JAC Advance Access published online on February 12, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh103
© 2004 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Istituto di Malattie Infettive
e Tropicali, Università degli Studi, Ospedale Luigi Sacco,
Via GB Grassi 74,
20157 Milano, Italy;
* Corresponding author. E-mail: stefano.rusconi{at}unimi.it.
Received 13 July 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
Analysis of protease inhibitor combinations in
vitro: activity of lopinavir, amprenavir and tipranavir against
HIV type 1 wild-type and drug-resistant isolates
2 Molecular
Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer
Center, New York, NY, USA
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