SNP Influence on HCV Therapy
• JID 2010:202 (15 October) • 1185
M A J O R A R T I C L E
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
Judit Morello,1Lorena Cuenca,1Vincent Soriano,2,3Jose ´ Medrano,3Antonio Madejo ´n,2Eugenia Vispo,3
Pablo Barreiro,3Pablo Labarga,3Inmaculada Jime ´nez-Na ´cher,1and Sonia Rodrı ´guez-No ´voa1,2
1Laboratory of Pharmacology,
Hospital Carlos III, Madrid, Spain
2Laboratory of Molecular Biology, and
3Clinical Unit, Department of Infectious Diseases,
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 pegylatedinterferon(pegIFN)-ribavirin.Singlenucleotide
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 morefrequent
in GG carriers than in AA/AG carriers (50% vs 17%, respectively;
genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8–92.2;
level !600,000 IU/mL (OR, 45.7; 95% CI, 8.7–240.5;
P ! .001
mg/mL (OR, 4.8; 95% CI, 1.3–17.1;) were associated with rapid virological response. When 2 or more
P ! .016
of these factors were present, positive and negative predictive values of rapid virological response were 65%
and 91%, respectively. In summary, a SNP rs760370ArG 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.
). In multivariate analysis, the GG
), a baseline serum HCV-RNA
P ! .002
) and a serum ribavirin trough concentration 12.5
P p .007
The current treatment for chronic hepatitis C virus
(HCV) infection is the combination of pegylated in-
terferon a (pegIFN) plus ribavirin, which cures infec-
Received 15 February 2010; accepted 4 May 2010; electronically published 2
Potential conflicts of interest: none reported.
Financial support: This work was supported in part by grants from Fondo de
Investigacio ´n Sanitaria (grant FIS CP07–00016), Fundacio ´n Investigacio ´n y
Educacio ´n en SIDA, Red de Investigacio ´n en SIDA (grant ISCIII-RD06/0006/0040),
and the European NEAT project.
Reprints or correspondence: Dr Vincent Soriano, Infectious Diseases Depart-
ment, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain (vsoriano@
The Journal of Infectious Diseases
? 2010 by the Infectious Diseases Society of America. All rights reserved.
tion in ∼55% of HCV-monoinfected patients [1, 2].
This figure, however, is lower (25%–50%) in the subset
of patients coinfected with human immunodeficiency
virus (HIV) [3–6]. Approximately one-fourth of HIV-
infected individuals worldwide are coinfected with
HCV ; liver disease progresses faster to cirrhosis in
this population [7, 8]. As classical opportunistic infec-
tions have dramatically declined as a result of using
highly active antiretroviral therapy (HAART), HCV-
related liver disease has emerged as the leading cause
management and treatment of chronic HCV infection
is currently a priority in HIV-infected individuals .
Given that pegIFN-ribavirin therapy is poorly tolerated
and has several contraindications, the identification of
at Shanghai Jiao Tong University on February 2, 2016
SNP Influence on HCV Therapy • JID 2010:202 (15 October) • 1191
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