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Antimicrobial Agents and Chemotherapy, December 2008, p. 4251-4257, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00514-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

Anne-Geneviève Marcelin,^1,2* Philippe Flandre,³ Jean-Michel Molina,^4,5 Christine Katlama,^3,6 Patrick Yeni,^4,7 Francois Raffi,⁸ Zeina Antoun,⁹ Mounir Ait-Khaled,¹⁰ and Vincent Calvez^1,2

UPMC University of Paris 06, EA 2387, F-75005 Paris, France,¹ AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de Virologie, F-75013 Paris, France,² INSERM, U720, F-75013 Paris, France,³ Université Denis Diderot-Paris 7, Paris, France,⁴ AP-HP, Hôpital Saint Louis, Service de Maladies Infectieuses, F-75009 Paris, France,⁵ AP-HP, Hôpital Pitié-Salpêtrière, Service de Maladies Infectieuses, F-75013 Paris, France,⁶ AP-HP, Hôpital Bichat-Claude Bernard, Service de Maladies Infectieuses, F-75018 Paris, France,⁷ CHU Nantes, Service de Maladies Infectieuses, Nantes, France,⁸ GSK France,⁹ Infectious Diseases Medicines Development Centre, GlaxoSmithKline, Middlesex, United Kingdom,¹⁰

Received 21 April 2008/ Returned for modification 4 June 2008/ Accepted 3 October 2008

The aim of this study was to identify human immunodeficiency virus (HIV) protease mutations associated with virological response (VR) to fosamprenavir-ritonavir (FPV/r) in 113 protease inhibitor (PI)-experienced patients randomized in both CONTEXT and TRIAD clinical trials and receiving the same dose (700/100 mg twice daily) of FPV/r. The impact of each protease mutation on the VR to FPV/r, defined as the decrease in HIV RNA at week 12, was investigated with nonparametric analyses. A step-by-step procedure was done using a Jonckheere-Terpstra (JT) test that retains the group of mutations most strongly associated with the VR. Mutations at the following 14 codons were associated with a reduced VR to FPV/r: 10, 15, 33, 46, 54, 60, 62, 63, 72, 73, 82, 84, 89, and 90. The JT procedure led to selecting the CONTEXT/TRIAD genotypic set of mutations, I15V, M46I/L, I54L/M/V, D60E, L63P/T, and I84V, as providing the strongest association with the VR (P = 1.45 x 10^–11). In the nine patients with zero mutations within this set, the median decrease in HIV RNA was –2.63 log copies/ml, and was –2.22 (n = 45), –1.50 (n = 26), –0.58 (n = 23), –0.47 (n = 6), –0.13 (n = 3), and 0.04 (n = 1) log copies/ml in those with one, two, three, four, five, and six mutations, respectively. This study identified six mutations associated with VR to FPV/r. Some of these mutations are shared with the current FPV/r Agence Nationale de Recherches sur le SIDA (ANRS) resistance score, which has been cross-validated in the CONTEXT/TRIAD data set, suggesting that the current ANRS FPV/r score is a useful tool for the prediction of VR to FPV/r in PI-experienced patients.

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* Corresponding author. Mailing address: Department of Virology, Pitié-Salpêtrière Hospital, 83 Boulevard de l'Hôpital, 75013 Paris, France. Phone: 33142177401. Fax: 33142177411. E-mail: anne-genevieve.marcelin{at}psl.aphp.fr

Published ahead of print on 13 October 2008.

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Antimicrobial Agents and Chemotherapy, December 2008, p. 4251-4257, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00514-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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