Predictive values of the human immunodeficiency virus phenotype and genotype and of amprenavir and lopinavir inhibitory quotients in heavily pretreated patients on a ritonavir-boosted dual-protease-inhibitor regimen.
The inhibitory quotient (IQ) of human immunodeficiency virus (HIV) protease inhibitors (PIs), which is the ratio of drug concentration to viral susceptibility, is considered to be predictive of the virological response. We used several approaches to calculate the IQs of amprenavir and lopinavir in a subset of heavily pretreated patients participating in the French National Agency for AIDS Research (ANRS) 104 trial and then compared their potentials for predicting changes in the plasma HIV RNA level. Thirty-seven patients were randomly assigned to receive either amprenavir (600 mg twice a day [BID]) or lopinavir (400 mg BID) plus ritonavir (100 or 200 mg BID) for 2 weeks before combining the two PIs. The 90% inhibitory concentration (IC(90)) was measured using a recombinant assay without or with additional human serum (IC(90+serum)). Total and unbound PI concentrations in plasma were measured. Univariate linear regression was used to estimate the relation between the change in viral load and the IC(90) or IQ values. The amprenavir phenotypic IQ values were very similar when measured with the standard and protein binding-adjusted IC(90)s. No relationship was found between the viral load decline and the lopinavir IQ. During combination therapy, the amprenavir and lopinavir genotypic IQ values were predictive of the viral response at week 6 (P = 0.03). The number of protease mutations (< 5 or > or = 5) was related to the virological response throughout the study. These findings suggest that the combined genotypic IQ and the number of protease mutations are the best predictors of virological response. High amprenavir and lopinavir concentrations in these patients might explain why plasma concentrations and the phenotypic IQ have poor predictive value.
Barrail-Tran
Aurélie
A
Assistance Publique hôpitaux de Paris, Hôpital Bicêtre, Service de Pharmacie Clinique, Paris, France.
Morand-Joubert
Laurence
L
Poizat
Gwendoline
G
Raguin
Gilles
G
Le Tiec
Clotilde
C
Clavel
François
F
Dam
Elisabeth
E
Chêne
Geneviève
G
Girard
Pierre-Marie
PM
Taburet
Anne-Marie
AM
D000328:Adult; D000368:Aged; D002219:Carbamates / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005602:France; D005663:Furans; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D011744:Pyrimidinones / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral; D013449:Sulfonamides; D061466:Lopinavir; C095108:amprenavir; D019438:Ritonavir