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Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.

Eskesen, Arne Nørgaard; Melum, Espen; Moghaddam, Amir; Bjøro, Kristian; Verbaan, Hans LU ; Ring-Larsen, Helmer and Dalgard, Olav (2012) In European Journal of Gastroenterology and Hepathology 24(8). p.890-896
Abstract
OBJECTIVES:

Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response.



METHODS:

Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite... (More)
OBJECTIVES:

Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response.



METHODS:

Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4.



RESULTS:

Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22).



CONCLUSION:

We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Gastroenterology and Hepathology
volume
24
issue
8
pages
890 - 896
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000306289300004
  • pmid:22584257
  • scopus:84864041176
ISSN
1473-5687
DOI
10.1097/MEG.0b013e3283546efd
language
English
LU publication?
yes
id
9b75cc90-c47a-4872-aded-44a5a4148657 (old id 2608835)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22584257?dopt=Abstract
date added to LUP
2012-06-03 13:46:52
date last changed
2017-08-06 03:20:42
@article{9b75cc90-c47a-4872-aded-44a5a4148657,
  abstract     = {OBJECTIVES: <br/><br>
Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response. <br/><br>
<br/><br>
METHODS: <br/><br>
Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4. <br/><br>
<br/><br>
RESULTS: <br/><br>
Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22). <br/><br>
<br/><br>
CONCLUSION: <br/><br>
We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.},
  author       = {Eskesen, Arne Nørgaard and Melum, Espen and Moghaddam, Amir and Bjøro, Kristian and Verbaan, Hans and Ring-Larsen, Helmer and Dalgard, Olav},
  issn         = {1473-5687},
  language     = {eng},
  number       = {8},
  pages        = {890--896},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {European Journal of Gastroenterology and Hepathology},
  title        = {Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.},
  url          = {http://dx.doi.org/10.1097/MEG.0b013e3283546efd},
  volume       = {24},
  year         = {2012},
}