title: Synergistic inhibition of protease-inhibitor-resistant HIV type 1 by saquinavir in combination with atazanavir or lopinavir.
abstract: BACKGROUND
  Double-boosted protease inhibitors (PIs) are under investigation for the treatment of patients who are unable to take nucleoside reverse transcriptase inhibitors because of cross-resistance and/or intolerance. Evidence of synergistic inhibition of wild-type HIV has been reported for saquinavir with atazanavir or lopinavir.
  
  
  METHODS
  We investigated the activity of these two combinations against a panel of six site-directed mutant HIV-1 strains and 14 clinically derived recombinant HIV-1 strains presenting a range of PI-resistance profiles.
  
  
  RESULTS
  No evidence of synergy was observed against wild-type virus for either combination. The combination of saquinavir and lopinavir showed evidence of synergy against four viruses displaying high-level resistance to lopinavir and low-level resistance to saquinavir. Similarly, evidence of synergy between saquinavir and atazanavir was only observed in two viruses which were more susceptible to saquinavir than to atazanavir.
  
  
  CONCLUSIONS
  We hypothesize that differences between the PIs in intracellular protein-binding behaviour or inhibition of drug transporters (P glycoprotein, MDR1 and MDR2) could result in intracellular levels of saquinavir being increased by co-administration with lopinavir or atazanavir. The effect of this increase would be masked in cases involving viruses that were susceptible to atazanavir or lopinavir. In virus resistant to lopinavir or atazanavir but susceptible to saquinavir, the majority of the antiviral effect is due to saquinavir; thus even small increases in intracellular concentration could significantly increase virus inhibition. These results confirm that in vitro synergy can be observed between PIs and suggest that the degree of synergy observed might depend on the resistance profile of the virus.
authors.affiliation: Viralliance, Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dam
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebel-Binay
authors.forename: Séverine
authors.initials: S
authors.lastname: Rochas
authors.forename: Laurent
authors.initials: L
authors.lastname: Thibaut
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Faudon
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Thomas
authors.forename: Laurent
authors.initials: L
authors.lastname: Essioux
authors.forename: Andrew
authors.initials: A
authors.lastname: Hill
authors.forename: Malte
authors.initials: M
authors.lastname: Schutz
authors.forename: François
authors.initials: F
authors.lastname: Clavel
mesh_terms: D000069446:Atazanavir Sulfate; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D061466:Lopinavir; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D011995:Recombination, Genetic; D019258:Saquinavir / Q000494:pharmacology*; D014162:Transfection
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019258:Saquinavir