title: Modeling viral evolutionary dynamics after telaprevir-based treatment.
abstract: For patients infected with hepatitis C virus (HCV), the combination of the direct-acting antiviral agent telaprevir, pegylated-interferon alfa (Peg-IFN), and ribavirin (RBV) significantly increases the chances of sustained virologic response (SVR) over treatment with Peg-IFN and RBV alone. If patients do not achieve SVR with telaprevir-based treatment, their viral population is often significantly enriched with telaprevir-resistant variants at the end of treatment. We sought to quantify the evolutionary dynamics of these post-treatment resistant variant populations. Previous estimates of these dynamics were limited by analyzing only population sequence data (20% sensitivity, qualitative resistance information) from 388 patients enrolled in Phase 3 clinical studies. Here we add clonal sequence analysis (5% sensitivity, quantitative) for a subset of these patients. We developed a computational model which integrates both the qualitative and quantitative sequence data, and which forms a framework for future analyses of drug resistance. The model was qualified by showing that deep-sequence data (1% sensitivity) from a subset of these patients are consistent with model predictions. When determining the median time for viral populations to revert to 20% resistance in these patients, the model predicts 8.3 (95% CI: 7.6, 8.4) months versus 10.7 (9.9, 12.8) months estimated using solely population sequence data for genotype 1a, and 1.0 (0.0, 1.4) months versus 0.9 (0.0, 2.7) months for genotype 1b. For each individual patient, the time to revert to 20% resistance predicted by the model was typically comparable to or faster than that estimated using solely population sequence data. Furthermore, the model predicts a median of 11.0 and 2.1 months after treatment failure for viral populations to revert to 99% wild-type in patients with HCV genotypes 1a or 1b, respectively. Our modeling approach provides a framework for projecting accurate, quantitative assessment of HCV resistance dynamics from a data set consisting of largely qualitative information.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Haseltine
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bartels
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Ghys
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davis
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Tigges
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Joan
authors.initials: J
authors.lastname: Spanks
authors.affiliation: Janssen Research & Development, Titusville, New Jersey, United States of America.
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachussets, United States of America.
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D019295:Computational Biology; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; C486464:telaprevir
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