Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Hepatitis C Treatment [T88.7]

OMIM numbers: 609532, 607402 (IL28B), 609532, 147520 (ITPA)

Dipl.-Biol. Birgit Busse

Scientific Background

Administration of peginterferon alfa-2a/b in combination with ribavirin (Peg-IFN/RBV) is one of the standard treatments for a hepatitis C (HCV) infection. Besides the genotype, genetic variants of the host (host factors) play a role regarding the efficacy and compatibility of treatment as well. The IL28B C/T polymorphism rs12979860 in the human genome is associated with the efficacy (sustained virological response (SVR)). Patients with the C/C genotype (two C alleles) respond better to a treatment with Peg-IFN/RBV than carriers of the T allele (OR 5.8) and exhibit a higher rate of spontaneous remission of the disease. The polymorphism rs12979860 is located approx. 3kb upstream of the interleukin 28B gene IL28B (interferon, lambda 3), outside the coding region. It is, however, almost in complete linkage disequilibrium to other SNPs, for which studies showed an association to SVR and spontaneous remissions as well. Within the Caucasian population group, frequency of the rs12979860 T allele is approx. 40%. 

Hemolytic anemia is among the most frequent complications during HCV treatment with ribavirin (RBV). Within the first 12 weeks of treatment, up to 25% of all patients develop anemia requiring treatment and discontinuation of therapy or at least a reduction in dosage. The success of treatment with RBV is therefore considerably impaired. Deficiency of the enzyme inosin triphosphatase (ITPA) is associated with a protective effect regarding RBV induced hemolytic anemia. Two polymorphisms in exon 2 of the ITPA gene (rs1127354, rs7270101) are associated with a reduced ITPA activity. Carriers of the variant alleles are considerably less prone to develop Hb reduction requiring treatment than homozygous carriers of the wild type alleles (rs1127354 A genotype, rs 7270101 C genotype). Early dose reduction and/or co-medication with erythropoetin in homozygous carriers of the wild type alleles (normal ITPA activity) may lower the risk for hemolytic anemia. The literature currently discusses an elevation in dose of RBV for homozygous carriers of the variant alleles, since a high-dose therapy with RBV is associated with an elevated SVR rate.