title: Predictive value of pharmacokinetics-adjusted phenotypic susceptibility on response to ritonavir-enhanced protease inhibitors (PIs) in human immunodeficiency virus-infected subjects failing prior PI therapy.
abstract: The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC(50)s) to the study PI were high. Median 2-week VL changes were -0.7, -0.1, and -1.0 log(10) for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, -0.39 to -0.50; P < or = 0.029). The strongest correlation with response to FPV/r was the IC(50) FC (r = 0.57; P = 0.001), which improved when only adherent subjects were included (r = 0.68; P = 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P < 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r = -0.72; P < 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed.
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, 130 Mason Farm Rd., Bio-Informatics Building CB No. 7215, Chapel Hill, NC 27599-7215, USA. jeron@med.unc.edu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Jeong-Gun
authors.initials: JG
authors.lastname: Park
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
authors.forename: Francesca
authors.initials: F
authors.lastname: Aweeka
authors.forename: Barbara
authors.initials: B
authors.lastname: Bastow
authors.forename: Gary E
authors.initials: GE
authors.lastname: Pakes
authors.forename: Song
authors.initials: S
authors.lastname: Yu
authors.forename: Hulin
authors.initials: H
authors.lastname: Wu
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D019540:Area Under Curve; D024882:Drug Resistance, Viral; D005260:Female; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1; D006801:Humans; D008297:Male; D010641:Phenotype; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000032:analysis; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019438:Ritonavir