title: Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3.
abstract: The present study evaluated the impact of variations in the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) on treatment outcome in patients with hepatitis C virus (HCV) genotype 2/3 infection receiving peginterferon-α2a and lower, conventional 800 mg daily dose of ribavirin. Previous studies using higher, weight-based ribavirin dosing report that patients carrying polymorphisms encoding reduced predicted ITPase activity show decreased risk of ribavirin-induced anemia but increased risk of thrombocytopenia, with no impact on elimination of virus. In all, 354 treatment-naïve HCV genotype 2/3-infected patients, enrolled in a phase III trial (NORDynamIC), were genotyped for ITPA (rs1127354 and rs7270101). Homo- or heterozygosity at Ars1127354 or Crs7270101 , entailing reduced ITPase activity, was observed in 37% of patients and was associated with increased likelihood of achieving sustained virological response (SVR) (P = 0.0003 in univariate and P = 0.0002 in multivariate analyses) accompanied by a reduced risk of relapse among treatment-adherent patients. The association between ITPA variants and SVR remained significant when patients were subdivided by the 12- and 24-week treatment duration arms, HCV genotype, fibrosis stage, and IL28B genotype, and was not secondary to improved adherence to therapy or less pronounced anemia. Gene variants predicting reduced predicted ITPase activity were also associated with decreased risk of anemia (P < 0.0001), increased risk of thrombocytopenia (P = 0.007), and lower ribavirin concentrations (P = 0.02).
  
  
  CONCLUSIONS
  These findings demonstrate a novel ribavirin-like association between polymorphisms at ITPA and treatment efficacy in chronic hepatitis C mediated by reduced relapse risk. We hypothesize that patients (63%) being homozygous for both major alleles, leading to normal ITPase activity, may benefit more from the addition of ribavirin to present and future treatment regimens for HCV in spite of concomitant increased risk of anemia.
authors: Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Karolina
authors: K
authors: Rembeck
authors: Jesper
authors: J
authors: Waldenström
authors: Kristoffer
authors: K
authors: Hellstrand
authors: Staffan
authors: S
authors: Nilsson
authors: Kristina
authors: K
authors: Nyström
authors: Anna
authors: A
authors: Martner
authors: Magnus
authors: M
authors: Lindh
authors: Gunnar
authors: G
authors: Norkrans
authors: Johan
authors: J
authors: Westin
authors: Court
authors: C
authors: Pedersen
authors: Martti
authors: M
authors: Färkkilä
authors: Nina
authors: N
authors: Langeland
authors: Mads Rauning
authors: MR
authors: Buhl
authors: Kristine
authors: K
authors: Mørch
authors: Peer Brehm
authors: PB
authors: Christensen
authors: Martin
authors: M
authors: Lagging
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011755:Pyrophosphatases / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012008:Recurrence; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage*; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C100416:peginterferon alfa-2a