Impact of genetic concentrative nucleoside transporter variants on interferon/ribavirin therapy response in hepatitis C patients

Aims: Treatment of HCV infection will change in the near future and direct acting antiviral drugs (DAA) will be added to existing antiviral therapy with peg-interferon-α and ribavirin (RBV). Side effects such as RBV-induced hemolytic anemia will be even worsened in combination with DAAs. Therefore, understanding of genetic host factors determining RBV bioavailability and therapeutic efficacy will remain crucial for individualized treatment. Recent data showed an association between RBV-induced hemolytic anemia and polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3). Aim: To analyze the association of genetic variants of various SLC28 transporters regarding therapeutic outcome with standard therapy. Methods: 174 patients from the Swiss Hepatitis C Cohort study and 15 patients of the SASL–26 study (HCV GT1 59.8%, GT2/3 40.2%) were genotyped for SLC28A2 rs11854484 C>T, SLC28A3 rs56350726 A>T and SLC28A3 rs10868138 C>T as well as ITPA polymorphisms rs1127354 C>A and rs7270101 A>C. Data for sustained viral response (SVR) and hemoglobin levels were available for all patients. Results: Compared to the normal caucasian population (NCBI databank) no overrepresentation of respective genetic variants could be observed in HCV patients. 103 of 189 patients (54.5%) in our study achieved SVR. The SLC28A3 rs56350726 TT genotype (vs. AT/AA; p=0.05) and the T allele (vs. A; p=0.02) were both associated with increased SVR rate. No such association was found for SLC28A2 rs11854484 or SLC28A3 rs10868138 as well as ITPA rs1127354 and rs7270101 and genotype combinations thereof with therapy outcome (ITPA function 0–+++). Conclusion: Our results show a genetic association between the SLC28A3 polymorphism rs56350726 and therapeutic outcome. This particular polymorphism represents a genetic host factor which putatively affects RBV uptake and consecutively SVR and hemolytic anemia.

HCV - RBV - SVR - concentrative nucleoside transporter