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

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

Raoel Maan  1 , Adriaan J van der Meer  1 , Willem Pieter Brouwer  1 , Elisabeth P C Plompen  1 , Milan J Sonneveld  1 , Robert Roomer  1 , Annemiek A van der Eijk  2 , Zwier M A Groothuismink  1 , Bettina E Hansen  1 , Bart J Veldt  1 , Harry L A Janssen  3 , Andre Boonstra  1 , Robert J de Knegt  1
Affiliations

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

Raoel Maan et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: RM received financial compensation for consultancy activities from AbbVie. AJM received financial compensation for lecture activities for MSD and Gilead. WPB received speaker’s fee from Roche. MJS received speaker’s fees and research support from Roche, BMS, Merck and Innogenetics. BJV received financial compensation for a board membership at GlaxoSmithKline and Janssen Therapeutics. HLAJ received financial compensation for consultancy activities and/ or payment for lectures from Roche, Merck, Abbott, Santaris, Anadys, Medtronic, Tibotec, Bristol Myers Squibb, Innogenetics, and Gilead, and his institution received grants from Roche, Merck, Abbott, Santaris, Anadys, Medtronic, and Tibotec. AB received financial compensation for consultancy activities for Bristol Myers Squibb and his studies received financial support from Tibotec, Roche, Bristol Myers Squibbm Innogenetics and MSD. RJK reported that his institution received financial compensation for consultancy activities and/ or lecture activities from Janssen, Roche, Gilead, AbbVie, BMS and GlaxoSmithKline, and research grants from Roche, Gilead, BMS and Janssen. EPCP, RR, AAE, ZMAG and BEH have nothing to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Median hemoglobin and platelet count.
Median hemoglobin (A) and platelet counts (B) at baseline, at week 4, 8 and 12 and the nadir hemoglobin and platelet count during treatment. Dashed line represents the patients with ITPase deficiency and the black line represents patients with normal ITPase activity. Abbreviations: ITPase, inosine triphosphaye pyrophosphatase.
Fig 2
Fig 2. ITPase deficiency, dose reductions, EPO and blood transfusions.
Percentage of patients with at least one dose reduction of RBV or PegIFN, at least one blood transfusion or one dose of EPO during treatment. White bars represent the patients with normal ITPase activity and the black bars represent patients with ITPase deficiency. Abbreviations: ITPase, inosine triphosphate pyrophosphatase; RBV, ribavirin; PegIFN, pegylated interferon; EPO, erythropoietin.
See this image and copyright information in PMC

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