ABSTRACT:
Amprenavir (Agenerase, 141-W94, VX-478) is an HIV-1 protease inhibitor (PI) recently approved for marketing in the USA for treatment of HIV-1 infection. One of the potential uses for amprenavir is in salvage therapy regimens for patients who have experienced viral load rebound after treatment including other approved PIs. Since one cause of treatment failure is the development of resistance to PIs, we determined patterns of cross-resistance to amprenavir of viruses resistant to other PIs.
The phenotypes and genotypes of 200 viruses from patients failing therapy with indinavir or nelfinavir were evaluated. An increase in susceptibility (2.5- to 10-fold) to amprenavir was found in 20 viruses. The most pronounced increases in susceptibility were strongly associated with the presence of the N88S mutation in the protease. This substitution has been described previously in viruses isolated after in vitro passage in the presence of an investigational PI, SC-55389A. Other combinations of mutations were also found to be associated with amprenavir hypersensitivity. Some of these viruses were also hypersensitive to saquinavir. Site-directed mutagenesis studies designed to test directly the rold of the N88S and other mutations in amprenavir and saquinavir hypersensitivity are in progress. The presence of the N88S mutation may predict a strong clinical response to amprenavir salvage therapy.
