title: Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/μL: TB-HAART Study, a Randomized Clinical Trial.
abstract: BACKGROUND
  Given the high death rate the first two months of tuberculosis (TB) therapy in HIV patients, it is critical defining the optimal time to initiate combination antiretroviral therapy (cART).
  
  
  METHODS
  A randomized, open-label, clinical trial comparing efficacy and safety of efavirenz-based cART initiated one week, four weeks, and eight weeks after TB therapy in patients with baseline CD4 count < 200 cells/μL was conducted. The primary endpoint was all-cause mortality rate at 48 weeks. The secondary endpoints were hepatotoxicity-requiring interruption of TB therapy, TB-associated immune reconstitution inflammatory syndrome, new AIDS defining illnesses, CD4 counts, HIV RNA levels, and AFB smear conversion rates. All analyses were intention-to-treat.
  
  
  RESULTS
  We studied 478 patients with median CD4 count of 73 cells/μL and 5.2 logs HIV RNA randomized to week one (n = 163), week four (n = 160), and week eight (n = 155). Sixty-four deaths (13.4%) occurred in 339.2 person-years. All-cause mortality rates at 48 weeks were 25 per 100 person-years in week one, 18 per 100 person-years in week four and 15 per 100 person-years in week eight (P = 0.2 by the log-rank test). All-cause mortality incidence rate ratios in subgroups with CD4 count below 50 cells/μL versus above were 2.8 in week one (95% CI 1.2-6.7), 3.1 in week four (95% CI 1.2-8.6) and 5.1 in week eight (95% CI 1.8-16). Serum albumin < 3 gms/dL (adjusted HR, aHR = 2.3) and CD4 < 50 cells/μL (aHR = 2.7) were independent predictors of mortality. Compared with similar subgroups from weeks four and eight, first-line TB treatment interruption was high in week one deaths (P = 0.03) and in the CD4 subgroup <50 cells/μL (P = 0.02).
  
  
  CONCLUSIONS
  Antiretroviral therapy one week after TB therapy doesn't improve overall survival. Despite increased mortality with CD4 < 50 cells/μL, we recommend cART later than the first week of TB therapy to avoid serious hepatotoxicity and treatment interruption.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT 01315301.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Wondwossen
authors.initials: W
authors.lastname: Amogne
authors.affiliation: Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge C1: 68, Karolinska Institute, Stockholm, Sweden; Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Abiy
authors.initials: A
authors.lastname: Habtewold
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge C1: 68, Karolinska Institute, Stockholm, Sweden; Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.affiliation: Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.affiliation: School of Public Health, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Alemayhu
authors.initials: A
authors.lastname: Worku
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sonnerborg
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge C1: 68, Karolinska Institute, Stockholm, Sweden.
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lindquist
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000209:etiology; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014376:Tuberculosis / Q000188:drug therapy* / Q000209:etiology
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents