General Medicine and Infectious Disease, Massachusetts General Hospital, Boston, MA, USA.|The Medical Practice Evaluation Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.|Harvard University Center for AIDS Research, Harvard Medical School, Boston, MA, USA.
authors.forename: Rochelle P
authors.initials: RP
authors.lastname: Walensky
authors.affiliation: Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Jurgens A
authors.initials: JA
authors.lastname: Peters
authors.affiliation: Dignitas International, Zomba, Malawi.
authors.forename: Melanie
authors.initials: M
authors.lastname: Alufandika-Moyo
authors.affiliation: Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK.|The Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lawn
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000175:diagnosis / Q000652:urine*; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000382:microbiology / Q000401:mortality; D000328:Adult; D015658:HIV Infections / Q000150:complications* / Q000382:microbiology; D006760:Hospitalization; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008295:Malawi; D008403:Mass Screening; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D013019:South Africa; D013183:Sputum / Q000382:microbiology; D014376:Tuberculosis / Q000175:diagnosis / Q000517:prevention & control / Q000652:urine*; D016482:Urinalysis / Q000379:methods
chemical_list: D007538:Isoniazid
keywords: HIV; HIV-associated TB; LAM; Screening; TB; Xpert