title: Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients.
abstract: OBJECTIVE
  To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF).
  
  
  METHODS
  This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined.
  
  
  RESULTS
  Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (-0.15 log10 per day vs. -0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/10 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/10 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (rho = -0.529; P = 0.045).
  
  
  CONCLUSIONS
  In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.
authors.affiliation: University California San Diego, San Diego, California, USA. mgoicoechea@ucsd.edu
authors.forename: Miguel
authors.initials: M
authors.lastname: Goicoechea
authors.forename: Sonia
authors.initials: S
authors.lastname: Jain
authors.forename: Lucun
authors.initials: L
authors.lastname: Bi
authors.forename: Carol
authors.initials: C
authors.lastname: Kemper
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.forename: Catherine
authors.initials: C
authors.lastname: Diamond
authors.forename: Belinda
authors.initials: B
authors.lastname: Ha
authors.forename: John
authors.initials: J
authors.lastname: Flaherty
authors.forename: Shelly
authors.initials: S
authors.lastname: Sun
authors.forename: Douglas
authors.initials: D
authors.lastname: Richman
authors.forename: Stan
authors.initials: S
authors.lastname: Louie
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003848:Deoxyguanine Nucleotides / Q000097:blood; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012367:RNA, Viral / Q000187:drug effects*; D000068698:Tenofovir; D016896:Treatment Outcome; D000099227:Abacavir; D006160:Guanosine Triphosphate
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D003848:Deoxyguanine Nucleotides; D015224:Dideoxynucleosides; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir; D000099227:Abacavir; C066928:carbovir triphosphate; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate