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

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

ITPase deficiency, dose reductions, EPO and blood transfusions.

<p>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.</p

Median hemoglobin and platelet count.

<p>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.</p

Univariable and multivariable linear regression analysis for absolute decline in platelet count at week 4.

<p>a. Abbreviations: CI, confidence interval; DM, diabetes mellitus; BMI, body mass index; Hb, hemoglobin; PegIFN, pegylated interferon; RBV, ribavirin; HCV, hepatitis C virus; IL28B, interleukin-28B; ITPA, inosine triphosphatase; ITPase, inosine triphosphaye pyrophosphatase</p><p>b. The final model was created by using a backward stepwise method. Confounding was checked.</p><p>Univariable and multivariable linear regression analysis for absolute decline in platelet count at week 4.</p

Univariable and multivariable linear regression analysis for absolute hemoglobin decline at week 4.

<p>a. Abbreviations: CI, confidence interval; DM, diabetes mellitus; BMI, body mass index; Hb, hemoglobin; PegIFN, pegylated interferon; RBV, ribavirin; HCV, hepatitis C virus; IL28B, interleukin-28B; ITPA, inosine triphosphatase; ITPase, inosine triphosphaye pyrophosphatase</p><p>b. The final model was created by using a backward stepwise method. Confounding was checked.</p><p>Univariable and multivariable linear regression analysis for absolute hemoglobin decline at week 4.</p

Baseline characteristics.

<p>a. Abbreviations: ITPase, inosine triphosphaye pyrophosphatase; BMI, body mass index; HCV, hepatitis C virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; DM, diabetes mellitus; IV, intravenous; PegIFN, pegylated interferon; RBV, ribavirin</p><p>b. Medians are presented as number (IQR). Numbers are presented as n, (percentage of whole group)</p><p>c. Variables with a ‘c’ were missing in ≥ 10%</p><p>d. Liver biopsy or elastography was available in 195 patients</p><p>e. Anemia was defined as a Hb concentration below 8.1 mmol/L for men and below 7.45 mmol/L for women, thrombocytopenia was defined as a platelet count below 150*109/L</p><p>Baseline characteristics.</p