JAC Advance Access originally published online on February 12, 2004
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Journal of Antimicrobial Chemotherapy (2004) 53, 464-468
© 2004 The British Society for Antimicrobial Chemotherapy
Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drug-resistant isolates
1 Istituto di Malattie Infettive e Tropicali, Università degli Studi, Ospedale Luigi Sacco, Via GB Grassi 74, 20157 Milano, Italy; 2 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Received 13 July 2003; returned 23 October 2003; revised 13 November 2003; accepted 8 December 2003
Background: 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 (IC50), an additive effect at IC75 and antagonism at IC90–IC95; tipranavir + amprenavir were antagonistic at all concentrations except IC95, 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 IC95.
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 IC95 in infections by a wild-type isolate.
Keywords: HIV-1, protease inhibitors, in vitro combinations, drug resistance, combination index
* E. Bulgheroni and P. Citterio contributed equally to this work.
E. Bulgheroni and P. Citterio contributed equally to this work.
¶ Corresponding author. Tel: + 39-02-39043350; Fax: + 39-02-3560805; E-mail: stefano.rusconi{at}unimi.it
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