Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
A SPECIFIC HAPLOTYPE AT THE ENT1 GENE INFLUENCES THE RATE OF SUSTAINED VIROLOGICAL RESPONSE TO PEGINTERFERON-RIBAVIRIN IN HIV/HCV-COINFECTED PATIENTS
J. Morello*, L. Cuenca, V. Soriano, J. Medrano, G. González-Pardo, E. Álvarez, A. Madejón, J. González-Lahoz, S. Rodríguez-Nóvoa
Hospital Carlos III, Madrid, Spain. *firstname.lastname@example.org
Background: Response to peginterferon (pegIFN)-ribavirin (RBV) is lower in HIV/HCV-coinfected vs. HCV-monoinfected patients. Several reasons may explain it. The equilibrative nucleoside transporter type 1 (ENT1) is the primary transporter involved in RBV cellular uptake. Genetic polymorphisms at the ENT1 gene may affect the expression and/or activity of this protein, thus influencing intracellular RBV concentrations. Herein, we analyze the impact of ENT1 haplotypes on the rate of sustained virological response (SVR) to HCV therapy in HIV/HCV-coinfected patients.
Methods: HIV/HCV-coinfected patients carrying HCV genotype 1 who had received pegIFN-2a or -2b at standard doses plus weight-adjusted RBV (~13 mg/kg/day) at our institution were identified. Patients who discontinued treatment for other reasons than virological failure were excluded from this analysis. Five single nucleotide polymorphisms (SNPs) at the ENT1 gene were identified by allelic discrimination using TaqMan 5´-nuclease assays (rs1057985C>T, rs9394992C>T, rs324148C>T, rs324149C>T and rs760370A>G). Haplotypes were obtained by combining these five SNPs using the PHASE program. RBV plasma trough concentrations (RBV Ctrough) were measured by HPLC-UV at week 4. SVR was defined as serum HCV-RNA< 10 IU/ml at week 24 after the end-of-treatment.
Results: A total of 94 patients were analyzed [81% male, 94% Caucasian, median age (IQR) 41 (38-45) years, baseline serum HCV-RNA 6.5 (5.6-6.8) log IU/mL, 88% on HAART]. Overall, 35 (37%) achieved SVR.The “TTCTG” haplotype (6% carriers) was associated with SVR: 83% of patients carrying the “TTCTG” haplotype achieved SVR vs. 34% of non-carriers (p=0.026). In a multivariate analysis (OR 95%CI, p) including all relevant factors associated with the achievement of SVR, the “TTCTG” haplotype (12.9 [1.1-148.4], p=0.04), baseline serum HCV-RNA< 600,000 IU/mL (12.9 [4.1-40.6], p< 0.001) and RBV Ctrough>2.5 µg/mL (3.2 [1.1-9.2], p=0.03) were independently associated with RVR. When considering having ≥2 of these three independent predictors of RVR, the PPV and NPV were 78% and 72%, respectively.
Conclusions: The “TTCTG” haplotype at the ENT1 gene influences the chance of SVR to pegIFN-RBV in HIV/HCV-coinfected patients with genotype 1. Hypothetically, it may occur through a modulation of intracellular RBV exposure within hepatocytes. Studies assessing the impact of RBV dose adjustments on virological responses according to ENT1 haplotypes are warranted.