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Genotypic, phenotypic and virtual phenotypic resistance patterns for tipranavir (TPV) and darunavir (DRV): an independent analysis of a Quebec HIV-1 cohort highly resistant to all other protease inhibitors
A. Talbot1,2,3, P. Grant2, J. Taylor4, J.-G. Baril1,3, H. Charest5, T. Fulisma Liu2, B. Brenner6, M. Roger7, R. Shafer2, R. Cantin5, A. Zolopa2
1Centre Hospitalier de l'Université de Montreal, Family Practice, Montreal, Canada, 2Stanford University School of Medecine, Infectious Disease, Stanford, United States, 3Quartier Latin Clinic, Family Practice, Montreal, Canada, 4Stanford University School of Medecine, Statistics, Stanford, United States, 5LSPQ, Institut National de Santé Publique du Québec/Laboratoire de Santé Publique du Québe, Montreal, Canada, 6Centre de Santé Mc Gill, Infectious Disease, Montreal, Canada, 7Centre Hospitalier de l'Université de Montreal, Infectious Disease, Montreal, Canada
Background: Genotypic interpretation systems (GIS) are available to predict susceptibility to DRV and TPV. Few independent datasets have been used to test their performance. We selected a set of highly resistant clinical isolates to test performance of various GIS and develop models to predict relative susceptibility to TPV and DRV.
Methods: Vircotype virtual phenotype has been used for interpretation of all genotypic resistance tests in Quebec. A phenotype was performed on isolates predicted to be resistant to all PIs except DRV and TPV. We constructed linear regression models to predict relative phenotypic susceptibility to DRV or TPV, confirmed by bootstrap analyses. We compared the performance of ANRS, the Stanford HIV database, Vircotype, and DRV and TPV manufacturer's scores in predicting phenotype.
Results: Phenotypic testing was performed on 100 isolates. 89 isolates were susceptible to DRV. Of these 67 were susceptible, 16 intermediate, and 6 resistant to TPV. Two and 3 isolates were intermediate and resistant to DRV, respectively, with full susceptibility to TPV. Four isolates were resistant to DRV with intermediate resistance to TPV. Only 2 isolates were resistant to both DRV and TPV. In bootstrap analyses, presence of 84V, 82T, and 35D and lack of 10F were the strongest predictors of relative susceptibility to DRV compared to TPV. Presence of 54L, 32I, and 47V predicted isolates relative susceptibility to TPV compared to DRV. All GIS performed well in predicting the DRV phenotype (R2 = 0.61-0.69). However, for TPV, the GIS were not as predictive of the phenotype with R2 of 0.03-0.31. Vircotype was unique in its ability to predict TPV susceptibility (R2 =0.80).
Conclusions: In this independent cohort with highly PI-resistant HIV, phenotypic resistance to DRV and TPV was rare. GIS, other than the Vircotype , do not predict TPV susceptibility well, but do predict DRV susceptibility.
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