Predictive genotypic algorithm for virologic response to lopinavir-ritonavir in protease inhibitor-experienced patients.
Several genotypic resistance algorithms have been proposed for quantitation of the degree of phenotypic resistance to the human immunodeficiency virus (HIV) protease inhibitor (PI) lopinavir (LPV), including the original LPV mutation score. In this study, we retrospectively evaluated 21 codons in HIV protease known to be associated with PI resistance in a large antiretroviral agent-experienced observational patient cohort, "Autorisation Temporaire d'Utilization" (ATU), to assess whether a more optimal algorithm could be derived by using virologic response data from patients treated with LPV in combination with ritonavir (LPV/r). Five of the 11 mutations constituting the LPV mutation score were not associated with a virologic response, while 4 additional mutations not included in this score demonstrated an association. Therefore, the LPV ATU score, which includes mutations at codons 10, 20, 24, 33, 36, 47, 48, 54, 82, and 84, was constructed and shown in two different types of multivariable analyses of the ATU cohort to be a better predictor of the virologic response than the LPV mutation score. The LPV ATU score was also more strongly associated with a virologic response when it was applied to independent clinical trial populations of PI-experienced patients receiving LPV/r. This study provides the basis for a new genotypic resistance algorithm that is useful for predicting the antiviral activities of LPV/r-based regimens in PI-experienced patients. The refined algorithm may be useful in making clinical treatment decisions and in refining genetic and pharmacologic methods for assessing the activity of LPV/r.
King
Martin S
MS
Global Pharmaceutical Research and Development, Abbott, 100 Abbott Park Rd., R436 AP9A-2, Abbott Park, IL 60064, USA. martin.king@abbott.com
Rode
Richard
R
Cohen-Codar
Isabelle
I
Calvez
Vincent
V
Marcelin
Anne-Geneviève
AG
Hanna
George J
GJ
Kempf
Dale J
DJ
D000328:Adult; D000465:Algorithms; D000704:Analysis of Variance; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011744:Pyrimidinones / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D019438:Ritonavir / Q000627:therapeutic use*
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir