Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction

Abstract

Background & aims: In a genome-wide association study of patients being treated for chronic hepatitis C, 2 functional variants in ITPA that cause inosine triphosphatase (ITPase) deficiency were shown to protect against ribavirin (RBV)-induced hemolytic anemia during early stages of treatment. We aimed to replicate this finding in an independent cohort from the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C and to investigate the effects of these variants beyond week 4.

Methods: Genetic material was available from 318 patients. The ITPA variants, rs1127354 (exon 2, P32T) and rs7270101 (intron 2, splice altering), were genotyped and tested for association with hemoglobin (Hb) reduction at week 4. An ITPase deficiency variable was defined that combined both ITPA variants according to documented effect on ITPase activity. We investigated the impact of ITPA variants on Hb levels over the course of therapy and on the need for RBV dose reduction.

Results: The final analysis included 304 patients with genotype 1 hepatitis C virus (167 white patients and 137 black patients). The polymorphisms rs1127354 and rs7270101 were associated with Hb reduction at week 4 (P = 3.1 × 10(-13) and 1.3 × 10(-3), respectively). The minor alleles of each variant protected against Hb reduction. Combining the variants into the ITPase deficiency variable strengthened the association (P = 2.4 × 10(-18)). The ITPase deficiency variable was associated with lower rates of anemia over the entire treatment period (48 weeks), as well as a lower rate of anemia-related RBV dose reduction (hazard ratio, 0.52; P = .0037). No association with sustained virological response was observed.

Conclusions: Two polymorphisms that cause ITPase deficiency are strongly associated with protection from RBV-induced hemolytic anemia and decrease the need for RBV dose reduction.

Figure 1

(A) Quantitative Hb reduction from baseline. The ITPase deficiency variable was associated with less absolute reduction in median Hb level at all time points on treatment. There was only 1 patient with severe (+ + +) ITPase deficiency, and this patient was excluded from the analysis. Data are presented as median and interquartile range. P values are listed above the relevant time points (^*P ≤ .001). (B) Hb reduction >3 g/dL from baseline. The ITPase deficiency variable was protective against clinically significant reductions (>3 g/dL) in Hb throughout the course of pegIFN plus RBV combination therapy. There was only 1 patient with severe (+ + +) ITPase deficiency, and this patient was excluded from the analysis. P values for each time point are listed above the columns. ViraHep-C protocol involved a week 24 stopping rule for virological nonresponders, explaining the decreased cohort size after 24 weeks.

Figure 2

Survival analysis of ribavirin dose reduction. Survival analysis of time to first dose reduction (indication = anemia) according to ITPase deficiency variable, showing that mild or moderate ITPase deficiency protects against the need for RBV dose reduction. Censor criteria: 1 = dose reduction for anemia, 0 = last follow-up or date of dose reduction for an indication not related to anemia.