Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR

Abstract

Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphos-phatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10−6 for rs1127354 and P = 10−7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10−11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08–0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR. Conclusion Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.

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

“…As reported by recent studies (5,(12)(13)(14), Hb decrease is faster and more severe during the first 4 weeks of treatment in patients with the ITPA major allele (CC). The rapid decrease of Hb observed in major allele CC patients was associated with early reduction of RBV dosage, resulting in a lower total RBV administration.…”

“…Recently, a genome-wide association study of determinants of treatmentrelated anemia in individuals with chronic HCV genotype 1 infection identified that genetic variants leading to ITPA deficiency protect against hemolytic anemia in HCV-infected patients receiving RBV (12). In the Caucasian population, there are two SNPs (rs7270101 and rs1127354) that are associated with ITPA enzyme activity (12,13), but one of these SNPs (rs7270101) is absent in Japanese patients (14). In this study, we confirmed the absence of rs7270101; the frequency of the rs1127354 major allele (CC) was 76.3% and that of the minor allele (CA and AA) was 23.7%.…”

“…De Franceschi et al previously reported that membrane oxidative damage as well as impairment of erythrocyte Na/K pump activity are responsible for RBV-induced hemolytic anemia (11). Studies show that single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) locus are associated with anemia in patients treated with combination therapy (12)(13)(14). Two SNPs that are associated with ITPA enzyme activity were identified in the Caucasian population (12), but the Japanese population lacks one of these SNPs (14,15).…”

Variants of the inosine triphosphate pyrophosphatase gene and relapse risk following treatment for HCV genotype 2/3

“…3,4 Because the RVR was reported as the most important predictor of SVR in HCV G2-infected patients, even when interleukin-28B variants were taken into consideration, 5,6 and ITPA variants were reported not to increase SVR in G2/3-infected patients with higher dose of RBV, 7 it is interesting to know whether the RVR is associated with ITPA variations and SVR in the present study of the NORDynamIC trial. 4 Particularly, because RVR is currently the most important factor for individualized therapy for G2/3-infected patients, the effect of the ITPA variants on determining the duration of Peg-IFN/RBV therapy for patients with or without RVR deserves to be explored.…”

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

“…Recent results by the same group analyzed patients infected with HCV genotypes 2 and 3, showing that ITPA variants are protective against treatment-related anemia, but are not related to the rate of SVR [134]. Among Japanese patients, only the SNP rs1127354 was strongly associated with the incidence and severity of RBV-induced HA [135,136].…”