title: Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial.
abstract: BACKGROUND
  Alovudine inhibits replication of highly nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV strains in vitro. However, dose-dependent safety concerns resulted in its initial development being halted. Recently, a 4-week course of alovudine 7.5 mg/day added to a stavudine-free failing regimen yielded a significant decrease in viral load by -1.88 log(10) HIV-1 RNA copies/mL. The magnitude of the reduction in viral load suggested that lower doses might still be effective while offering adequate safety during long-term use.
  
  
  OBJECTIVE
  To determine whether lower dosages of alovudine still provide significant antiviral activity in patients with broad NRTI resistance.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled trial investigating three doses of alovudine (0.5, 1 and 2 mg) or placebo added for 4 weeks to a failing regimen in patients with evidence of NRTI-resistant HIV strains [>or=2 thymidine-associated mutations (TAMs)]. The primary endpoint was the mean viral load reduction between baseline and week 4.
  
  
  RESULTS
  Seventy-two patients were enrolled in the study: 21, 13, 18 and 20 in the placebo and 0.5, 1 and 2 mg arms, respectively. Baseline median CD4 count and viral load were 298 cells/microL (range 44-692 cells/microL) and 3.9 log(10) copies/mL (range 2.5-5.2 log(10) copies/mL), respectively. Baseline viral isolates harboured a median of four TAMs. Alovudine was added to a median four-drug failing regimen. At week 4, compared with placebo, mean viral load changes were -0.42 log(10) [95% confidence interval (CI) -0.67 to -0.18] and -0.30 log(10) (-0.55 to -0.06) in the 2 and 1 mg arms, respectively. There was no significant change in CD4 cell count. Alovudine was well tolerated.
  
  
  CONCLUSIONS
  A 4-week course of alovudine 2 mg/day provided a modest but significant viral load reduction in patients harbouring viruses with a median of four TAMs.
authors.affiliation: Service des Maladies Infectieuses, Hôpital Pitié-Salpêtrière, Paris, France. jade.ghosn@psl.ap-hop-paris.fr
authors.forename: J
authors.initials: J
authors.lastname: Ghosn
authors.forename: A-M
authors.initials: AM
authors.lastname: Quinson
authors.forename: Nd
authors.initials: N
authors.lastname: Sabo
authors.forename: L
authors.initials: L
authors.lastname: Cotte
authors.forename: C
authors.initials: C
authors.lastname: Piketty
authors.forename: N
authors.initials: N
authors.lastname: Dorléacq
authors.forename: M-L
authors.initials: ML
authors.lastname: Bravo
authors.forename: D
authors.initials: D
authors.lastname: Mayers
authors.forename: J
authors.initials: J
authors.lastname: Harmenberg
authors.forename: G
authors.initials: G
authors.lastname: Mårdh
authors.forename: H
authors.initials: H
authors.lastname: Valdez
authors.forename: C
authors.initials: C
authors.lastname: Katlama
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D015224:Dideoxynucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006678:HIV / Q000235:genetics / Q000254:growth & development*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D012367:RNA, Viral; C002854:alovudine