title: Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors.
abstract: The therapeutic success of an antiretroviral salvage regimen containing protease inhibitors (PI) is limited by PI-resistant viral strains exhibiting various degrees of resistance and cross-resistance. To evaluate the extent of cross-resistance to the new PI amprenavir, 155 samples from 132 human immunodeficiency virus type 1-infected patients were analyzed for viral genotype by direct sequencing of the protease gene. Concomitantly, drug sensitivity to indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir was analyzed by a recombinant virus assay. A total of 111 patients had been pretreated with 1-4 PI, but all were naive to amprenavir. A total of 105 samples (67.7%) were sensitive to amprenavir; 25 samples (16.1%) were intermediately resistant, and another 25 samples were highly resistant (4- to 8-fold- and >8-fold-reduced sensitivity, respectively). The mutations 46I/L, 54L/V, 84V, and 90M showed the strongest association with amprenavir resistance (P < 0. 0001). The scoring system using 84V and/or any two of a number of mutations (10I/R/V/F, 46I/L, 54L/V, and 90M) predicted amprenavir resistance with a sensitivity of 86.0% and a specificity of 81.0% within the analyzed group of samples. Of 62 samples with resistance against 4 PI, 23 (37.1%) were still sensitive to amprenavir. In comparison, only 2 of 23 samples (8.7%) from nelfinavir-naive patients with resistance against indinavir, saquinavir, and ritonavir were still sensitive to nelfinavir. Amprenavir thus appears to be an interesting alternative for PI salvage therapy.
authors.affiliation: Institute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, University of Erlangen-Nürnberg, Erlangen, Germany. baschmid@viro.med.uni-erlangen.de
authors.forename: B
authors.initials: B
authors.lastname: Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Korn
authors.forename: B
authors.initials: B
authors.lastname: Moschik
authors.forename: C
authors.initials: C
authors.lastname: Paatz
authors.forename: K
authors.initials: K
authors.lastname: Uberla
authors.forename: H
authors.initials: H
authors.lastname: Walter
mesh_terms: D002219:Carbamates; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D019258:Saquinavir / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D019258:Saquinavir; D019438:Ritonavir