title: ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection.
abstract: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin.
  
  
  
  HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression.
  
  
  
  In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12.
  
  
  
  The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes.
  
  
  
  ClinicalTrials.gov: NCT01132313.
authors.affiliation: Service d'Hépatologie, Hôpital Beaujon, INSERM UMR S 1149, CRI, Université Paris Diderot, DHU UNITY, Clichy, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
authors.affiliation: J. W. Goethe University Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Soriano
authors.affiliation: INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Department of Internal Medicine I, University Hospital Mainz, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schuchmann
authors.affiliation: Service d'hépato-gastro-entérologie, Hôpital Saint Joseph, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.affiliation: Liver Unit, Hospital Universitario Valle de Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Department of Gastroenterology, Alfred Hospital, Melbourne, Australia.
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Roberts
authors.affiliation: Auckland Clinical Studies, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States of America.
authors.forename: Jerry O
authors.initials: JO
authors.lastname: Stern
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Voss
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Baum
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Gallivan
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Wulf O
authors.initials: WO
authors.lastname: Böcher
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States of America.
authors.forename: Federico J
authors.initials: FJ
authors.lastname: Mensa
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D000621:Aminoisobutyric Acids; D000740:Anemia / Q000175:diagnosis* / Q000209:etiology; D000998:Antiviral Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007372:Interferons / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011392:Proline / Q000031:analogs & derivatives; D011755:Pyrophosphatases / Q000235:genetics*; D011804:Quinolines; D060888:Real-Time Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D000097630:Inosine Triphosphatase
chemical_list: D000179:Acrylates; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D001562:Benzimidazoles; D007372:Interferons; D007930:Leucine; D009842:Oligopeptides; D011392:Proline; D011755:Pyrophosphatases; D011804:Quinolines; D012254:Ribavirin; D013844:Thiazoles; C000592437:deleobuvir; C552340:faldaprevir; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase