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

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.

SUBMITTER: Maan R

PROVIDER: S-EPMC4595504 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Maan Raoel R van der Meer Adriaan J AJ Brouwer Willem Pieter WP Plompen Elisabeth P C EP Sonneveld Milan J MJ Roomer Robert R van der Eijk Annemiek A AA Groothuismink Zwier M A ZM Hansen Bettina E BE Veldt Bart J BJ Janssen Harry L A HL Boonstra Andre A de Knegt Robert J RJ

PloS one 20151006 10

<h4>Background/objective</h4>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.<h4>Patients and methods</h4>This cohort study inclu ...[more]

PMID: 26441325

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Project description:BACKGROUND:There is growing evidence that variations in the gene encoding inosine triphosphate pyrophosphohydrolase (ITPase), known as inosine triphosphatase (ITPA), are related to hemolytic anemia, which is frequently observed among hepatitis C virus (HCV)-infected patients receiving ribavirin (RBV)-based therapy. We performed a meta-analysis of all eligible studies assessing ITPA gene polymorphisms related to RBV-induced hemolytic anemia in HCV-infected patients published in PubMed, Embase and the Cochrane library prior to the end of 2014. METHODS:Three outcomes were evaluated: (1) hemoglobin decline, (2) severe anemia, and (3) RBV dose reduction or treatment discontinuation. Pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were estimated by either fixed or random effects models. RESULTS:Twenty-nine studies were selected from the literature search: 20 references involving 6533 individuals for hemoglobin decline, 13 references on 3764 patients for severe anemia, and 16 references on 3918 patients for RBV dose reduction or discontinuation. Significant associations with hemoglobin decline were found for rs1127354 CC [OR = 12.84 (95 % CI 7.44; 22.17)], rs7270101 AA [OR = 3.41 (95 % CI 2.08; 5.59)] and rs6051702 AA [OR = 4.43 (95 % CI 2.80; 7.00)] genotypes. Moreover, significant associations with hemoglobin decline were also found for absent [OR = 6.01 (95 % CI 4.84; 7.46)] and mild [OR = 4.68 (95 % CI 2.83; 7.74)] ITPase deficiency haplotypes. The ITPA rs1127354 CC genotype and absent ITPase deficiency haplotype were also associated with severe anemia {[OR = 7.77 (95 % CI 5.03; 12.00)] and [OR = 4.79 (95 % CI 1.69; 13.56)], respectively}. Additionally, the rs1127354 CC genotype showed significant association with RBV dose reduction or stopping treatment (OR = 2.24; 95 % CI 1.79; 2.81). CONCLUSIONS:ITPA polymorphisms increase the likelihood of developing hemolytic anemia for HCV-infected patients on RBV-based therapy, particularly rs1127354 CC and rs7270101 AA genotypes, suggesting the utility of screening for ITPA polymorphisms to avoid hematological toxicity and increase adherence to RBV-based therapy.

Project description:Background and aimsTRIM5 and TRIM22 are restriction factors involved in innate immune response and exhibit anti-viral activity. Single nucleotide polymorphisms (SNPs) at TRIM5 and TRIM22 genes have shown to influence several viral infections such as human immunodeficiency virus (HIV), hepatitis B, as well as measles and rubella vaccination. The aim of this study is to analyze whether TRIM5 and TRIM22 polymorphisms are associated with liver fibrosis inflammation-related biomarkers and response to pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) therapy in HIV/hepatitis C virus (HCV) coinfected patients.MethodsA retrospective study was performed in 319 patients who started pegIFNα/RBV therapy. Liver fibrosis stage was characterized in 288 patients. TRIM5 rs3824949 and TRIM22 polymorphisms (rs1063303, rs7935564, and rs7113258) were genotyped using the GoldenGate assay. The primary outcomes were: a) significant liver fibrosis (≥F2) evaluated by liver biopsy or transient elastography (liver stiffness values ≥7.1 Kpa); b) sustained virological response (SVR) defined as no detectable HCV viral load (<10 IU/mL) at week 24 after the end of the treatment. The secondary outcome variable was plasma chemokine levels.ResultsPatients with TRIM5 rs3824949 GG genotype had higher SVR rate than patients with TRIM5 rs3824949 CC/CG genotypes (p = 0.013), and they had increased odds of achieving SVR (adjusted odds ratio (aOR = 2.58; p = 0.012). Patients with TRIM22 rs1063303 GG genotype had higher proportion of significant liver fibrosis than patients with rs1063303 CC/CG genotypes (p = 0.021), and they had increased odds of having significant hepatic fibrosis (aOR = 2.19; p = 0.034). Patients with TRIM22 rs7113258 AT/AA genotype had higher SVR rate than patients with rs7113258 TT genotypes (p = 0.013), and they had increased odds of achieving SVR (aOR = 1.88; p = 0.041). The TRIM22 haplotype conformed by rs1063303_C and rs7113258_A was more frequent in patients with SVR (p = 0.018) and was significantly associated with achieving SVR (aOR = 2.80; p = 0.013). The TRIM5 rs3824949 GG genotype was significantly associated with higher levels of GRO-α (adjusted arithmetic mean ratio ((aAMR) = 1.40; p = 0.011) and MCP-1 (aAMR = 1.61; p = 0.003).ConclusionsTRIM5 and TRIM22 SNPs are associated to increased odds of significant liver fibrosis and SVR after pegIFNα/RBV therapy in HIV/HCV coinfected patients. Besides, TRIM5 SNP was associated to higher baseline levels of circulating biomarkers GRO and MCP-1.

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

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

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