Resistance to Protease Inhibitors

Abstract

The availability of protease inhibitors (PIs) and their combination with nucleoside reverse transcriptase inhibitors marked the passage of antiretroviral therapy (ART) from potential for control to effective suppression and thus substantially reduced rates of morbidity and mortality related to HIV. Even so, what was first hoped to be an immutable HIV DNA treatment target has proved to be prone to resistance mutations, with substitutions identified at more than 20 amino acid sites, which reduces PI susceptibility and increases resistance to treatment. The mutation patterns associated with each PI have been defined, and have been observed to occur at one of two locations: at or near the active site, or in the substrate cleavage site. The natural history of PI resistance has been extensively studied, and the genetic and cellular pathways are described in detail in this article. In addition, cross-resistance among PIs is now recognized to be fairly extensive, although the degree of cross-resistance varies with the number of mutations and the variants selected by drug pressure. Thus, it is still possible to salvage a response with another PI after a first regimen with another PI has failed. The extensive basic science and clinical experience with PIs in the fight against HIV are reviewed in this article, which provides data on resistance-mutation profiles, cellular resistance mechanisms, viral fitness studies, and clinical outcome trials with various first-line and subsequent regimens that contain PIs. It is hoped that the information provided will guide physicians in best using PIs as part of a logical and successful ART strategy.