Polymorphism of the inosine triphosphate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients

Abstract

Abstract. Ribavirin (RBV)-induced anemia is a serious side effect of pegylated interferon (PEG-IFN) plus RBV therapy which is the standard care most effective for hepatitis C virus (HCV) infection. In the present study, we investigated the association of inosine triphosphate pyrophosphatase (ITPA) genotypes with RBV-induced hemoglobin (Hb) reduction in HCV patients treated with PEG-IFN/RBV therapy. The genotypes of the ITPA rs1127354 single nucleotide polymorphism were determined in 179 patients with HCV infection. Among them, 52 patients were treated with PEG-IFN/RBV. The frequency of the ITPA major allele (CC) was 76.3% and that of the minor allele (CA and AA) was 23.7%. A rapid decrease in Hb levels during the initial 4 weeks was observed in patients with the ITPA major allele (CC), but not in patients with the ITPA minor allele (C/A and AA). Hb levels at 4 weeks were significantly lower in patients with the ITPA major allele than the levels in patients with the minor allele. Out of the 41 patients, 6 (14.6%) with ITPA major allele had Hb levels <10 g/dl and 11 patients (26.8%) had a decline in Hb of >3 g/dl. None of the patients with the ITPA minor allele had such data. There were no significant differences in virological responses of HCV-RNA between patients with the ITPA major allele and those with the minor allele. In conclusion, the ITPA genotypes may be a useful marker for prediction of RBV-induced anemia. IntroductionHepatitis C virus (HCV) is the leading cause of chronic liver disease. It accounts for 70% of all chronic hepatitis cases, 40% of all cases of liver cirrhosis and 60% of hepatocellular carcinomas (HCC) (1,2). Since the successful eradication of HCV is associated with a reduced risk of liver cirrhosis and HCC (3,4), antiviral therapy plays a crucial role in the management of HCV-infected patients. Currently, pegylated interferon (PEG-IFN) plus ribavirin (RBV) is considered to be the standard of care most effective for chronic hepatitis C (5-7), but the rate of sustained virological response (SVR; HCV RNA negative for 24 weeks after the cessation of therapy) is approximately 50% in patients with HCV genotype 1, the most common genotype found in populations in many countries (5,6). Furthermore, 20-30% of HCV genotype 1 patients are non-responders to PEG-IFN/RBV therapy (3).PEG-IFN therapy sometimes causes bone marrow suppression (8,9), and dose reduction may be required in such cases. However, dose reduction is associated with a potentially compromised treatment outcome. Rates of viral clearance are significantly reduced in patients who cannot be maintained on at least 80% of their PEG-IFN/RBV dosage for the duration of treatment (10). Prediction of risk for such complications would be clinically useful for selecting patients for therapy, as well as planning the monitoring frequency. Since bone marrow suppression remains prevalent in patients with early-stage fibrosis, a genetic biomarker for predicting risk of treatment for bone marrow suppression would be particularly useful at the start of...

Relationship between ITPA polymorphisms and hemolytic anemia in HCV-infected patients after ribavirin-based therapy: a meta-analysis

“…Three outcome variables were evaluated: (1) Hemoglobin decline a decrease in hemoglobin of more than 2 or 3 g/dL [ 8 , 10 , 15 – 32 ]; (2) Severe anemia hemoglobin levels less than 8.5, 8.9, 10 or 10.5 g/dL [ 8 , 18 , 20 , 23 , 24 , 26 , 27 , 30 – 35 ]; (3) Ribavirin dose reduction or discontinuation of treatment that resulted from significant anemia defined by several cut-offs (8.5, 10 or 12 g/dL) or physician’s criteria [ 10 , 15 – 18 , 22 , 27 , 30 , 34 – 41 ].…”

Erythrocyte Inosine triphosphatase activity: A potential biomarker for adverse events during combination antiretroviral therapy for HIV

“…True ITPase deficiency in humans is very rare and causes a severe form of early infantile encephalopathy [ 9 ]. Decreased ITPase activity and the frequent ITPA SNPs are associated with a reduced risk to develop ribavirin-induced haemolytic anaemia in patients on treatment for hepatitis C [ 10 – 12 ], and with an increased risk of AEs in patients treated with thiopurines [ 13 – 15 ].…”

Host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients

“…Side effects of treatment such as anemia and psychiatric adverse events (e.g. depression, anger-hostility and anxiety) lead to dose reduction and premature termination of HCV treatment [6] , [7] .…”