a multi-variant, viral dynamic model of genotype 1 hcv to assess the in vivo evolution of protease-inhibitor resistant variants一个多变量,丙肝病毒病毒基因型1的动态模型评估体内蛋白酶抑制剂耐药变异的进化.pdfVIP

A Multi-Variant, Viral Dynamic Model of Genotype 1 HCV to Assess the in vivo Evolution of Protease-Inhibitor Resistant Variants 1 2 1 1 1 1 Bambang S. Adiwijaya *, Eva Herrmann , Brian Hare , Tara Kieffer , Chao Lin , Ann D. Kwong , Varun 1 1 3 3 1 Garg , John C. R. Randle , Christoph Sarrazin , Stefan Zeuzem , Paul R. Caron 1Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America, 2 Institute of Biostatistics and Mathematical Modeling, Faculty of Medicine, Johann Wolfgang Goethe University, Frankfurt am Main, Germany, 3 Medizinische Klinik 1, J. W. Goethe-University Hospital, Frankfurt am Main, Germany Abstract Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed