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Antimicrobial Agents and Chemotherapy, September 2007, p. 3067-3074, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00388-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Predictive Genotypic Algorithm for Virologic Response to Lopinavir-Ritonavir in Protease Inhibitor-Experienced Patients

Martin S. King,^1* Richard Rode,¹ Isabelle Cohen-Codar,² Vincent Calvez,³ Anne-Geneviève Marcelin,³ George J. Hanna,¹ and Dale J. Kempf¹

Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois,¹ Abbott Laboratories, Rungis, France,² Department of Virology, Pitié-Salpêtrière, Paris, France³

Received 22 March 2007/ Returned for modification 15 May 2007/ Accepted 8 June 2007

Several genotypic resistance algorithms have been proposed for quantitation of the degree of phenotypic resistance to the human immunodeficiency virus (HIV) protease inhibitor (PI) lopinavir (LPV), including the original LPV mutation score. In this study, we retrospectively evaluated 21 codons in HIV protease known to be associated with PI resistance in a large antiretroviral agent-experienced observational patient cohort, "Autorisation Temporaire d'Utilization" (ATU), to assess whether a more optimal algorithm could be derived by using virologic response data from patients treated with LPV in combination with ritonavir (LPV/r). Five of the 11 mutations constituting the LPV mutation score were not associated with a virologic response, while 4 additional mutations not included in this score demonstrated an association. Therefore, the LPV ATU score, which includes mutations at codons 10, 20, 24, 33, 36, 47, 48, 54, 82, and 84, was constructed and shown in two different types of multivariable analyses of the ATU cohort to be a better predictor of the virologic response than the LPV mutation score. The LPV ATU score was also more strongly associated with a virologic response when it was applied to independent clinical trial populations of PI-experienced patients receiving LPV/r. This study provides the basis for a new genotypic resistance algorithm that is useful for predicting the antiviral activities of LPV/r-based regimens in PI-experienced patients. The refined algorithm may be useful in making clinical treatment decisions and in refining genetic and pharmacologic methods for assessing the activity of LPV/r.

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* Corresponding author. Mailing address: Global Pharmaceutical Research and Development, Abbott, 100 Abbott Park Rd., R436 AP9A-2, Abbott Park, IL 60064. Phone: (847) 938-3775. Fax: (847) 938-6001. E-mail: martin.king{at}abbott.com

Published ahead of print on 18 June 2007.

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Antimicrobial Agents and Chemotherapy, September 2007, p. 3067-3074, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00388-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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