HIV protease mutations associated with amprenavir resistance during salvage therapy: importance of I54M.

Abstract

To examine the clinical significance of HIV protease mutations detected before and after therapy with amprenavir. Serial plasma HIV loads and protease gene mutations were monitored in 31 patients who received amprenavir, including 19 who had been exposed to other protease inhibitors (salvage therapy). Recombinant phenotyping was used to assess the significance of new mutations appearing after amprenavir therapy. After 6-8 months of amprenavir, 4 treatment-naïve and 5 salvage patients had an undetectable plasma HIV load, while 12 other salvage patients showed less than 10-fold HIV load reduction. HIV protease mutations associated with amprenavir resistance included I84V, I50V, I47V, V32I, and I54M. Among mutations newly detected after amprenavir treatment, I54M occurred in six cases, I54L in two cases, M46I in two cases, I47V in one case and I50V in one case. When compared with pretreatment plasma without the mutation, recombinant phenotyping showed that I54M increased the amprenavir resistance by at least 6-fold, resulting in up to 48-fold resistance over a drug-sensitive control. Protease I54M frequently appears after amprenavir therapy, and when combined with pre-existing mutations, leads to high-level amprenavir resistance and treatment failure.