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

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 (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.