Clinically relevant interpretation of genotype and relationship to plasma drug concentrations for resistance to saquinavir-ritonavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients.
It has been shown that virological protease inhibitor (PI) resistance mutations present at the initiation of saquinavir (SQV) plus ritonavir (RTV) therapy in PI-experienced patients are the strongest predictors of virological response. But most of the current resistance algorithms are adapted for unboosted SQV regimens. We applied a stepwise methodology for the development and validation of a clinically relevant genotypic resistance score for an SQV (800 mg twice per day [b.i.d.]) plus RTV (100 mg b.i.d.)-containing regimen. PI-experienced patients treated by this regimen achieved a human immunodeficiency virus plasma viral load (VL) of <200 copies/ml at months 3 to 5 for 41.7% of subjects. Adjusted in a multivariate analysis, taking into account all the confounding factors, such as the nucleoside used, five mutations were combined in a resistance score associated with a reduced virological response to an SQV-plus-RTV regimen: L24I, I62V, V82A/F/T/S, I84V, and L90IM. Patients with isolates harboring 0 to 1 mutation among the score achieved -2.20 log10 and -1.23 log10 copies/ml of VL reduction, respectively, while it was -0.27 log10 copies/ml for those with at least two mutations, classifying the isolates as "no evidence of resistance" (0 or 1 mutation) or "resistance " (> or =2 mutations). The minimum concentration in plasma (Cmin) of SQV alone was not associated with the virological response. However, the combination of the SQV Cmin and the genotypic score, expressed as the genotypic inhibitory quotient, was predictive of the virological response, suggesting that the interpretation of SQV concentrations in plasma should be done only in the context of the resistance index provided by viral genotype for PI-experienced patients.
Marcelin
Anne-Geneviève
AG
Department of Virology, Pitié-Salpêtrière Hospital, Paris, France. anne-genevieve.marcelin@psl.ap-hop-paris.fr
Dalban
Cécile
C
Peytavin
Gilles
G
Lamotte
Claire
C
Agher
Rachid
R
Delaugerre
Constance
C
Wirden
Marc
M
Conan
Françoise
F
Dantin
Sylvie
S
Katlama
Christine
C
Costagliola
Dominique
D
Calvez
Vincent
V
D003062:Codon / Q000235:genetics; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D005838:Genotype; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D019438:Ritonavir / Q000494:pharmacology*; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D003062:Codon; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D016333:HIV Protease; D019258:Saquinavir; D019438:Ritonavir