HIV protease mutations associated with amprenavir resistance during salvage therapy: importance of I54M.
OBJECTIVE
To examine the clinical significance of HIV protease mutations detected before and after therapy with amprenavir.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Protease I54M frequently appears after amprenavir therapy, and when combined with pre-existing mutations, leads to high-level amprenavir resistance and treatment failure.
Murphy
Melissa D
MD
Medical and Research Services, VA Medical Center P3ID, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA. melissa.murphy@med.va.gov
Marousek
Gail I
GI
Chou
Sunwen
S
D019943:Amino Acid Substitution; D002219:Carbamates; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D005663:Furans; D006678:HIV / Q000187:drug effects* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012189:Retrospective Studies; D016879:Salvage Therapy; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D019562:Viral Load
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D016333:HIV Protease