title: Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir.
abstract: AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.).
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA preethi.krishnan@abbvie.com.
authors.forename: Preethi
authors.initials: P
authors.lastname: Krishnan
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Gretja
authors.initials: G
authors.lastname: Schnell
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reisch
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Beyer
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Irvin
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Wangang
authors.initials: W
authors.lastname: Xie
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Larsen
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Podsadecki
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Collins
mesh_terms: D015081:2-Naphthylamine; D000813:Anilides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D003521:Cyclopropanes; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014633:Valine
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir