This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marcelin, A.-G. Articles by Calvez, V. Search for Related Content PubMed PubMed Citation Articles by Marcelin, A.-G. Articles by Calvez, V.

 Previous Article  |  Next Article 

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

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.

This article has been cited by other articles:

• Barrail-Tran, A., Morand-Joubert, L., Poizat, G., Raguin, G., Le Tiec, C., Clavel, F., Dam, E., Chene, G., Girard, P.-M., Taburet, A.-M., and the Puzzle-1 (ANRS 104) Study Group, (2008). Predictive Values of the Human Immunodeficiency Virus Phenotype and Genotype and of Amprenavir and Lopinavir Inhibitory Quotients in Heavily Pretreated Patients on a Ritonavir-Boosted Dual-Protease-Inhibitor Regimen. Antimicrob. Agents Chemother. 52: 1642-1646 [Abstract] [Full Text]  
• de Requena, D. G., Bonora, S., Calcagno, A., D'Avolio, A., Siccardi, M., Fontana, S., Milia, M. G., Sciandra, M., Garazzino, S., Di Garbo, A., Baietto, L., Trentini, L., Di Perri, G. (2008). Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens. Antimicrob. Agents Chemother. 52: 1066-1071 [Abstract] [Full Text]  
• King, M. S., Rode, R., Cohen-Codar, I., Calvez, V., Marcelin, A.-G., Hanna, G. J., Kempf, D. J. (2007). Predictive Genotypic Algorithm for Virologic Response to Lopinavir-Ritonavir in Protease Inhibitor-Experienced Patients. Antimicrob. Agents Chemother. 51: 3067-3074 [Abstract] [Full Text]  
• Pellegrin, I., Breilh, D., Coureau, G., Boucher, S., Neau, D., Merel, P., Lacoste, D., Fleury, H., Saux, M.-C., Pellegrin, J.-L., Lazaro, E., Dabis, F., Thiebaut, R., for the ANRS Co3 Aquitaine Cohort, (2007). Interpretation of Genotype and Pharmacokinetics for Resistance to Fosamprenavir-Ritonavir-Based Regimens in Antiretroviral-Experienced Patients. Antimicrob. Agents Chemother. 51: 1473-1480 [Abstract] [Full Text]