title: Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial.
abstract: BACKGROUND
  WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per μL or more.
  
  
  METHODS
  We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per μL vs ≥350 cells per μL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053).
  
  
  RESULTS
  We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64-1·30; p=0·9). Of patients with a CD4 cell count of 220-349 cells per μL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46-1·39; p=0·6). For those with 350 cells per μL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63-1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8-2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56).
  
  
  CONCLUSIONS
  ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per μL. WHO guidelines should be updated accordingly.
  
  
  BACKGROUND
  USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.
authors.affiliation: National Institute for Medical Research, Muhumbili, Tanzania.
authors.forename: Sayoki G
authors.initials: SG
authors.lastname: Mfinanga
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Mulago Hospital, Kampala, Uganda.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Kirenga
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia. Electronic address: duncanchanda@gmail.com.
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Chanda
authors.affiliation: National Institute for Medical Research, Muhumbili, Tanzania.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mutayoba
authors.affiliation: Clinical Trials Unit, Medical Research Council, Durban, South Africa.
authors.forename: Thuli
authors.initials: T
authors.lastname: Mthiyane
authors.affiliation: Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.affiliation: Division of Clinical Sciences, Nigerian Institute of Medical Research, Lagos, Nigeria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Ezechi
authors.affiliation: Clinical Trials Unit, Medical Research Council, Durban, South Africa.
authors.forename: Cathy
authors.initials: C
authors.lastname: Connolly
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Vincent
authors.initials: V
authors.lastname: Kapotwe
authors.affiliation: WHO/TDR TB-HAART Project, Kampala, Uganda.
authors.forename: Catherine
authors.initials: C
authors.lastname: Muwonge
authors.affiliation: National Institute for Medical Research, Muhumbili, Tanzania.
authors.forename: Julius
authors.initials: J
authors.lastname: Massaga
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Edford
authors.initials: E
authors.lastname: Sinkala
authors.affiliation: National Institute for Medical Research, Muhumbili, Tanzania.
authors.forename: Wanze
authors.initials: W
authors.lastname: Kohi
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Lyantumba
authors.affiliation: National TB/Leprosy Programme, Ministry of Health, Kampala, Uganda.
authors.forename: Grace
authors.initials: G
authors.lastname: Nyakoojo
authors.affiliation: National TB/Leprosy Programme, Ministry of Health, Kampala, Uganda.
authors.forename: Henry
authors.initials: H
authors.lastname: Luwaga
authors.affiliation: National TB Reference Laboratory, Muhimbili National Hospital, Dar-es-Salaam, Tanzania.
authors.forename: Basra
authors.initials: B
authors.lastname: Doulla
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Judith
authors.initials: J
authors.lastname: Mzyece
authors.affiliation: National TB/Leprosy Program, Ministry of Health, Lusaka, Zambia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Kapata
authors.affiliation: Special Programme for Research and Training in Tropical Diseases, WHO, Geneva, Switzerland.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Vahedi
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia; Ministry of Health, Lusaka, Zambia.
authors.forename: Peter
authors.initials: P
authors.lastname: Mwaba
authors.affiliation: National TB/Leprosy Programme, Ministry of Health and Social Welfare, Dar-es-Salaam, Tanzania.
authors.forename: Saidi
authors.initials: S
authors.lastname: Egwaga
authors.affiliation: National TB/Leprosy Programme, Ministry of Health, Kampala, Uganda.
authors.forename: Francis
authors.initials: F
authors.lastname: Adatu
authors.affiliation: Clinical Trials Unit, Medical Research Council, Durban, South Africa.
authors.forename: Alex
authors.initials: A
authors.lastname: Pym
authors.affiliation: Supra-National TB Laboratory, Ministry of Health, Lusaka, Zambia.
authors.forename: Moses
authors.initials: M
authors.lastname: Joloba
authors.affiliation: Clinical Trials Unit, Medical Research Council, Durban, South Africa.
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.affiliation: Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia; Center for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK; NIHR Biomedical Research Centre, University College Hospitals, London, UK.
authors.forename: Alimuddin
authors.initials: A
authors.lastname: Zumla
authors.affiliation: Inter-country Support Team for East and Southern Africa, WHO Regional Office for Africa, Harare, Zimbabwe.
authors.forename: Philip
authors.initials: P
authors.lastname: Onyebujoh
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018791:CD4 Lymphocyte Count / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D006679:HIV Seropositivity / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008297:Male; D011446:Prospective Studies; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000821:virology
chemical_list: D019380:Anti-HIV Agents