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Journal of Virology, November 2006, p. 10794-10801, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00712-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Genotypic Changes in Human Immunodeficiency Virus Type 1 Protease Associated with Reduced Susceptibility and Virologic Response to the Protease Inhibitor Tipranavir{triangledown}

John D. Baxter,1* Jonathan M. Schapiro,2 Charles A. B. Boucher,3 Veronika M. Kohlbrenner,4 David B. Hall,4 Joseph R. Scherer,4 and Douglas L. Mayers4

Cooper University Hospital/UMDNJ-Robert Wood Johnson Medical School, Camden, New Jersey,1 Stanford University, Stanford, California,2 Eijkman-Winkler Center, University Medical Center Utrecht, Utrecht, The Netherlands,3 Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut4

Received 7 April 2006/ Accepted 14 August 2006

Tipranavir is a novel, nonpeptidic protease inhibitor of human immunodeficiency virus type 1 (HIV-1) with activity against clinical HIV-1 isolates from treatment-experienced patients. HIV-1 genotypic and phenotypic data from phase II and III clinical trials of tipranavir with protease inhibitor-experienced patients were analyzed to determine the association of protease mutations with reduced susceptibility and virologic response to tipranavir. Specific protease mutations were identified based on stepwise multiple-regression analyses of phase II study data sets. Validation included analyses of phase III study data sets to determine if the same mutations would be selected and to assess how these mutations contribute to multiple-regression models of tipranavir-related phenotype and of virologic response. A tipranavir mutation score was developed from these analyses, which consisted of a unique string of 16 protease positions and 21 mutations (10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V). HIV-1 isolates displaying an increasing number of these tipranavir resistance-associated mutations had a reduced phenotypic susceptibility and virologic response to tipranavir. Regression models for predicting virologic response in phase III trials revealed that each point in the tipranavir score was associated with a 0.16-log10 copies/ml-lower virologic response to tipranavir at week 24 of treatment. A lower number of points in the tipranavir score and a greater number of active drugs in the background regimen were predictive of virologic success. These analyses demonstrate that the tipranavir mutation score is a potentially valuable tool for predicting the virologic response to tipranavir in protease inhibitor-experienced patients.

* Corresponding author. Mailing address: Division of Infectious Diseases, Suite 513, Cooper Plaza, Camden, NJ 08103. Phone: (856) 757-7767. Fax: (856) 757-7803. E-mail: baxter{at}umdnj.edu.

{triangledown} Published ahead of print on 23 August 2006.

Journal of Virology, November 2006, p. 10794-10801, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00712-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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