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.

TitlePredictive value of pharmacokinetics-adjusted phenotypic susceptibility on response to ritonavir-enhanced protease inhibitors (PIs) in human immunodeficiency virus-infected subjects failing prior PI therapy.
Publication TypeJournal Article
Year of Publication2009
AuthorsEron JJ, Park J-G, Haubrich R, Aweeka F, Bastow B, Pakes GE, Yu S, Wu H, Richman DD
Corporate AuthorsACTG5126 Study Team
JournalAntimicrob Agents Chemother
Volume53
Issue6
Pagination2335-41
Date Published2009 Jun
ISSN1098-6596
KeywordsAcquired Immunodeficiency Syndrome, Area Under Curve, Drug Resistance, Viral, Female, HIV Protease Inhibitors, HIV-1, Humans, Male, Phenotype, Predictive Value of Tests, Ritonavir, RNA, Viral
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.

DOI10.1128/AAC.01387-08
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID19307363
PubMed Central IDPMC2687257
Grant List1U01AI / AI / NIAID NIH HHS / United States
5 U01 A1069415-02 / / PHS HHS / United States
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RR024977 / RR / NCRR NIH HHS / United States
U01 AI046376 / AI / NIAID NIH HHS / United States
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UO1AL32782 / / PHS HHS / United States