title: Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy.
abstract: BACKGROUND
  Azodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity.
  
  
  OBJECTIVE
  A first phase I/II clinical study of ADA.
  
  
  METHODS
  ADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage.
  
  
  RESULTS
  Fifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 x 10(6) cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10 copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P < 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10 copies/ml compared with baseline and 5/ 11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47-243%), and viral load decrease of 1.04 log10 copies/ml (range 0.52-1.23).
  
  
  CONCLUSIONS
  The maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.
authors.affiliation: Medizinische Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: F D
authors.initials: FD
authors.lastname: Goebel
authors.forename: R
authors.initials: R
authors.lastname: Hemmer
authors.forename: J C
authors.initials: JC
authors.lastname: Schmit
authors.forename: J R
authors.initials: JR
authors.lastname: Bogner
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: R
authors.initials: R
authors.lastname: Valeyev
authors.forename: M
authors.initials: M
authors.lastname: Vandevelde
authors.forename: H
authors.initials: H
authors.lastname: Margery
authors.forename: J P
authors.initials: JP
authors.lastname: Tassignon
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001391:Azo Compounds / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D003257:Consumer Product Safety; D004311:Double-Blind Method; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents; D001391:Azo Compounds; C004525:azodicarbonamide