Influence of a Single Nucleotide Polymorphism at the Main Ribavirin Transporter Gene on the Rapid Virological Response to Pegylated Interferon–Ribavirin Therapy in Patients with Chronic Hepatitis C Virus Infection

Abstract

The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin. Single nucleotide polymorphisms (SNPs) at the ENT1 gene were examined using TaqMan 5'-nuclease assays. In the study population, allelic frequencies at rs760370 were as follows: A3 (43 [39%] of 109 patients), AG (50 [46%] of 109 patients), and GG (16 [15%] of 109 patients). Achievement of rapid virological response was more frequent in GG carriers than in AA/AG carriers (50% vs 17%, respectively; P = .007). In multivariate analysis, the GG genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8-92.2; P < .002), a baseline serum HCV-RNA level <600,000 IU/mL (OR, 45.7; 95% CI, 8.7-240.5; P <.001) and a serum ribavirin trough concentration >2.5 μg/mL (OR, 4.8; 95% CI, 1.3-17.1; P < .016) were associated with rapid virological response. When 2 or more of these factors were present, positive and negative predictive values of rapid virological response were 65% and 91%, respectively. In summary, a SNP rs760370A→G at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy in HIV-infected patients with chronic HCV infection due to HCV genotypes 1 or 4, most likely modulating intracellular ribavirin exposure within hepatocytes.

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

“…A polymorphism within the transmembrane domain of human CNT3 has been shown to alter transport specificity for several nucleoside-derived drugs (11,12). Several single-nucleotide polymorphisms (SNPs) within the ENT1 gene (SLC29A1) have been reported (38). One of the SNPs (rs760370A 3 G) correlated with rapid treatment response in HCV patients, further supporting the role of ENT1-mediated RBV uptake in HCV treatment response.…”

ENT1, a Ribavirin Transporter, Plays a Pivotal Role in Antiviral Efficacy of Ribavirin in a Hepatitis C Virus Replication Cell System

“…The mechanisms underlying the interindividual difference in the hepatic ENT1 activity level remain unclear, but SNPs are promising candidates for the causal factors that result in the difference. Since two intronic SNPs have been revealed to be associated with RVR (and SVR) (12,18), investigations should be conducted to determine whether these SNPs have a positive effect on the hepatic ENT1 expression level.…”

“…In addition, Morello et al (12) reported the association of an intronic single nucleotide polymorphism (SNP) of the SLC29A1 (ENT1) gene with rapid virologic response (RVR; defined as an undetectable serum HCV RNA level at week 4) of treatment of genotype-1 Caucasian patients. More recently, Tsubota and colleagues revealed that another intronic SNP in the SLC29A1 gene is associated with SVR, as well as RVR, in genotype-1 Japanese patients (18).…”

Impact of Solute Carrier Family 29 Member 1 (SLC29A1) Single Nucleotide Polymorphisms on mRNA Expression in Peripheral Blood Mononuclear Cells

“…3,4) On the other hand, it has been reported that three SNPs, rs6932345, rs747199 and rs760370, existing on intron of SLC29A1 gene were associated with drug response and mRNA expression with the frequency of >0.1 in Japanese. [5][6][7][8] Tsubota et al recently reported that rs6932345 in SLC29A1, a major RBV transporter gene, was a significant genetic factor associated with the outcome of pegylated-interferon (IFN)/ RBV combination therapy in patients with monoinfected hepatitis C virus (HCV). 5) They found that patients with the rs6932345 AA genotype (wild-type) had a higher rate of rapid and sustained virological response and a higher RBV trough concentration than did patients with the AC/CC genotypes (mutation carrier).…”

“…Another research group also found that rs760370, an SNP highly linked with rs6932345, was associated with rapid virological response in IFN/RBV therapy for patients co-infected with human immunodeficiency virus and HCV. 5,7) These observations are quite interesting to understand the impact of SLC29A1 activity on IFN/RBV combination therapy, in which SLC29A1 plays an important role in intracellular uptake and gastrointestinal absorption of RBV. 9) Although wild-type rs6932345 may provide higher activity of SLC29A1 than the mutant type, no data have been available on such an association, including data on mRNA expression.…”