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 triphosphatase (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.

Fig. 1

Quantitative Hb reduction from the baseline. The predicted ITPase deficiency was associated with a less absolute reduction in the median Hb levels at all time points during treatment. Only six patients were predicted to have severe (+++) ITPase deficiency; therefore, patients with moderate or severe ITPase deficiency were combined into a single variable. Data are presented as medians and interquartile ranges. The statistical analysis compares patients with normal ITPase activity to the composite group of patients with mild or moderate to severe ITPase deficiency. P values are listed above the relevant time points.

Fig. 2

Hb reduction > 3 g/dL from the baseline. The predicted ITPase deficiency was associated with protection against clinically significant reductions (>3 g/dL) in Hb throughout the course of PEG-IFN/RBV combination therapy. Only six patients were predicted to have severe (+++) ITPase deficiency; therefore, patients with moderate or severe ITPase deficiency were combined into a single variable. The statistical analysis compares patients with normal ITPase activity to the composite group of patients with predicted ITPase deficiency. P values for each time point are listed above the columns.