Potential conflict of interest: Dr. Lagging is on the speakers' bureau for MSD, Roche, and Janssen/Medivir.
Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3
Article first published online: 25 APR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 6, pages 2131–2139, June 2014
How to Cite
Rembeck, K., Waldenström, J., Hellstrand, K., Nilsson, S., Nyström, K., Martner, A., Lindh, M., Norkrans, G., Westin, J., Pedersen, C., Färkkilä, M., Langeland, N., Buhl, M. R., Mørch, K., Christensen, P. B. and Lagging, M. (2014), Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3. Hepatology, 59: 2131–2139. doi: 10.1002/hep.27009
The Swedish Medical Research Council and ALF Funds at Sahlgrenska University Hospital supported this study. Unrestricted grants from Roche affiliates in the Nordic region also supported this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
- Issue published online: 28 MAY 2014
- Article first published online: 25 APR 2014
- Accepted manuscript online: 13 JAN 2014 01:41PM EST
- Manuscript Accepted: 9 JAN 2014
- Manuscript Received: 7 OCT 2013
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. (Hepatology 2014;59:2131–2139)