The effect of increasing alpha(1)-acid glycoprotein concentration on the antiviral efficacy of human immunodeficiency virus protease inhibitors

The effect of a 4-fold increase in alpha(1)-acid glycoprotein (AGP) on the antiviral efficacy of 5 human immunodeficiency virus (HIV) protease inhibit ors (PIs) was examined by the effect of HIV PIs on p24 production in periph eral blood mononuclear cells infected with protease wild-type and PI-resist ant HIV isolates. For wild-type virus, the efficacy of the PIs at trough co ncentrations was unaffected by a 4-fold increase in AGP. With the partially HIV PI-resistant isolate, a 4-fold increase in AGP resulted in 2%, 30%, 37 %, 37%, and 42% loss of activity for indinavir, saquinavir, nelfinavir, rit onavir, and amprenavir, respectively. The high-level HIV PI-resistant isola te had a greater loss in activity. The change in IC50 secondary to the addi tion of AGP was the greatest for ritonavir, nelfinavir, and amprenavir and lowest for indinavir, These data suggest that the target plasma concentrati on for the highly bound HIV PIs may need to be raised in subjects with elev ated AGP who harbor partially PI-resistant isolates.