JAC Advance Access originally published online on March 3, 2009
Journal of Antimicrobial Chemotherapy 2009 63(5):1006-1010; doi:10.1093/jac/dkp063
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Original research |
Design and validation of new genotypic tools for easy and reliable estimation of HIV tropism before using CCR5 antagonists
1 Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain 2 Department of Microbiology, Hospital San Cecilio, Granada, Spain 3 Department of Microbiology, Hospital CHUS-Conxo, Santiago de Compostela, Spain
Received 24 November 2008; returned 17 January 2009; revised 21 January 2009; accepted 30 January 2009
* Corresponding author. Tel: +34-91-4532500; Fax: +34-91-7336614; E-mail: evapoveda{at}hotmail.com
Background: Genotypic tools may allow easier and less expensive estimation of HIV tropism before prescription of CCR5 antagonists compared with the Trofile® assay (Monogram Biosciences, South San Francisco, CA, USA).
Methods: Paired genotypic and Trofile® results were compared in plasma samples derived from the maraviroc expanded access programme (EAP) in Europe. A new genotypic approach was built to improve the sensitivity to detect X4 variants based on an optimization of the webPSSM algorithm. Then, the new tool was validated in specimens from patients included in the ALLEGRO trial, a multicentre study conducted in Spain to assess the prevalence of R5 variants in treatment-experienced HIV patients.
Results: A total of 266 specimens from the maraviroc EAP were tested. Overall geno/pheno concordance was above 72%. A high specificity was generally seen for the detection of X4 variants using genotypic tools (ranging from 58% to 95%), while sensitivity was low (ranging from 31% to 76%). The PSSM score was then optimized to enhance the sensitivity to detect X4 variants changing the original threshold for R5 categorization. The new PSSM algorithms, PSSMX4R5-8 and PSSMSINSI-6.4, considered as X4 all V3 scoring values above –8 or –6.4, respectively, increasing the sensitivity to detect X4 variants up to 80%. The new algorithms were then validated in 148 specimens derived from patients included in the ALLEGRO trial. The sensitivity/specificity to detect X4 variants was 93%/69% for PSSMX4R5-8 and 93%/70% for PSSMSINSI-6.4.
Conclusions: PSSMX4R5-8 and PSSMSINSI-6.4 may confidently assist therapeutic decisions for using CCR5 antagonists in HIV patients, providing an easier and rapid estimation of tropism in clinical samples.
Keywords: maraviroc , tropism , Trofile , genotypic algorithm , PSSM
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