ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection

Raoel Maan; Adriaan J van der Meer; Willem Pieter Brouwer; Elisabeth P C Plompen; Milan J Sonneveld; Robert Roomer; Annemiek A van der Eijk; Zwier M A Groothuismink; Bettina E Hansen; Bart J Veldt; Harry L A Janssen; Andre Boonstra; Robert J de Knegt

doi:10.1371/journal.pone.0139317

ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection

PLoS One. 2015 Oct 6;10(10):e0139317. doi: 10.1371/journal.pone.0139317. eCollection 2015.

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
² Department of Viroscience, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
³ Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Toronto Centre for Liver Disease, Toronto Western & General Hospital, University Health Network, Toronto, Canada.

Abstract

Background/objective: Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV.

Patients and methods: This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed.

Results: In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04-0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64-1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024).

Conclusion: Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antiviral Agents / adverse effects
Antiviral Agents / therapeutic use*
Female
Genotype
Hemoglobins / metabolism
Hepatitis C, Chronic / drug therapy*
Hepatitis C, Chronic / genetics*
Humans
Logistic Models
Male
Middle Aged
Platelet Count
Polymorphism, Genetic / genetics*
Pyrophosphatases / genetics*

Substances

Antiviral Agents
Hemoglobins
Pyrophosphatases
ITPA protein, human

Grants and funding

This study was sponsored by the Virgo consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 050-060-452. The study was also funded by the Foundation for Liver and Gastrointestinal Research in Rotterdam. This foundation was established in 1985 as an institution without purpose of financial gain and has the mission to stimulate scientific research in the field of diseases of the liver and the gastrointestinal tract. A major part of its activities are undertaken at the Erasmus MC in Rotterdam, the Netherlands.