title: Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial.
abstract: 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.
  
  
  RESULTS
  Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.
  
  
  CONCLUSIONS
  Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.
  
  
  BACKGROUND
  National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.
authors.affiliation: UNC Project, Lilongwe, Malawi; University of North Carolina School of Medicine, Chapel Hill, NC, USA. Electronic address: mina_hosseinipour@med.unc.edu.
authors.forename: Mina C
authors.initials: MC
authors.lastname: Hosseinipour
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, PA, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Bisson
authors.affiliation: Harvard University, Boston, MA, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyahara
authors.affiliation: Harvard University, Boston, MA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: UNC Project, Lilongwe, Malawi.
authors.forename: Agnes
authors.initials: A
authors.lastname: Moses
authors.affiliation: GHESKIO, Port-au-Prince, Haiti.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Riviere
authors.affiliation: Kenya Medical Research Institute, Kisumu, Kenya.
authors.forename: Fredrick K
authors.initials: FK
authors.lastname: Kirui
authors.affiliation: Clinical HIV Research Unit, Department of Medicine, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Sharlaa
authors.initials: S
authors.lastname: Badal-Faesen
authors.affiliation: Moi University School of Medicine, Eldoret, Kenya.
authors.forename: David
authors.initials: D
authors.lastname: Lagat
authors.affiliation: Johns Hopkins Project, Blantyre, Malawi.
authors.forename: Mulinda
authors.initials: M
authors.lastname: Nyirenda
authors.affiliation: Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
authors.forename: Kogieleum
authors.initials: K
authors.lastname: Naidoo
authors.affiliation: University of Zimbabwe, Harare, Zimbabwe.
authors.forename: James
authors.initials: J
authors.lastname: Hakim
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: Peter
authors.initials: P
authors.lastname: Mugyenyi
authors.affiliation: Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.
authors.forename: German
authors.initials: G
authors.lastname: Henostroza
authors.affiliation: GHESKIO, Port-au-Prince, Haiti.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Leger
authors.affiliation: Asociacion Civil Impacta Salud y Educacion, Lima, Peru.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Lama
authors.affiliation: Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Lerato
authors.initials: L
authors.lastname: Mohapi
authors.affiliation: Asociacion Civil Impacta Salud y Educacion, Lima, Peru.
authors.forename: Jorge
authors.initials: J
authors.lastname: Alave
authors.affiliation: BJ Medical College-Johns Hopkins Clinical Trials Unit, Pune, India.
authors.forename: Vidya
authors.initials: V
authors.lastname: Mave
authors.affiliation: Evandro Chagas National Institute of Infectious Diseases/Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Valdilea G
authors.initials: VG
authors.lastname: Veloso
authors.affiliation: Durban International CRS, Durban University of Technology, Durban, South Africa.
authors.forename: Sandy
authors.initials: S
authors.lastname: Pillay
authors.affiliation: YRGCARE Medical Centre, VHS, Chennai, India.
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: 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, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Bao
authors.affiliation: Social and Scientific Systems, Silver Spring, MD, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hogg
authors.affiliation: Frontier Science, Buffalo, NY, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Jones
authors.affiliation: Stanford University, Palo Alto, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zolopa
authors.affiliation: Johns Hopkins Project, Blantyre, Malawi.
authors.forename: Johnstone
authors.initials: J
authors.lastname: Kumwenda
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Gupta
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000276:immunology / Q000517:prevention & control*; D000328:Adult; D000554:Ambulatory Care Facilities; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D016896:Treatment Outcome; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D007538:Isoniazid