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Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drug-resistant isolates.

AbstractBACKGROUND:
Despite the increasing number of antiretroviral compounds, the number of useful drug regimens is limited owing to the high frequency of cross-resistance.
PATIENTS AND METHODS:
We studied in vitro two-drug combinations using three protease inhibitors (PIs), tipranavir, amprenavir and lopinavir, on isolates (003 and 004) derived from patients with resistance to multiple PIs compared with the drug-susceptible isolate 14aPre in peripheral blood mononuclear cells. Drug interactions were determined by median dose-effect analysis, with the combination index calculated at several inhibitory concentrations (IC).
RESULTS:
In 14aPre experiments, the combination tipranavir + lopinavir demonstrated synergy at low concentrations (IC(50)), an additive effect at IC(75) and antagonism at IC(90)-IC(95); tipranavir + amprenavir were antagonistic at all concentrations except IC(95), where they were synergic; and the lopinavir + amprenavir combination was always antagonistic. In 003 and 004 infections, tipranavir + lopinavir and tipranavir + amprenavir combinations were antagonistic, and lopinavir + amprenavir were synergic, at all concentrations, with the exception of being additive at IC(95).
CONCLUSIONS:
Our in vitro experiments did not show any advantage in combining second generation PIs as a therapeutic strategy in naive or multi-treatment failure subjects, with the exception of tipranavir + amprenavir at IC(95) in infections by a wild-type isolate.
AuthorsElisabetta Bulgheroni, Paola Citterio, Francesco Croce, Mirko Lo Cicero, Ottavia Viganò, Francesca Soster, Ting-Chao Chou, Massimo Galli, Stefano Rusconi
JournalThe Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 53 Issue 3 Pg. 464-8 (Mar 2004) ISSN: 0305-7453 [Print] England
PMID14963061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carbamates
  • Furans
  • HIV Protease Inhibitors
  • Pyridines
  • Pyrimidinones
  • Pyrones
  • RNA, Viral
  • Sulfonamides
  • Lopinavir
  • amprenavir
  • tipranavir
Topics
  • Carbamates
  • Drug Resistance, Viral
  • Enzyme-Linked Immunosorbent Assay
  • Furans
  • Genotype
  • HIV Infections (virology)
  • HIV Protease Inhibitors (pharmacology)
  • HIV-1 (drug effects)
  • Humans
  • Lopinavir
  • Pyridines (pharmacology)
  • Pyrimidinones (pharmacology)
  • Pyrones (pharmacology)
  • RNA, Viral (biosynthesis, genetics)
  • Sulfonamides (pharmacology)

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