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Antimicrobial Agents and Chemotherapy, April 2007, p. 1473-1480, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00481-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Interpretation of Genotype and Pharmacokinetics for Resistance to Fosamprenavir-Ritonavir-Based Regimens in Antiretroviral-Experienced Patients{triangledown}

Isabelle Pellegrin,1,{dagger}* Dominique Breilh,2,{dagger} Gaelle Coureau,4 Sébastien Boucher,1 Didier Neau,3 Patrick Merel,1 Denis Lacoste,3 Hervé Fleury,1 Marie-Claude Saux,2 Jean-Luc Pellegrin,3 Estibaliz Lazaro,3 François Dabis,4 Rodolphe Thiébaut,4 for the ANRS Co3 Aquitaine Cohort {ddagger}

Departments of Virology,1 Clinical Pharmacokinetics and Pharmacy,2 Internal Medicine and Infectious Diseases,3 INSERM U593, Bordeaux University Hospital, Bordeaux, France4

Received 19 April 2006/ Returned for modification 31 October 2006/ Accepted 12 January 2007

In this study, named the Zephir study (Telzir-pharmacokinetics), 121 antiretroviral-experienced human immunodeficiency virus (HIV) patients failing on highly active antiretroviral therapy (HAART) were included in a prospective cohort and received a fosamprenavir-ritonavir (700 mg/100 mg twice a day)-based regimen. The impact of baseline HIV type 1 (HIV-1) mutations, pharmacokinetic (PK) parameters, and genotype inhibitory quotient (GIQ) on the virological response at week 12 (W12) was assessed. HIV reverse transcriptase and protease were sequenced at W0. The response at W12 was defined as <2.3 log10 HIV-1 RNA copies/ml or a virus load decrease of ≥1 log10 copies/ml. W4 amprenavir PK were determined by high-performance liquid chromatography. Patients had a median of nine previous treatments over 8 years. Median W0 values were as follows: 295 CD4+/µl, 4.4 log10 HIV-1 RNA copies/ml, and 6 protease- and 5 nucleotide reverse transcription inhibitor-related mutations. Respective values for minimum concentration of drug in serum (Cmin) and area under the concentration-time curve (AUC) from 0 to 24 h were 1,400 ng/ml and 35 mg·h/ml. At W12, 52% of the patients were successes, with a median decrease of –0.7 log10 HIV-1 RNA copies/ml. The Zephir mutation score included 12 IAS protease mutations associated with poorer virological response: L10I/F/R/V, L33F, M36I, M46I/L, I54L/M/T/V, I62V, L63P, A71I/L/V/T, G73A/C/F/T, V82A/F/S/T, I84V, L90M, and polymorphism mutations I13V, L19I, K55R, and L89M. Comparing <4 versus ≥4 mutations, HIV-1 RNA decreases were –2.3 log10 copies/ml versus –0.1 log10 copies/ml (P < 10–4) with 93% versus 19% successes (P < 10–4), respectively. This score predicted W12 failure with 94% sensitivity, versus 31% for the ANRS 2005 algorithm. Cmin (<1,600 ng/ml), AUC (<40 mg·h/ml), and GIQ (<300) values were associated with failure (all P values were <10–4). The need to test genotype-based algorithms using different patient databases before their implementation in clinical practice is highlighted. Specific mutations, PK and GIQ, provide relevant information for monitoring fosamprenavir-ritonavir-based HAART.

* Corresponding author. Mailing address: Laboratoire de Virologie, Hôpital Pellegrin, place Amélie Raba-Léon, 33076 Bordeaux Cedex, France. Phone: 33 5 5679 5510. Fax: 33 5 5679 5673. E-mail: isabelle.pellegrin{at}chu-bordeaux.fr

{triangledown} Published ahead of print on 12 February 2007.

{dagger} The first two authors contributed equally to this study.

{ddagger} For composition of the ANRS Co3 Aquitaine Cohort, see Acknowledgments.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1473-1480, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00481-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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