Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial

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The Lancet

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.


Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.

Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, MBBCh, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A, for the Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team. Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. The Lancet. 2016;387(10024).
  • UNC Project, Lilongwe, Malawi
  • University of North Carolina School of Medicine, Chapel Hill, NC 
  • Perelman School of Medicine at the University of Pennsylvania, PA 
  • Harvard University, Boston, MA 
  • GHESKIO, Port-au-Prince, Haiti
  • Kenya Medical Research Institute, Kisumu, Kenya
  • Clinical HIV Research Unit, Department of Medicine, University of Witwatersrand, Johannesburg, South Africa
  • Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa
  • Moi University School of Medicine, Eldoret, Kenya
  • Johns Hopkins Project, Blantyre, Malawi
  • Centre for the AIDS Programme of Research in South Africa, Durban, South Africa
  • University of Zimbabwe, Harare, Zimbabwe
  • Joint Clinical Research Centre, Kampala, Uganda
  • Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia
  • Asociacion Civil Impacta Salud y Educacion, Lima, Peru
  • BJ Medical College-Johns Hopkins Clinical Trials Unit, Pune, India
  • Evandro Chagas National Institute of Infectious Diseases/Fiocruz, Rio de Janeiro, Brazil
  • Durban International CRS, Durban University of Technology, Durban, South Africa
  • YRGCARE Medical Centre, VHS, Chennai, India
  • HJF-DAIDS, a Division of The Henry M Jackson Foundation for the Advancement of Military Medicine, Contractor to National Institute of Allergy and Infectious Diseases, Bethesda, MD 
  • Social and Scientific Systems, Silver Spring, MD 
  • Frontier Science, Buffalo, NY 
  • Stanford University, Palo Alto, CA 
  • Johns Hopkins University School of Medicine, Baltimore, MD