Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
ABSTRACT Given that peginterferon-ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes.
From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon-ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion.
A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6-8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1-21.0; <0.001), serum HCV-RNA less than 600,000 IU/ml (11.9; 3.8-37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4-8.9; 0.009).
The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.
SourceAvailable from: Diego Flichman[Show abstract] [Hide abstract]
ABSTRACT: Hepatitis C virus (HCV) was identified for the first time more than 20 years ago. Since then, several studies have highlighted the complicated aspects of this viral infection in relation to its worldwide prevalence, its clinical presentation, and its therapeutic response. Recently, two landmark scientific breakthroughs have moved us closer to the successful eradication of chronic HCV infection. First, response rates in treatment-naïve patients and in prior non-responders to pegylated-interferon-α and ribavirin therapy are increasing as a direct consequence of the development of direct-acting antiviral drugs. Secondly, the discovery of single-nucleotide polymorphisms near the interleukin 28B gene significantly related to spontaneous and treatment-induced HCV clearance represents a milestone in the HCV therapeutic landscape. The implementation of this pharmacogenomics finding as a routine test for HCV-infected patients has enhanced our understanding of viral pathogenesis, has encouraged the design of ground-breaking antiviral treatment regimens, and has become useful for pretreatment decision making. Nowadays, interleukin 28B genotyping is considered to be a key diagnostic tool for the management of HCV-infected patients and will maintain its significance for new combination treatment schemes using direct-acting antiviral agents and even in interferon-free regimens. Such pharmacogenomics insights represent a challenge to clinicians, researchers, and health administrators to transform this information into knowledge with the aim of elaborating safer and more effective therapeutic strategies specifically designed for each patient. In conclusion, the individualization of treatment regimens for patients with hepatitis C, that may lead to a universal cure in future years, is becoming a reality due to recent developments in biomarker and genomic medicine. In light of these advances, we review the scientific evidence and clinical implications of recent findings related to host genetic factors in the management of HCV infection.Pharmacogenomics and Personalized Medicine 01/2014; 7:339-47. DOI:10.2147/PGPM.S52624
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ABSTRACT: Single-nucleotide polymorphisms (SNPs) associated with hepatitis C virus (HCV) clearance were identified near the IL28B gene. Coinfection by the human immunodeficiency virus (HIV) influences the course of HCV contributing to liver damage. Nevertheless, little is known about the relationship between these SNPs and HCV/HIV coinfection. Our aim was to estimate the frequencies of the allelic and genotypic variants of the IL28B polymorphisms rs12979860 (C/T) and rs8099917 (T/G) and their possible association with the establishment of HCV infection. A total of 199 non-infected controls and 230 patients with chronic hepatitis C, including 53 coinfected with HIV, participated in the study. Genotyping consisted of polymerase chain reaction and subsequent analysis of the restriction patterns resulting from exposure to endonucleases. Among the controls with established results, 47.4% (90/190) exhibited the rs12979860 CC genotype, 43.7 CT, and 8.9% TT, whereas 29.1% (66/227), 51.5%, and 19.4% of the patients exhibited the CC, CT, and TT genotypes, respectively. With respect to rs8099917, 66.8% (133/199) of the controls exhibited the TT genotype, 31.2% TG, and 2.0% GG, whereas 56.1% (129/230), 40.9%, and 3.0% of the patients exhibited the TT, TG, and GG genotypes, respectively. The frequencies of the rs12979860 C allele and CC genotype and of the rs8099917 T allele and TT genotype were significantly higher among controls compared with patients, thus confirming the suggested protective effect against HCV infection. No significant difference was observed in the genotype and allelic distributions between the mono- and coinfected patients.Frontiers in Microbiology 03/2015; 6:153. DOI:10.3389/fmicb.2015.00153 · 3.94 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.04/2015; 7(6):831-845. DOI:10.4254/wjh.v7.i6.831