title: Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial.
abstract: BACKGROUND
  The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa.
  
  
  METHODS
  In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384.
  
  
  RESULTS
  Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0·25-3] in the MTB/RIF group; p=0·85) or 6 months (1 [0-3] vs 1 [0-3]; p=0·35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0·23) or 6 months (100 [90-100] vs 100 [90-100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0·0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408).
  
  
  CONCLUSIONS
  Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients.
  
  
  BACKGROUND
  European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Grant
authors.initials: G
authors.lastname: Theron
authors.affiliation: Department of Immunology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.
authors.forename: Lynn
authors.initials: L
authors.lastname: Zijenah
authors.affiliation: University Teaching Hospital, Lusaka, Zambia.
authors.forename: Duncan
authors.initials: D
authors.lastname: Chanda
authors.affiliation: National Institute of Medical Research, Mbeya Medical Research Centre, Mbeya, Tanzania; Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Clowes
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rachow
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Maia
authors.initials: M
authors.lastname: Lesosky
authors.affiliation: City of Harare Health Services, Rowan Martin Building, Harare, Zimbabwe.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bara
authors.affiliation: City of Harare Health Services, Rowan Martin Building, Harare, Zimbabwe.
authors.forename: Stanley
authors.initials: S
authors.lastname: Mungofa
authors.affiliation: McGill International TB Centre and Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada.
authors.forename: Madhukar
authors.initials: M
authors.lastname: Pai
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dowdy
authors.affiliation: South African Medical Research Council, Durban, South Africa; KwaZulu Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Alex
authors.initials: A
authors.lastname: Pym
authors.affiliation: University Teaching Hospital, Lusaka, Zambia.
authors.forename: Peter
authors.initials: P
authors.lastname: Mwaba
authors.affiliation: Biomedical Research and Training Institute, Harare, Zimbabwe.
authors.forename: Peter
authors.initials: P
authors.lastname: Mason
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Jonny
authors.initials: J
authors.lastname: Peter
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa; University of Cape Town Lung Institute, University of Cape Town, Cape Town, South Africa; Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: keertan.dheda@uct.ac.za.
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
mesh_terms: D000328:Adult; D000349:Africa; D001431:Bacteriological Techniques / Q000592:standards; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019095:Point-of-Care Systems / Q000592:standards*; D011320:Primary Health Care; D013183:Sputum / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000451:nursing; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis* / Q000451:nursing