Sequencing of protease inhibitor therapy: insights from an analysis of HIVphenotypic resistance in patients failing protease inhibitors

Objective: To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing reg imen. Design: A cross-sectional analysis of antiretroviral susceptibility. Setting: HIV clinics in six metropolitan areas. Patients: Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml aft er greater than or equal to 6 months of antiretroviral therapy, including t he use of one protease inhibitor for greater than or equal to 3 months. Measurements: The frequency and magnitude of decreased susceptibility, meas ured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC50) compared with drug sensitive contr ol virus. Results: At study entry patients were being treated with nelfinavir (63%), indinavir (2.5%), or another protease inhibitor (11%). HIV isolates from th ese patients were susceptible (fold change < 2.5) to all five protease inhi bitors in 18% of patients and to none in 8%. Isolates from patients receivi ng nelfinavir were less likely to have reduced susceptibility to other prot ease inhibitors than isolates from patients treated with indinavir (P < 0.0 07) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to sa quinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors. Conclusion: The frequency of protease inhibitor cross-resistance and the ma gnitude of changes in susceptibility varied according to the initial protea se inhibitor used in the failing treatment regimen. Significantly less prot ease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors. <(c)> 2001 Lippincott Williams & Wilki ns.