Erythropoietin rs1617640 G allele associates with an attenuated rise of serum erythropoietin and a marked decline of hemoglobin in hepatitis C patients undergoing antiviral therapy

Abstract

Background: A decline in hemoglobin (Hb) concentration during antiviral therapy in chronic hepatitis C (CHC) is a serious side effect. It may compel to dose reduction or even termination of antiviral treatment. The activation of erythropoietin (EPO) synthesis as a physiological response to anemia and its relation to a genetic variation within the EPO gene has not been evaluated yet.

Methods: Data of 348 CHC patients were reviewed retrospectively. Samples were genotyped for EPO rs1617640 and inosine triphosphatase (ITPA) rs1127354. Serum EPO concentrations were determined before and during therapy. Primary endpoints were set as Hb decline >3 g/dl at weeks 4 and 12.

Results: EPO rs1617640 G homozygotes showed a significantly lower rise of serum EPO level over time than T allele carriers (p < 0.001). The cumulative frequency of a significant Hb reduction added up to 40%. Multivariate analysis revealed that besides age, ribavirin starting dose and baseline Hb also EPO rs1617640 G homozygosity associates with Hb reduction at week 4 (p = 0.025) and 12 (p = 0.029), while ITPA C homozygotes are at risk for Hb decline particularly early during treatment. Furthermore, EPO rs1617640 G homozygotes were more frequently in need for blood transfusion, epoetin-α supplementation, or ribavirin dose reduction (p < 0.001).

Conclusions: Our data suggest that EPO rs1617640 genotype, the rise of serum EPO concentration as well as ITPA rs1127354 genotype are promising parameters to evaluate the Hb decline during antiviral therapy. A rational adjustment of therapy with epoetin-α supplementation might prevent serious adverse events or the need to terminate treatment.

Figure 1

Pre- and on-treatment serum EPO levels with regard to EPO rs1617640 genotypes. Pretreatment serum EPO concentrations were equally distributed among major T allele carriers and minor G homozygotes. On-treatment serum EPO concentrations of EPO rs1617640 G homozygotes and T allele carriers at week 4 and 8 of therapy, however, differed significantly in a linear model. Data on serum EPO concentrations were available in 181, 112 and 78 individuals at week 0, 4 and 8, respectively. Medians and IQRs are given.

Figure 2

Cumulative proportion of patients with an Hb reduction >3 g/dl during antiviral combination therapy with regard to EPO rs1617640 (A) and ITPA rs1127354 (B) genotypes. A marked Hb reduction was more frequent among EPO rs1617640 minor allele G homozygotes and ITPA rs1127354 major allele C homozygotes than among EPO rs1617640 T allele and ITPA rs1127354 A allele carriers.

Figure 3

Linear regression analysis of serum EPO levels and Hb levels at week 4. This analysis revealed an inverse relationship between the increase of serum EPO levels and the decline of Hb levels in 112 patients of whom data on serum EPO levels were available (A). This relationship is valid for carriers of the T allele (C) but not for G homozygous patients (B). Correlation coefficients and levels of significance are given.