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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 3  |  Page : 670-676

Interleukin 28B polymorphism as a predictor of response to interferon therapy in hepatitis C virus patients


1 Department of Microbiology and Immunology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Microbiology and Immunology, National Liver Institute, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, National Liver Institute, Menoufia University, Menoufia, Egypt
4 Department of Hepatology, National Liver Institute, Menoufia University, Menoufia, Egypt

Date of Submission21-Jan-2015
Date of Acceptance15-Mar-2015
Date of Web Publication22-Oct-2015

Correspondence Address:
Samah Awad
National Liver Institute, Shibin Al Kom, 32513 Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.167879

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  Abstract 

Objective
The aim of the study was to assess the predictive value of interleukin 28B (IL-28B) rs12979860 polymorphism in the response to interferon (IFN)/ribavirin (RBV) therapy in hepatitis C virus (HCV) patients and the allele frequencies of this gene in HCV patients as compared with healthy controls.
Background
HCV infection, one of the major causes of liver disease worldwide, is highly prevalent in Egypt, with a predominance of HCV genotype 4. The standard of care for chronic HCV infection consists of treatment with pegylated interferon-a plus ribavirin (PegIFN/RBV), which is prolonged and costly and is associated with dose-limiting side effects, increasing the need for accurate prediction of treatment failure. IL-28B gene polymorphism has been shown to be related to HCV treatment response, mainly in genotype 1.
Patients and methods
This study included 130 HCV-positive Egyptian patients treated with IFN/RBV therapy. They were divided into three groups according to their response to therapy. Group I included 70 patients with sustained viral response (SVR). Group II included 49 patients with no response. Group III included 11 patients with relapse, and group IV included 40 healthy controls. Liver function tests, complete blood count, evaluation of viral markers, HCV-RNA by PCR, and evaluation for IL-28B single nucleotide polymorphisms for rs12979860 were performed by PCR-RFLP in all patients.
Results
IL-28B genotype CC was present in 34.6% of patients, whereas CT and TT genotypes were detected in 42.3 and 23.1% of patients, respectively. Seventeen (53.8%) patients achieved an SVR, whereas 60 (46.2%) did not. Of the 70 patients with an SVR, 38 had genotype CC, 25 had genotype CT, and seven had genotype TT. Patients having the CC genotype achieved significantly higher SVR rates (84.4%) compared with CT (45.5%) and TT patients (23.3%).
Conclusion
The IL-28B polymorphism is an independent predictor of SVR to PegIFN/RBV in Egyptian HCV-positive patients with genotype 4.

Keywords: Chronic hepatitis C, IL-28B polymorphism, interferon therapy


How to cite this article:
Bakr A, Ghoneim E, Sayed M, El-Mottaleb TA, Sabawy ME, Awad S. Interleukin 28B polymorphism as a predictor of response to interferon therapy in hepatitis C virus patients. Menoufia Med J 2015;28:670-6

How to cite this URL:
Bakr A, Ghoneim E, Sayed M, El-Mottaleb TA, Sabawy ME, Awad S. Interleukin 28B polymorphism as a predictor of response to interferon therapy in hepatitis C virus patients. Menoufia Med J [serial online] 2015 [cited 2020 Feb 24];28:670-6. Available from: http://www.mmj.eg.net/text.asp?2015/28/3/670/167879


  Introduction Top


The hepatitis C virus (HCV) represents a global problem for public healthcare systems worldwide because of its high prevalence, high rates of transfer, and severe health-related complications [1]. According to the WHO there are 130-150 million people infected with HCV, who constitute 3% of the world's population. Each year 3-4 million new patients with HCV are diagnosed [2].

The standard of care for chronic HCV infection consists of treatment with pegylated interferon-a plus ribavirin (PegIFN/RBV). However, this treatment produces sustained viral response (SVR) rates in only about 40-50% of patients with HCV genotype 1 and in ~60% of those infected with genotype 4, whereas over 80% of patients with genotypes 2 or 3 achieve SVR [3].

PegIFN/RBV treatment is prolonged and costly, and is associated with dose-limiting side effects, highlighting the need for an accurate prediction of treatment failure [4]. Treatment decisions should be based on criteria and factors that affect the likelihood of treatment outcome. The treatment of HCV genotype 4 is affected by many host/virus factors that must be precisely evaluated and optimized before treatment initiation [5]. Furthermore, it has recently been reported that a single nucleotide polymorphism (SNP) of the host gene interleukin 28B (IL-28B) is significantly associated with the response to PegIFN/RBV therapy [6].

IL-28B is a Th1 type cytokine, a class II cytokine receptor ligand, a 200 amino acid long protein, a member of type III interferons (IFNs), which is distantly structurally related to the members of the IL-10 superfamily of cytokines, but also shares limited sequence similarity and functional characteristics with the type I IFNs (a and b). IL-28B has a role in the regulation of intracellular IFN-stimulated gene (ISG) expression [7].

It is expressed by peripheral blood mononuclear cells, dendritic cells, upon infection with viruses. IL-28B exhibits antiviral activity, having an impact on the natural clearance of HCV [8].

IL-28B encodes IFN-l3, which induces antiviral activity by itself and through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) complex, which induces ISGs, which also have antiviral activity against HCV [9].

IL-28B variants might cause an abnormal expression of endogenous IFN-l3 (nonfunctioning, weakly functioning, or hyperfunctioning variants). This might alter the host response to antiviral therapy by negative feedback [10].

The use of IL-28B polymorphisms as a predictive tool will have a major impact on the treatment strategies for chronic HCV infection, particularly in the context of emerging therapies and direct-acting antiviral agents. It may help in identifying patients for whom therapy is likely to be successful [11].


  Aim Top


The aim of the study was to assess the predictive value of IL-28B rs12979860 polymorphism in the response to IFN/RBV therapy in HCV patients and the allele frequencies of this gene in HCV patients as compared with healthy controls.


  Patients and methods Top


This study included 130 chronic HCV-positive Egyptian patients who were recruited from the Interferon Clinic of National Liver Institute, Menoufia University, during the period from July 2011 to July 2013. They included 92 (70.8%) men and 38 (29.2%) women and their ages ranged from 18 to 57 years (mean 39.60 ± 9.28 years). The study also included 40 healthy volunteers as controls.

All chronic HCV patients were of genotype 4 by the INNoLiPA (Fujirebio Europe, NV, Ghent, Belgium) test. All patients received weekly injection of pegIFN-a, plus daily oral RBV treatment for 48 weeks. According to the response to therapy, they were classified into three groups. The first group included patients with SVR: the chronic HCV patients who had received the therapy and had shown negative HCV-RNA 6 months (24 weeks) following completion of a 48-week treatment course. The second group included nonresponders to the therapy )no disappearance of HCV-RNA at the end of the 12 weeks), and the third group were the patients who relapsed - those patients who had detectable HCV-RNA 24 weeks after stoppage of treatment. Informed consent was obtained from all patients before the study and this study was approved by the ethical committee of the National Liver Institute, Menoufia University.

All patients and controls were subjected to the following laboratory investigations: liver function tests, complete blood counts, evaluation of prothrombin time and concentration, test for hepatitis B surface antigen (HBsAg) by ELISA, test for HCV antibodies by ELISA, and indirect hemagglutination inhibition assay for schistosomal antibody [12],[13],[14],[15],[16].

HCV-RNA was performed by RT-PCR before treatment and at 4, 12, 24, and 48 weeks [17], and liver biopsy was performed before treatment to assess fibrosis stage [18].

Molecular detection of interleukin 28B genotypes

Genotyping for the IL-28B rs12979860 polymorphism was performed by means of PCR-based restriction fragment length polymorphism (RFLP) assay.

Genomic DNA was extracted from whole blood samples by means of the QIAamp DNA Blood Mini Kit (Qiagen, Milan, Italy) according to the manufacturer's instruction. For rs12979860, oligonucleotide primers used were: 5΄-GCTTATCGCATACGGCTAGG-3΄ and the reverse primer 5΄-AGGCTCAGGGTCAATCACAG-3΄. PCR amplification was carried out in a total volume of 10 μl containing 10 mmol/l Tris-HCl (pH 8.3), 50 mmol/l KCl, Tween-20 0.01%, 0.2 mol/l deoxyribonucleotides, 2-4 pmol of each primer, 2.0 mmol/l MgCl 2 , and 0.5 U hot-start Taq DNA polymerase (RighTaq; Euroclone, Milan, Italy). Samples containing 10 ng of genomic DNA were subjected to 40 cycles of denaturation (at 95°C for 30 s), annealing (at 62°C for 30 s), and elongation (at 72°C for 30 s) using a Techne TC-412 (Ghent, Belgium) thermal cycler [19]. Then RFLP was done as follows: 10 μl of the amplicons was digested with 1 U of the BstU-I restriction endonuclease (New England Bioloabs; Hitchin, UK) at 60°C overnight. The fragments digested were, respectively, 135+82+25 bp for the C allele and 160 + 82 bp for the T allele variant. The fragments were resolved by electrophoresis in 3.5% agarose gel after staining with ethidium bromide [19].

Statistical analysis

The data were collected, tabulated, and analyzed using statistical package for the social sciences (SPSS Inc. Released 2008, SPSS Statistics for Windows, Version 17.0. Chicago, USA) on an IBM compatible computer. The χ2 -test was conducted to study the association between two qualitative variables. Fisher's exact test was used in the analysis of 2 × 2 contingency tables. The Student t-test was for comparison between two groups having normally distributed quantitative variables. The Mann-Whitney U-test was conducted as a nonparametric test of significance for comparison between two groups having not normally distributed quantitative variables. Analysis of variance was used as a parametric test for comparison between more than two groups having normally distributed quantitative variables. The Kruskal-Wallis test was used as a nonparametric test of significance for comparison between more than two groups having not normally distributed quantitative variables. Regression analysis is a statistical process for estimating the relationships among variables [20].


  Results Top


The baseline characteristics of the 130 patients with chronic HCV infection (before therapy) and of 40 controls are presented in [Table 1]. The mean age of HCV patients was 39.60 ± 9.28 years and that of controls was 35.56 ± 11.25 years; the mean BMI was 26.41 ± 2.55 for HCV patients and 26.28 ± 1.98 for controls. Among the baseline laboratory values, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly higher in patients than in controls (P < 0.01).
Table 1: Characteristics of the studied hepatitis C virus patients (pretreatment) and healthy controls

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Among the 130 chronic HCV patients, the rs12979860 CC, CT, and TT genotypes were present in 34.6, 42.3, and 23.1% of patients, respectively, but for controls the frequency was 52.2, 32.5, and 15% for CC, CT, and TT, respectively, with no statistically significant difference between them [Figure 1].
Figure 1: Distribution of the interleukin 28B (IL-28B) genotypes among hepatitis C virus (HCV) patients and healthy co ntrols.

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As regards response to treatment, 70 (53.8%) of the studied patients achieved an SVR, whereas 60 (46.2%) did not. In the latter group 49 were nonresponders and 11 relapsed. Of the 70 patients with an SVR, 38 had genotype CC, 25 had genotype CT, and seven had genotype TT [Table 2].
Table 2: Relationship between different interleukin 28B genotypes and sustained viral response in hepatitis C virus patients

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The C allele was significantly higher in responders (72.1%) than in nonresponders (35.7%) and higher than in those who relapsed (40.9%) [Figure 2].
Figure 2: Distribution of the interleukin 28B (IL-28B) alleles in relation to interferon response. NR, nonresponder; SVR, sustained viral re sponse.

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Fibrosis and IL-28B genotypes are independent predictors of SVR to IFN therapy with odds ratio 2.10 and 5.39, respectively (P < 0.05 and 0.01, respectively), whereas age and BMI were nonsignificant, as shown in [Table 3].
Table 3: Multivariate regression analysis of predictors of sustained viral response in the studied hepatitis C virus patients

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The comparison between different IL-28B genotypes (CC, CT, and TT) in HCV patients revealed no significant difference as regards ALT, AST, albumin, platelets, fibrosis, and bilharziasis [Table 4].
Table 4: Comparison between interleukin 28B genotypes and pretreatment parameters

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Agarose gel electrophoresis illustrated the PCR-RFLP products for the IL-28B gene polymorphism. Lane 1 corresponds to 50 bp molecular weight marker. Lanes 3, 4, 7, and 8 correspond to blood samples from homozygous CC participants. Lanes 5 and 9 correspond to blood samples from homozygous TT participants. Lanes 2, 6, and 10 correspond to blood samples from heterozygous CT participants [Figure 3].
Figure 3: PCR-RFLP products on agarose gel electrophoresis illustrating for the interleukin 28B gene polymo rphism.

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  Discussion Top


The present work aimed to assess the predictive value of the IL-28B polymorphism in the treatment of chronic HCV in Egyptian patients and its allele frequency in HCV patients compared with controls.

The current study showed that, among the 130 Egyptian chronic HCV patients, the IL-28B rs12979860 CC, CT, and TT genotypes were present in 34.6, 42.3, and 23.1% of patients, respectively; thus, the CT genotype was the most common in the studied patients.

Nearly similar results were reported in many recent Egyptian studies. For example, Hendy et al. [21] detected that the incidence of CC, CT, and TT genotypes was 39, 51, and 10, respectively, and Khairy et al. [22] found that the incidence of IL-28 genotypes CC, CT, and TT in Egyptian patients was 25, 56, and 19%, respectively, with the CT genotype being the most common in their study. El-Awady et al. [23], in a study on Egyptian patients, found that the incidence of IL-28B genotypes was 48% CC, 14% TT, and 38% CT in their studied patients and Asselah et al. [24] found the incidence to be 55% CC, 11% TT, and 34% CT, adding that the CC genotype was the most common in these studies.

Similarly, De Nicola et al. [25] found that the incidence of IL-28 genotypes CC, CT, and TT in Italian patients was 23, 63, and 14%, respectively. In the study by Tolmane et al. [26] on the IL-28 gene polymorphism in Latvia, the most common genotype of IL-28B was CT, with an incidence of 53%, followed by the CC genotype (33%) and the TT genotype (14%).

In the present study, the frequency of IL-28B genotypes CC, CT, and TT in healthy controls was 52.5, 32.5, and 15%, respectively. The frequency of the IL-28B C/C genotype was lower in HCV patients than in controls (34.6 vs. 52.5%); this difference is not significant. However, there was significant difference between HCV patients and controls as regards the IL-28B alleles, as the frequency of the C allele was lower in HCV patients than in healthy controls (55.8 vs. 68.8%) and the T allele was higher in HCV patients than in controls (44.2 vs. 31.2%).

In agreement with our study is the one by Par et al. [8], who reported that the frequency of the IL-28B C/C genotype was lower in HCV patients than in controls; it may be regarded as being protective against chronic HCV infection.

In the present study after therapy, 70 (53.8%) patients among the overall 130 HCV patients achieved SVR (responders), and the remaining 60 (46.2%) patients failed to respond (which included 49 primary nonresponders and 11 who relapsed). This finding was supported by previous studies by Al Ashgar and colleagues [21],[25],[27],[28].

This study showed that the CC genotype of rs12979860, which achieved SVR, was 84.4%, which is significantly higher compared with CT (45.5%) and TT (23.3%) genotypes. Similar results were observed by Asselah et al. [24], who found that the response rates were 81.8, 46.5, and 29.4% for genotypes CC, CT, and TT, respectively. Nearly similar results were detected by Khairy et al. [22], who found that the response rates in a study conducted on Egyptian patients were 50, 47.4, and 25% for genotypes CC, CT, and TT, respectively, with better response rates in the CC genotype. In studies conducted on HCV genotype 1 patients in different geographical areas, patients with the CC genotype achieved SVR more often than CT or TT subgroups. Ge et al. [11] found that the SVR rates in CC patients were 77% in Whites and 53% in African Americans. Also, Mangia et al. [29] reported that 82% of patients with the CC genotype achieved an SVR among patients infected with genotype 2/3 HCV, compared with 75% with the CT and 58% with the TT genotypes.

However, Abdo et al. [30] found that patients carrying CC and CT genotypes achieved SVR equally (47%) in comparison with those with the TT genotype (56%) and Stδttermayer et al. [31] found that SVR rates were similar between those with CC and who carry the T allele.

This study showed that the C allele was significantly higher in responders (72.1%) than in nonresponders (35.7%) and relapsers (40.9%), whereas the T allele was higher in nonresponders (64.3%) and relapsers (59.1%) than in responders (27.9%). Similar results were detected by Asselah et al. [24] and Khairy et al. [22].

The exact biological pathways underlining the IL-28B gene SNP association with treatment response and viral clearance remain unknown. Host innate immune mechanisms including IFN-l, a direct product of the IL-28B gene, control viral infection [10]. Initial binding of IFN-l to its receptor is followed by several events that end with the induction of ISGs [32]. It is speculated that this mechanism suppresses viral infection. Moreover, IFN-l has been shown to block HCV replication in human hepatocytes in vitro [33].

It is well known that predictors of response serve as decision tools for physicians to help identify patients who are likely or unlikely to achieve SVR and thus reduce the risk of side effects and cost, and spare patients any disappointment from treatment [34].

In the present study, we found a statistically significant difference between SVR and non-SVR as regards age, BMI, fibrosis degree, and IL-28B genotypes. These factors are considered as predictive factors for SVR to PegIFN/RBV therapy on univariate analysis. However, in multivariable regression analysis, the current study showed that the fibrosis stage and IL-28B genotypes were independent predictors of SVR, whereas age and BMI were not significant.

Similar results were reported by De Nicola et al. [25] and Shehata et al. [35], who showed that fibrosis stage F0-2 and IL-28B genotype CC were significantly associated with SVR. In contrast, Mangia et al. [29] found in a multivariable regression analysis that the IL-28B genotype was the only independent predictor of SVR.

The current study showed no significant difference between IL-28B genotypes as regards pretreatment ALT and AST levels and viral load. Similar results were reported by Khairy et al. [22]. In disagreement with our study, Hendy et al. [21] detected significantly higher levels of ALT, AST, and viral load in the CC genotype, and Pablo et al. [36] reported that HIV/HCV-coinfected patients with the C allele at rs12979860 had significantly higher plasma HCV-RNA load compared with TT carriers.

In the present study, there was no statistically significant relationship between IL-28B genotypes and the degree of activity and stage of fibrosis. Similar results were reported by Asselah et al. [24] and Khairy et al. [22]. In contrast, Fabris et al. [19] and El-Awady et al. [23] reported that the TT genotype occurred more frequently in patients with end-stage liver disease.


  Conclusion Top


The IL-28B polymorphism is an independent predictor of SVR to PegIFN/RBV in Egyptian HCV patients with genotype 4. Besides increasing the chances of achieving SVR, determining IL-28B SNPs before initiating treatment will be cost-effective and will reduce adverse effects.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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