title: Isoniazid clearance is impaired among human immunodeficiency virus/tuberculosis patients with high levels of immune activation.
abstract: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid.
  
  
  
  We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation. Nonlinear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N-acetyltransferase-2 (NAT-2) genotype and interoccasional variability on clearance (thereby analyzing the PK data before and after ART initiation in a single model).
  
  
  
  We enrolled 40 patients in the PK visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a two-compartment model with first-order elimination. After accounting for NAT-2 genotype, increasing levels of CD38 and HLA-DR expression on CD8+ T cells (CD38+DR+CD8+) were associated with decreasing isoniazid clearance.
  
  
  
  HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.
authors: Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.
authors: Christopher
authors: C
authors: Vinnard
authors: University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Shruthi
authors: S
authors: Ravimohan
authors: Pennsylvania Botswana-UPenn Partnership, Gaborone, Botswana.
authors: Neo
authors: N
authors: Tamuhla
authors: Center for Translational Medicine, University of Maryland, Baltimore, Maryland, USA.
authors: Vijay
authors: 0000-0002-6433-1154
authors: V
authors: Ivaturi
authors: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors: Jotam
authors: J
authors: Pasipanodya
authors: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors: Shashikant
authors: S
authors: Srivastava
authors: Pennsylvania Botswana-UPenn Partnership, Gaborone, Botswana.
authors: Chawangwa
authors: C
authors: Modongo
authors: Pennsylvania Botswana-UPenn Partnership, Gaborone, Botswana.
authors: Nicola M
authors: NM
authors: Zetola
authors: University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Drew
authors: D
authors: Weissman
authors: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors: Tawanda
authors: T
authors: Gumbo
authors: University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Gregory P
authors: GP
authors: Bisson
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011446:Prospective Studies; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid
keywords: human immunodeficiency virus; immune activation; isoniazid; n-acetyltransferse-2; pharmacokinetics; tuberculosis