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Antimicrobial Agents and Chemotherapy, December 2004, p. 4687-4692, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4687-4692.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Clinically Relevant Interpretation of Genotype and Relationship to Plasma Drug Concentrations for Resistance to Saquinavir-Ritonavir in Human Immunodeficiency Virus Type 1 Protease Inhibitor-Experienced Patients

Anne-Geneviève Marcelin,^1* Cécile Dalban,² Gilles Peytavin,³ Claire Lamotte,³ Rachid Agher,⁴ Constance Delaugerre,¹ Marc Wirden,¹ Françoise Conan,¹ Sylvie Dantin,⁵ Christine Katlama,⁴ Dominique Costagliola,² and Vincent Calvez¹

Departments of Virology,¹ Inserm EMI 0214,² Infectious Diseases, Pitié-Salpêtrière Hospital,⁴ Department of Clinical Pharmacy, Bichat-Claude Bernard Hospital, Paris,³ ROCHE France Laboratory, Neuilly, France⁵

Received 23 January 2004/ Returned for modification 13 May 2004/ Accepted 17 August 2004

It has been shown that virological protease inhibitor (PI) resistance mutations present at the initiation of saquinavir (SQV) plus ritonavir (RTV) therapy in PI-experienced patients are the strongest predictors of virological response. But most of the current resistance algorithms are adapted for unboosted SQV regimens. We applied a stepwise methodology for the development and validation of a clinically relevant genotypic resistance score for an SQV (800 mg twice per day [b.i.d.]) plus RTV (100 mg b.i.d.)-containing regimen. PI-experienced patients treated by this regimen achieved a human immunodeficiency virus plasma viral load (VL) of <200 copies/ml at months 3 to 5 for 41.7% of subjects. Adjusted in a multivariate analysis, taking into account all the confounding factors, such as the nucleoside used, five mutations were combined in a resistance score associated with a reduced virological response to an SQV-plus-RTV regimen: L24I, I62V, V82A/F/T/S, I84V, and L90IM. Patients with isolates harboring 0 to 1 mutation among the score achieved –2.20 log₁₀ and –1.23 log₁₀ copies/ml of VL reduction, respectively, while it was –0.27 log₁₀ copies/ml for those with at least two mutations, classifying the isolates as "no evidence of resistance" (0 or 1 mutation) or "resistance " (2 mutations). The minimum concentration in plasma (C_min) of SQV alone was not associated with the virological response. However, the combination of the SQV C_min and the genotypic score, expressed as the genotypic inhibitory quotient, was predictive of the virological response, suggesting that the interpretation of SQV concentrations in plasma should be done only in the context of the resistance index provided by viral genotype for 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.ap-hop-paris.fr.

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Antimicrobial Agents and Chemotherapy, December 2004, p. 4687-4692, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4687-4692.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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