title: Analysis of Hepatitis C Virus Genotype 1b Resistance Variants in Japanese Patients Treated with Paritaprevir-Ritonavir and Ombitasvir.
abstract: Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance-conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR24) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients.
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: Gretja
authors.initials: G
authors.lastname: Schnell
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: Jill
authors.initials: J
authors.lastname: Beyer
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: Xinyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Setze
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Rodrigues
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Burroughs
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Redman
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Collins
authors.affiliation: Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
mesh_terms: D000813:Anilides / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use; D002219:Carbamates / Q000627:therapeutic use*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005828:Genetics, Population; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007564:Japan; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000627:therapeutic use*; D013449:Sulfonamides; D017211:Treatment Failure; D014633:Valine; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D011392:Proline; D019438:Ritonavir; D013449:Sulfonamides; D014633:Valine; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C586094:ombitasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C585405:paritaprevir