Activities of atazanavir (BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors

Abstract

To evaluate the cross-resistance profile of the human immunodeficiency virus type 1 protease inhibitor (PI) atazanavir (BMS-232632), a panel of 551 clinical isolates exhibiting a wide array of PI resistance profiles and a variety of genotypic patterns were assayed for susceptibility to atazanavir and six other PIs: amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. In general, reductions in atazanavir susceptibility in vitro required several amino acid changes and were relatively modest in degree, and susceptibility was retained among isolates resistant to one or two of the currently approved PIs. There was a clear trend toward loss of susceptibility to atazanavir, as isolates exhibited increasing levels of cross-resistance to multiple PIs. Atazanavir appeared to have a distinct resistance profile relative to each of the other six PIs tested based on susceptibility comparisons against this panel of resistant isolates. Analysis of the genotypic profiles of 943 PI-susceptible and -resistant clinical isolates identified a strong correlation between the presence of amino acid changes at specific residues (10I/V/F, 20R/M/I, 24I, 33I/F/V, 36I/L/V, 46I/L, 48V, 54V/L, 63P, 71V/T/I, 73C/S/T/A, 82A/F/S/T, 84V, and 90M) and decreased susceptibility to atazanavir. While no single substitution or combination of substitutions was predictive of atazanavir resistance (change, >3.0-fold), the presence of at least five of these substitutions correlated strongly with loss of atazanavir susceptibility. Mutations associated with reduced susceptibility to each of the other six PIs were also determined.

FIG. 1.

Relationship of atazanavir susceptibility and cross-resistance to other PIs. The atazanavir (ATV) FC for all 551 isolates listed in Table 1 are plotted based on their cross-resistance profile for five of the six marketed PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and susceptibility to atazanavir. Diameter of plotted points corresponds directly to the number of isolates displaying the indicated value. The dotted line identifies the position of a 3.0-fold change in susceptibility.

FIG. 2.

Comparative scatter plots of resistant isolates. Each panel plots individual isolates displaying a ≤3.0-fold change in susceptibility to atazanavir (ATV) and/or amprenavir (APV; panel A, 348 isolates), indinavir (IDV; panel B, 94 isolates), lopinavir (LPV; panel C, 265 isolates), nelfinavir (NFV; panel D, 492 isolates), ritonavir (RTV; panel E, 434 isolates), and saquinavir (SQV; panel F, 349 isolates). Open squares in panel D represent isolates containing D30N substitutions. Dotted lines identify the position of a 3.0-fold change in susceptibility to each of the PIs.

FIG. 3.

Relationship of atazanavir susceptibility and number of key substitutions. The atazanavir (ATV) FCs for 943 resistant and susceptible isolates are plotted based on the number of identified atazanavir key substitutions (Table 2) present. The dotted line identifies the position of a 3.0-fold change in susceptibility.

FIG. 4.

Relationship between number of key substitutions and susceptibility to PIs. Panel A plots the range of FCs for all seven PIs relative to a number of key substitutions present. The dotted line identifies the position of a 3.0-fold change in susceptibility. Panel B plots the percentage of isolates displaying a ≤3.0-fold change in susceptibility to each of the PIs for isolates containing one to eight key substitutions: atazanavir (⧫), amprenavir (▪), indinavir (▴), lopinavir (◊), nelfinavir (▵), ritonavir (○), and saquinavir (□).