title: Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors.
abstract: Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I+I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P = 0.014 and P = 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.
authors.affiliation: GlaxoSmithKline Research and Development, International Clinical Virology, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Maguire
authors.forename: Denise
authors.initials: D
authors.lastname: Shortino
authors.forename: Astrid
authors.initials: A
authors.lastname: Klein
authors.forename: Wendy
authors.initials: W
authors.lastname: Harris
authors.forename: Varsha
authors.initials: V
authors.lastname: Manohitharajah
authors.forename: Margaret
authors.initials: M
authors.lastname: Tisdale
authors.forename: Robert
authors.initials: R
authors.lastname: Elston
authors.forename: Jane
authors.initials: J
authors.lastname: Yeo
authors.forename: Sharon
authors.initials: S
authors.lastname: Randall
authors.forename: Fan
authors.initials: F
authors.lastname: Xu
authors.forename: Hayley
authors.initials: H
authors.lastname: Parker
authors.forename: Jackie
authors.initials: J
authors.lastname: May
authors.forename: Wendy
authors.initials: W
authors.lastname: Snowden
mesh_terms: D002219:Carbamates; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005663:Furans; D005838:Genotype; D016655:HIV Core Protein p24 / Q000187:drug effects / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009705:Nucleosides / Q000494:pharmacology; D010641:Phenotype; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D002219:Carbamates; D005663:Furans; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D009705:Nucleosides; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D054303:HIV Reverse Transcriptase; D016333:HIV Protease