Genotypic and phenotypic cross-resistance patterns to lopinavir and amprenavir in protease inhibitor-experienced patients with HIV viremia.
Genotypic correlates of reduced phenotypic susceptibility to amprenavir (APV) and lopinavir (LPV) were examined in 271 HIV isolates from 207 protease inhibitor (PI)-experienced subjects. All samples were from LPV-naive subjects; two were from APV-experienced subjects. Using a fold resistance (FR) of <2.5, 179 (66%) were APV susceptible. Using FRs of <2.5 and <10, 107 (39%) and 194 (72%), respectively, were LPV susceptible. The I84V mutation was the strongest APV resistance marker in PI-experienced subjects in both univariate and multivariate analyses, with an increased relative incidence (RI) of 6.9 with >2.5 FR. Mutations L10I (RI, 1.7), M46I (RI, 2.3), and L90M (RI, 1.9, but 65% linked with the I84V) were associated with decreased APV susceptibility in the univariate analysis (p < 0.001). Mutations L10I, G48V, I54T, I54V, and V82A were significantly associated with decreased LPV susceptibility (p < 0.001 for each) and had increased RIs of 2.2, 4.4, 13, 4.6, and 3.2, respectively. Decreased susceptibility to LPV (FR, >or=10) was significantly associated with prior exposure to the following PIs: ritonavir (RTV) (p < 0.001), saquinavir (SQV) (p < 0.001), nelfinavir (NFV) (p = 0.008), and indinavir (IDV) (p = 0.028). Decreased APV susceptibility (FR, >or=2.5) was significantly associated with prior exposure to RTV (p = 0.009), NFV (p = 0.003), and IDV (p = 0.021) but not with prior SQV (p = 0.103). These results suggest that APV and LPV have different cross-resistance mutation patterns that may help determine choice of PI therapy after therapy failure.
Paulsen
Denise
D
GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
Liao
Qiming
Q
Fusco
Gregory
G
St  Clair
Marty
M
Shaefer
Mark
M
Ross
Lisa
L
D002219:Carbamates; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D005663:Furans; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D061466:Lopinavir; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014766:Viremia / Q000188:drug therapy / Q000821:virology
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral; D013449:Sulfonamides; D061466:Lopinavir; C095108:amprenavir; D016333:HIV Protease