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.
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ABSTRACT: In chronic hepatitis C, higher ribavirin (RBV) concentrations are associated with sustained virological response (SVR); target concentration cutoffs have been proposed. As RBV displays interindividual variability, monitoring of RBV plasma levels appears relevant. The impact of RBV therapeutic drug monitoring (TDM(RBV)) on SVR has not been explored in current practice. Our study aimed to assess this impact. Three patient groups were defined as RBV cutoffs achieved at week 12 (group A1), not achieved (group A2), and one without RBV concentration assessment (group B). A predictive model assessed the group impact on SVR in multivariate analysis, while adjusting for additional predictive factors. A specific evaluation of HIV-HCV-coinfected patients was performed. A total of 122 patients were included. In group A1 (n=30, HIV-positive =18), SVR, relapse and non-response rates were 60%, 17% and 23%, respectively; in group A2 (n=32, HIV-positive =18), 25%, 19% and 56%, respectively; and in group B (n=60, HIV-positive =3), 52%, 33% and 15%, respectively (P=0.0004). The patient group was an independent predictor of SVR (P=0.01), along with baseline viral load and HCV genotype. HIV coinfection did not impede the SVR rate. The cutoffs were achieved in 62% and 28% (P=0.008) of patients, when TDM(RBV) was performed or not, respectively. The achievement of RBV cutoffs is a predictive factor of SVR independent of HIV coinfection. It makes it possible to reach high SVR rates, avoid relapse and obtain the same SVR rates in HIV-HCV-coinfected as in HCV-monoinfected patients. TDM(RBV) enables RBV concentration cutoffs to be reached more frequently and could thus be a useful tool to optimize hepatitis C treatment.Antiviral therapy 01/2011; 16(8):1317-26. DOI:10.3851/IMP1920 · 3.14 Impact Factor
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ABSTRACT: Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic-pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response.Digestive and Liver Disease 05/2011; 43(11):850-5. DOI:10.1016/j.dld.2011.04.002 · 2.89 Impact Factor