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Antimicrobial Agents and Chemotherapy, June 2009, p. 2335-2341, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01387-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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
Joseph J. Eron Jr.,1*
Jeong-Gun Park,2
Richard Haubrich,3
Francesca Aweeka,4
Barbara Bastow,5
Gary E. Pakes,6
Song Yu,2
Hulin Wu,7
Douglas D. Richman,3,8 for the ACTG5126 Study Team
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,1 Statistical and Data Analysis Center, Harvard University, Boston, Massachusetts,2 University of California—San Diego, San Diego, California,3 University of California—San Francisco, San Francisco, California,4 Social and Scientific Systems, Inc., Silver Spring, Maryland,5 GlaxoSmithKline, Research Triangle Park, North Carolina,6 University of Rochester, Rochester, New York,7 Veterans Administration San Diego Healthcare System, San Diego, California8
Received 15 October 2008/ Returned for modification 31 December 2008/ Accepted 16 March 2009
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 (IC50s) to the study PI were high. Median 2-week VL changes were –0.7, –0.1, and –1.0 log10 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 
0.029). The strongest correlation with response to FPV/r was the IC50 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.
* Corresponding author. Mailing address: 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. Phone: (919) 843-2722. Fax: (919) 966-8928. E-mail: jeron{at}med.unc.edu
Published ahead of print on 23 March 2009.
Antimicrobial Agents and Chemotherapy, June 2009, p. 2335-2341, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01387-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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