Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction.
OBJECTIVE
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.
Thompson
Alexander J
AJ
Duke Clinical Research Institute, Durham, North Carolina 27715, USA.
Fellay
Jacques
J
Patel
Keyur
K
Tillmann
Hans L
HL
Naggie
Susanna
S
Ge
Dongliang
D
Urban
Thomas J
TJ
Shianna
Kevin V
KV
Muir
Andrew J
AJ
Fried
Michael W
MW
Afdhal
Nezam H
NH
Goldstein
David B
DB
McHutchison
John G
JG
D000328:Adult; D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000517:prevention & control; D000998:Antiviral Agents / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics*; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
D000998:Antiviral Agents; D011755:Pyrophosphatases; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase