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Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3.

AbstractUNLABELLED:
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).
CONCLUSION:
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.
AuthorsKarolina Rembeck, Jesper Waldenström, Kristoffer Hellstrand, Staffan Nilsson, Kristina Nyström, Anna Martner, Magnus Lindh, Gunnar Norkrans, Johan Westin, Court Pedersen, Martti Färkkilä, Nina Langeland, Mads Rauning Buhl, Kristine Mørch, Peer Brehm Christensen, Martin Lagging
JournalHepatology (Baltimore, Md.) (Hepatology) Vol. 59 Issue 6 Pg. 2131-9 (Jun 2014) ISSN: 1527-3350 [Electronic] United States
PMID24519039 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Copyright© 2014 by the American Association for the Study of Liver Diseases.
Chemical References
  • Antiviral Agents
  • Interferon-alpha
  • Recombinant Proteins
  • Polyethylene Glycols
  • Ribavirin
  • Pyrophosphatases
  • ITPA protein, human
  • peginterferon alfa-2a
Topics
  • Adult
  • Antiviral Agents (administration & dosage)
  • Drug Therapy, Combination
  • Female
  • Genetic Variation
  • Genotype
  • Hepacivirus (genetics)
  • Hepatitis C (drug therapy, genetics, virology)
  • Humans
  • Interferon-alpha (administration & dosage)
  • Male
  • Middle Aged
  • Polyethylene Glycols (administration & dosage)
  • Pyrophosphatases (genetics)
  • Recombinant Proteins (administration & dosage)
  • Recurrence
  • Retrospective Studies
  • Ribavirin (administration & dosage)

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