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Antimicrobial Agents and Chemotherapy, September 2002, p. 2926-2932, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2926-2932.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Genotypic and Pharmacokinetic Determinants of the Virological Response to Lopinavir-Ritonavir-Containing Therapy in Protease Inhibitor-Experienced Patients

Bernard Masquelier,1* Dominique Breilh,2 Didier Neau,3 Sylvie Lawson-Ayayi,4,5 Valérie Lavignolle,5 Jean-Marie Ragnaud,3 Michel Dupon,3 Philippe Morlat,3 F. Dabis,5 H. Fleury,1 and the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine{dagger}

Laboratoire de Virologie, Hôpital Pellegrin,1 Laboratoire de Pharmacocinétique, Hôpital Haut Levêque,2 Service de Maladies Infectieuses, CHU de Bordeaux,3 Centre d'Information et de Soins de l'Immunodéficience Humaine de Bordeaux,4 INSERM U330, Université Victor Segalen Bordeaux 2, Bordeaux, France5

Received 7 February 2002/ Returned for modification 4 April 2002/ Accepted 10 June 2002

The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load >=400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75:7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.

* Corresponding author. Mailing address: Laboratoire de Virologie, Place Amélie Raba Léon, 33076 Bordeaux cedex, France. Phone: 33 5 56 79 55 10. Fax: 33 5 56 79 56 73. E-mail: bernard.masquelier{at}chu-bordeaux.fr.

{dagger} Participants in the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine: J. Beylot, M. Dupon, M. Le Bras, J. L. Pellegrin, J. M. Ragnaud, R. Salamon, F. Dabis, G. Chêne, N. Bernard, D. Lacoste, D. Malvy, D. Neau, J.-F. Moreau, P. Morlat, P. Mercié, D. Commenges, H. Jacqmin-Gadda, R. Thiébaut, S. Lawson-Ayayi, V. Lavignolle, M. J. Blaizeau, M. Decoin, A. M. Formaggio, S. Delveaux, S. Labarerre, B. Uwamaliya, E. Vimard, L. Merchadou, G. Palmer, D. Touchard, D. Dutoit, F. Pereira, B. Boulant, P. Couzigou, H. Fleury, M. Bonarek, F. Bonnet, B. Coadou, P. Gelie, D. Jaubert, C. Nouts, B. Masquelier, I. Pellegrin, H. Dutronc, G. Cipriano, S. Lafarie, J. Y. Lacut, J. F. Viallard, I. Faure, P. Rispal, C. Cipriano, B. Leng, F. Djossou, J. P. Pivetaud, J. L. Taupin, C. De La Taille, T. Galperine, A. Ochoa, and D. Chambon.

Antimicrobial Agents and Chemotherapy, September 2002, p. 2926-2932, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2926-2932.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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