IL28B Rs12979860 Research Articles

Pegylated interferon and ribavirin gone but not forgotten in the era of direct-acting antivirals

BACKGROUND Therapy with pegylated interferon and ribavirin (PEG-IFN+RBV) for chronic hepatitis C (CHC) still remains the only option available for children in many Eurasian and European countries. Our aim was to evaluate the influence of host and viral factors on response to IFN-based therapy to optimize it for those in whom directly acting antivirals (DAA) are currently unavailable. METHODS Seventeen vertically infected, treatment naive children (10 male and 7 female) aged 5-16 years with CHC underwent a course of PEG-IFN+RBV. The end point was sustained virologic response (SVR). Host and virus factors were divided into pre- and ontreatment predictors of response to therapy. RESULTS Eleven patients obtained SVR (64%), 4 were nonresponders (23%), and 2 were relapsers (12%). Significant relationship was found between HCV RNA elimination and following variables: virus genotype and early virologic response (EVR) (p< .037, p< .029 respectively). Higher eradication rate was observed in patients infected with genotype 3 HCV (100% vs. 65% with genotype 1 or 4), and in those with undetectable HCV RNA by week 12 (88% vs. 66% with viremia). EVR was associated with SVR (83% vs. 0% in nonresponders; p< .004). C allele of IL28B rs12979860 was a predictor of EVR (p < .043). The SVR rates among CC, CT, and TT carriers were as follows: 75%, 67%, and 33%. CONCLUSIONS Detection of favourable HCV and IL28B genotype prior to commencement of PEG-IFN+RBV, and continuing it in patients with EVR is of major importance for those in whom DAA are still unavailable.

Interferon-γ inducible protein-10 and interleukin 28B gene polymorphism as predictive markers for genotype 4 hepatitis C virus treatment response.

HCV genotype 4 dominates the HCV epidemic in Egypt. Drug resistance was the most serious side effect that reflects bad clinical outcome. Several studies had demonstrated that baseline serum interferon-γ-inducible-protein 10 (IP-10) levels and interleukin 28B polymorphisms were associated with the resistance to the standard of care pegylated interferon alpha and ribavirin (PEG-IFNα/RBV) therapy and development of post-treatment relapse. Our purpose was to assess the predictive value of combining IP-10 levels and IL28B genotypes to PEG-IFNα/RBV therapy response in Egyptian chronic HCV infection patients with genotype 4. Ninety Egyptian patients chronically infected by HCV genotype-4 treated with pegylated interferon alpha and ribavirin (PEG-IFNα/RBV) therapy were enrolled. Serum IP-10 levels were determined by enzyme linked immunosorbent assay pre- and post- treatment. IL-28B (rs12979860 and rs8099917) polymorphisms were performed by PCR-RFLP in all patients. Overall, 38 patients (42.2%) achieved sustained virologic response (SVR) and 52 (57.8%) patients have non-viral response (NVR). Pretreatment serum IP-10 mean levels were significantly lower in patients who achieved SVR than in NVR (P<0.05). CC genotype in IL28B polymorphism (rs12979860) was the favorable genotype as 65.8% achieved SVR, while TT genotype in IL-28B polymorphism (rs8099917) was the favorable genotype as 81.5% achieved SVR. Baseline IP-10 was significantly correlated to genotypes CC in rs12979860 and TT in rs8099917. Combined use of serum baseline IP-10 levels with IL-28B polymorphisms could improve the prediction of SVR to PEG-IFNα/RBV therapy in Egyptian chronic HCV infection patients with genotype 4.

Host genetic factors associated with hepatitis C spontaneous viral clearance: A meta-analysis

Background: In the age of Direct Acting Antiviral (DAA) treatment where the cost of treatment is still very high, it may make sense to prioritise early treatment for individuals who are unlikely to achieve spontaneous clearance. Host genetic predictors might help us to select the right candidate, as several potential host genetic determinants have proven as the strongest indicators of clearance. Thus, genetic testing may help select individuals that would profit most from immediate treatment (high risk of progression and/or low risk of clearance), versus individuals who could be given a chance to see if spontaneous clearance occurs. The aim of this study is to synthesise available studies to provide a more precise estimate of the role of genetic factors in hepatitis spontaneous viral clearance (SVC). Methods and materials: We performed a systematic search that reported for studies reporting the association between host genetic factors and SVC in 3 major databases (Ovid Medline, Ovid Embase, and Pubmed) between 1st January 1994 and 30th June 2015. We calculated odds ratios comparing patients who had achieved SVC to individuals who had not for each genetic predictor and undertook meta-analysis to identify genetic factors that were associated with clearance. Results: 86 studies met the inclusion criteria, representing 38,605 individuals. We identified 146 genetic factors, 24 of which were strongly associated with clearance. After we tabulate the odds ratio for SVC against allele frequency in those who cleared spontaneously, the strongest host genetic predictors of clearance were IL28B rs8103142 (OR = 4.06, 95% CI: 2.64–6.25), IL28B rs12979860 (OR = 3.27, 95% CI: 2.68–3.98), and IL28B rs8099917 (OR = 2.83, 95% CI: 2.36–3.39). Conclusion: This study suggests that patients with unfavorable IL28B genotypes could be given priority for early treatment with direct acting antivirals, given their low likelihood of spontaneous clearance. IL28B typing might help to inform the decision to start therapy in patients with chronic genotype 1 HCV infection, particularly in the context of the limited availability of Direct Acting Antiviral (DAA) therapy in many places. However, the benefits of genotyping would need to be considered in the context of the falling costs of DAA's treatment.

A Tetra-Primer Amplification Refractory Mutation System–Polymerase Chain Reaction (T-ARMS-PCR) for Genotyping of rs8099917 &amp; rs12979860 IL28B Polymorphisms and Its Correlation of Various Variables in Iranian HCV Patients

Background: Selecting patients for new direct acting antiviral treatment of HCV has prompted a conflicting matter worldwide because of its high cost and limited availability. Genotyping of IL28B polymorphisms will aid clinical decision making for identifying priorities of urgent treatment in resource-limited countries.&#x0D; Objectives: The aim of the present study was to design a simple tetra-primer amplification refractory mutation system–polymerase chain reaction (T-ARMS-PCR) for genotyping of the rs8099917 and rs12979860 IL28B gene polymorphisms. Furthermore, we identify the correlation of variables such as gender, serum ALT level, histology of liver and baseline viral load with these polymorphisms.&#x0D; Patients and Methods: We efficiently designed a T-ARMS-PCR for detection of rs12979860 and rs8099917 IL28B gene polymorphisms. Using this method, we genotyped 148 hepatitis C patients. To ensure T-ARMS genotyping quality, we, regenotyped samples with the PCR- sequencing method.&#x0D; Results: Results of genotyping of rs12979860 and rs8099917 by T-ARMS PCR method were 100% concordant with the sequencing results. Among these 148 patients with chronic hepatitis C, the frequency of the rs12979860 CT, TT and CC genotypes was 72.3%, 14.2% and 13.5%, respectively and the frequency of the rs8099917 TT, GT and GG genotypes was 58.1%, 38.5% and 3.4%. Low frequency (2.7%) of association of two unfavourable homozygous genotypes (TT rs12979860 / GG rs809917) as well as 56.7% of association of 3 or 4 favorable alleles could explain good response of Iranians to HCV treatment with interferon-based regimens. About correlation of polymorphisms with different variables, only high viral load showed a statistically significant correlation to unfavorable genotype of TT rs12979860 ( p value = 0/05 ) and there was no correlation of serum ALT level, gender and histology of liver to IL28B genotypes.&#x0D; Conclusions: We report that rs8099917 polymorphisms could predict outcomes better than rs12979860 in Iranian HCV patients.

Impact of Interleukin 28B and ICAM-1 Genetic Polymorphisms on Response to Direct Antiviral Treatment Among HCV Infected Patients.

Single nucleotide polymorphisms (SNPs) of IL-28B and/or ICAM-1 could have a role in expecting a response from HCV infected patients to direct antiviral agents (DAAs). The aim of the current study was to investigate the impact of IL-28B rs12979860 and rs8099917, and, ICAM-1 rs281437 SNPs on response to treatment with sofosbuvir + Daclatsvir ± Ribavirin, among HCV-infected Egyptian patients. Whole blood genomic DNA was extracted from 120 participants (80 HCV-infected patients and 40 healthy volunteers). HCV-infected patients were subdivided into responders and nonresponders to DAAs. Liver function testing, anti-HCV antibodies, HCV-RNA viral load and HCV genotyping were performed. IL-28B and ICAM-1 SNPs were evaluated by real-time PCR. ALT and AST levels were significantly higher among non-responder HCV infected patients (P = 0.001*). 90% of the patients had HCV genotype 4a and the remaining 10% had 4l genotype. Allelic discrimination revealed that IL-28B rs12979860 T, IL-28B rs809917 T and ICAM-1 rs281437 C alleles were more frequent among HCV-infected patients (responders or non-responders) than controls. However, IL-28B rs8099917 G allele was more frequent among healthy controls. Regarding the response to DAAs treatment, HCV-infected patients with IL-28B rs8099917 GG genotype showed a significantly earlier viral response compared to those carrying TT alleles. ICAM-1 rs281437 CT alleles were non significantly more frequent among responders. However, IL-28B rs12979860 alleles did not show any difference. Genotyping of IL-28B rs8099917 is a useful independent tool for expecting a response of Egyptian HCV-infected patients to DAAs.

Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population: An observational study.

Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case–control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-β (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69–11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08–10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49–10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25–1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25–1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01–13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14–82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00–18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.

Association Between IL28B, IL29 Gene Polymorphisms and Clinical Manifestations of Behçet’s Disease

ABSTRACT Background Behçet’s disease (BD) is a chronic, multisystemic, inflammatory disease characterized by relapsing episodes of a wide spectrum of clinical findings. The role and mechanism of IFN-λs in BD remain unknown. The aim of this study was to investigate the relationship between IL29 and IL28B gene polymorphisms and BD or clinical manifestations. Methods Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, single-nucleotide polymorphisms of IL28B rs8099917 (IL28 G/T), rs12979860 (IL28 C/T) and IL29 rs30461 (IL29 T/C) were studied in 94 patients with BD and 90 healthy controls. Results Our study did not show any relationship between Behçet Disease and genotype or allele frequencies of IL28B (rs8099917, rs12979860) and IL29 (rs30461) gene polymorphisms (p > .05). We found that the TT genotype of rs12979860 (IL28 C/T) polymorphism is higher in healthy controls and patients without central nervous system (CNS) involvement compared to patients with CNS involvement (p = .014 and p = .022). Conclusions As a result, although the relationship was found between IL28 and IL29 gene polymorphisms with some clinical manifestations of BD, it was not directly related to the predisposition of the disease. The relationship between IL-28 and IL-29 which act as regulators in inflammatory processes, with Behçet disease, needs to be investigated in further studies.

The Study of IFNL3 Gene Rs12979860 Polymorphism in the Hepatitis C Virus Patients and Healthy Population in Tehran Province, Iran

Background: Hepatitis C virus (HCV) infection can lead to a number of disorders and subsequent failures, including chronic liver disease and cancer. Genotype rs12979860 CC is an interleukin 28B gene polymorphism associated with an adequate response to treatment in HCV patients. However, its response quality varies in different races and populations. Objectives: The present study aimed to investigate this polymorphism in the Iranian population. Methods: In this study, 120 volunteers were evaluated as patient subjects and 120 volunteers as the control subject group. The collected serum samples were examined by the PCR-RFLP technique and the frequency of polymorphism at rs12979860 was tested in both groups. Results: The findings of this study showed that the risk of HCV infection in the subjects with CC genotype of IL-28B gene was less than (OR = 2.000, P = 0.009) that of subjects with other genotypes of rs12979860 polymorphism, including CT and TT. The frequency of genotypic variations of rs12979860 gene in patients were as CC = 33.3%, CT = 43.3%, TT = 23.3%, and in healthy subjects accorded with CC = 50%, CT = 32%, TT = 17%. A significant difference was also observed between the two healthy and HCV suffering groups in terms of gender (P < 0.02). Conclusions: In HCV patients, the frequency of CC variation in IL-28B rs12979860 gene leads to a more effective response to treatment than other genotypes in HCV patients. Also, the frequency of CC in healthy people was higher than patients.

Association between single nucleotide polymorphisms (SNPs) of IL1, IL12, IL28 and TLR4 and symptoms of congenital cytomegalovirus infection

Congenital cytomegalovirus (cCMV) infection is the most common intrauterine infection. A non-specific immune response is the first line of host defense mechanism against human cytomegalovirus (HCMV). There is limited data on associations between Single Nucleotide Polymorphisms (SNPs) in genes involving innate immunity and the risk and clinical manifestation of cCMV infection. The aim of the study was to investigate association between selected SNPs in genes encoding cytokines and cytokine receptors, and predisposition to cCMV infection including symptomatic course of disease and symptoms. A panel of eight SNPs: IL1B rs16944, IL12B rs3212227, IL28B rs12979860, CCL2 rs1024611, DC-SIGN rs735240, TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140 was analyzed in 233 infants (92 cCMV-infected and 141 healthy controls). Associations between genotyped SNPs and predisposition to cCMV infection and symptoms were analyzed. The association analysis was performed using SNPStats software. No statistically significant association was found between any genotyped SNPs and predisposition to cCMV infection and symptomatic course of disease. In relation to particular symptoms, polymorphism of IL12B rs3212227 was linked to decreased risk of prematurity (OR = 0.37;95%CI,0.14-0.98;p = 0.025), while polymorphism of IL1B rs16944 was linked to reduced risk of splenomegaly (OR = 0.36;95%CI,0.14-0.98; p = 0.034) in infants with cCMV infection. An increased risk of thrombocytopenia was associated with IL28B rs12979860 polymorphism (OR = 2.55;95%CI,1.03-6.32;p = 0.042), while hepatitis was associated with SNP of TLR4rs4986791 (OR = 7.80;95%CI,1.49-40,81; p = 0.024). This is the first study to demonstrate four new associations between SNPs in selected genes (IL1B, IL12B, IL28B, TLR4) and particular symptoms in cCMV disease. Further studies on the role of SNPs in the pathogenesis of cCMV infection and incorporation of selected SNPs in the clinical practice might be considered in the future.

Association of Interleukin 28B Polymorphism with Clearance of Hepatitis C Virus: A Mini Review.

The highly infectious hepatitis C virus (HCV) is the major cause of chronic hepatitis around the globe. Approximately 3% of the world's population has been affected by both chronic and acute HCV. In this study, we highlight the relationship between single-nucleotide proteins (SNPs) and interleukin (IL) IL28B on chromosome 19 with the treatment response of chronic HCV infection along with its sustained virologic response (SVR). Four SNPs are strongly linked with HCV self-clearance: rs8099917 TT, rs12980275 AA, rs8105790 TT, and rs10853728 CC. Most SNPs, including rs12979860, are located upstream of the IL28B gene fragment, encoding interferon (IFN)-λ3. We find that IL28B variants rs8099917 and rs12979860 strongly influence results of combined pegylated (PEG)-IFN/ribavirin (RBV) therapy. In the case of SNP rs12979860, the CC genotype is linked with greater than a twofold higher SVR than that with TT or CT genotypes. These SNPs are associated with expression of intrahepatic IFN-stimulated genes in liver. Past research shows that females are more efficient in resolving HCV infection, regardless of IL28B genotype. Similar results of IL28B polymorphisms associated with spontaneous HCV clearance were also obtained in Chinese and Taiwanese HCV patients. Another report of RBV and PEG-IFN-treated patients revealed that age, viral load, rs8099917 genotype, and fibrosis were major predictors of antiviral therapeutic response. To select favorable antiviral regimes for treatment using IFN, a combination of host genetic data and viral genotyping may be useful in treating chronic HCV. We propose that these predictive factors must be considered before commencing treatment in HCV patients.

Interleukin 28 Polymorphisms and Hepatocellular Carcinoma Development after Direct Acting Antiviral Therapy for Chronic Hepatitis C.

Cirrhotic patients with hepatitis C virus (HCV) infection remain at risk of developing hepatocellular carcinoma (HCC) even after the sustained virologic response (SVR). We aimed to evaluate whether the IL28 (rs12979860) single nucleotide polymorphism (SNP) may constitute a predisposing genetic factor and to identify the SVR patients at risk of HCC. Two hundred patients undergoing DAAs treatment for chronic hepatitis C with advanced fibrosis (F3- F4) were consecutively enrolled. Besides normal routine laboratory testing for HCV, patients' sera were evaluated also for retinol, retinol-binding protein 4 and the following SNPs: PNPLA3 (rs738409), TM6SF2 (rs58542926), MBOAT7 (rs641738), IL28B (rs12979860), TIMP-1 (rs4898), TIMP-2 (rs8179090), NF-kB promoter (rs28362491). Statistical analyses were conducted using Stata/SE 14.2 statistical software (Stata Corp, College Station, TX). Almost all patients (197/200) obtained SVR24. Seventeen patients had a previous history of treated HCC before DAAs. Six patients developed HCC recurrence and five patients developed de novo HCC after a mean period of 18 months since EOT. All these patients had SVR. A significant association between IL28B - TT genotype and HCC development after DAAs therapy was observed (OR 4.728, CI 95% 1.222 - 18.297, p=0.024). IL28B rs12979860 polymorphism was significantly associated with HCC development after DAAs. Assessment of this SNP may better identify patients at risk of developing HCC after treatment. Further prospective studies are required to confirm these hypotheses.

PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression

Background Association studies identified genetic polymorphisms as predictive risk factors of rapid fibrosis progression in chronic hepatitis C (CHC). This study aims to assess the impact of IL28B rs8099917 polymorphism on CHC genotype 4 (G4) susceptibility and liver fibrosis progression individually; and in combination with PNPLA3 rs738409. Patients and methods IL28B rs8099917 and PNPLA3 rs738409 were genotyped in 150 Egyptian CHC patients and 175 healthy controls using real-time PCR. Results IL28B rs8099917 genotype distribution significantly differs in healthy individuals versus CHC patients (p = .018); and in low versus advanced fibrosis IL28B (p = .013). The haplotype CC –GG (PNPLA3-IL28B) is considered a high-risk signature for susceptibility to CHC infection. Similarly, GG–GG (PNPLA3-IL28B) is considered a high-risk signature for higher degree of fibrosis. Conclusion IL28B rs8099917 and PNPLA3 rs738409 introduce genetic signature to identify patients at higher risk for CHC susceptibility and fibrosis progression in CHC G4.

The Synergistic Effect of Fluvastatin and IFN-λ on Peripheral Blood Mononuclear Cells of Chronic Hepatitis C Virus (HCV) Patients with IL-28B rs12979860 CC Genotype.

There is a relationship between the life cycle of the hepatitis C virus (HCV) and the synthesis and hemostasis of lipids as well as lipid metabolism and interferon (IFN) regulatory system. This study was aimed to examine the effect of fluvastatin and IFN-ƛ in the expression of mediators involved in lipid metabolism and HCV proliferation in patients with rs12979860 CC polymorphism. Thirteen patients with HCV and five controls with rs1297986CC polymorphism were included in this study. Peripheral blood mononuclear cells (PBMCs) of patients and controls were treated by fluvastatin, IFN-λ or fluvastatin+IFN-λ. Assessment of IL-28B polymorphism, RNA extraction, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed. The mRNA expression of sterol regulatory element-binding protein 1 c (SREBP1c), ATP-binding cassette transporter A1 (ABCA1), diacylglycerol acyltransferase 1 (DGAT1), and HCV core as well as measurement of ABCA1 protein level were evaluated before and after treatment. The results indicated that IFN-λ +fluvastatin acted as an inhibitor in mRNA expression of SREBP1c; while acting as an inducer in the expression of ABCA-1. The results of ABCA1 assay showed a significant increase of this protein after treatment with fluvastatin and IFN-λ compared with untreated cells (p=0.02). Moreover, the mRNA expression of HCV core was suppressed in all experimental groups treated with fluvastatin, IFN-λ or their combination which was more significant after treatment with fluvastatin+IFN-λ (p<0.001). The results of this study demonstrated the significant effect of treatment with fluvastatin+IFN-λ in PBMCs of HCV patients with rs12979860 CC polymorphism. According to the drug resistance of viruses and prevention of virus-induced steatosis in patients with HCV, using regulatory agents of lipid mediators in parallel with current medications could be considered as an effective therapeutic strategy.

Interleukin 28B Polymorphism as a Predictor of Response to Treatment of Egyptian HCV Patients Working in Nuclear Material Authority

Background: A Single nucleotide polymorphism upstream of the interferon-λ3 gene (IFNL3; formerly referred to IL28B), strongly linked to unprompted and treatment-induced HCV infection clearance. Interleukin 28B genotype predictive value over the outcome interferon-α/ribavirin treatment was assessed carefully and contrasted with virological predictors Objective: The study aimed to evaluate IL-28B rs12979860 polymorphism in the reaction of HCV patients with directacting antiviral (DAA) regimens (sovosbuvir) and ribavirin therapy and the allele frequencies of this gene in Egyptian HCV patients working in the Egyptian Nuclear Materials Authority contrasted to healthy control. Subjects and Methods: The study was conducted on randomly chosen fifty Egyptian patients infected with genotype 4 HCV aged 30 or more and received antiviral therapy (sovosbuvir and ribavirin) before six months or more. Another Fifty age and gender matched apparantely healthy individuals were also selected as a control group. The study was carried out in accordance with the ethical principles and guidelines of the Declaration of Helsinki and a written informed consent was obtained from all subjects. Results:IL-28B genotype CC was found in 34.6% of patients, while CT and TT genotypes were identified in 42.3 and 23.1% of patients, respectively. Forty (40%) patients achieved an SVR, whereas ten (20%) did not. Of the 40 patients with an SVR, 12 had genotype CC, 25 had genotype CT, and 3 had genotype TT. CT genotype patients has achieved considerably higher SVR rates (62.5%) compared with CC (30%) and TT patients (7.5%). Conclusion: Polymorphism Il-28B is an autonomous predictor of SVR to Peg IFN / RBV in patients with genotype 4 in Egyptian HCV favorable.

Interleukin 28B Polymorphism as a Predictor of Response to Treatment of Egyptian HCV Patients Working in Nuclear Material Authority

Background: A Single nucleotide polymorphism upstream of the interferon-λ3 gene (IFNL3; formerly referred to IL28B), strongly linked to unprompted and treatment-induced HCV infection clearance. Interleukin 28B genotype predictive value over the outcome interferon-α/ribavirin treatment was assessed carefully and contrasted with virological predictors Objective: The study aimed to evaluate IL-28B rs12979860 polymorphism in the reaction of HCV patients with directacting antiviral (DAA) regimens (sovosbuvir) and ribavirin therapy and the allele frequencies of this gene in Egyptian HCV patients working in the Egyptian Nuclear Materials Authority contrasted to healthy control. Subjects and Methods: The study was conducted on randomly chosen fifty Egyptian patients infected with genotype 4 HCV aged 30 or more and received antiviral therapy (sovosbuvir and ribavirin) before six months or more. Another Fifty age and gender matched apparantely healthy individuals were also selected as a control group. The study was carried out in accordance with the ethical principles and guidelines of the Declaration of Helsinki and a written informed consent was obtained from all subjects. Results:IL-28B genotype CC was found in 34.6% of patients, while CT and TT genotypes were identified in 42.3 and 23.1% of patients, respectively. Forty (40%) patients achieved an SVR, whereas ten (20%) did not. Of the 40 patients with an SVR, 12 had genotype CC, 25 had genotype CT, and 3 had genotype TT. CT genotype patients has achieved considerably higher SVR rates (62.5%) compared with CC (30%) and TT patients (7.5%). Conclusion: Polymorphism Il-28B is an autonomous predictor of SVR to Peg IFN / RBV in patients with genotype 4 in Egyptian HCV favorable.

Immunomodulation of CXCL10 Secretion by Hepatitis C Virus: Could CXCL10 Be a Prognostic Marker of Chronic Hepatitis C?

Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and “chronic hepatitis C virus (HCV) infection” (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.

IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment.

Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment. A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥140mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics. A total of 63, 3, and 55 patients were administered daclatasvir+asunaprevir, ombitasvir+paritaprevir+ritonavir, and ledipasvir+sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3±27.0 and 9.6±27.3mg/dL; P<0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P<0.001). An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.

IL28B rs12979860 T allele protects against CMV disease in liver transplant recipients in the post-prophylaxis and late period.

Cytomegalovirus (CMV) disease represents a serious complication in liver transplant (OLT) recipients. CMV prophylaxis reduces incidence of CMV disease in the early post-transplant period (on-prophylaxis disease, OPD) but may postpone its manifestation after the completion of prophylaxis. Post-prophylaxis disease (PPD) incidence after prophylaxis cessation may be modified by genetic factors. We analyzed impact of IL28B rs1297986 variants on CMV disease incidence in 743 adult OLT recipients receiving universal prophylaxis. One hundred and forty-four (19.4%) patients had at least one CMV disease episode. One hundred and two of them (70.8%) had at least one OPD and 36 (25%) patients had PPD, six (4.2%) patients had both. The rate of IL28B T allele carriers was lower in PPD group (38.9%) in comparison with OPD group (66.7%, P=0.005) and group without CMV disease (61.4%, P=0.009). The impact of IL28B genotype on the risk of CMV OPD was significant neither in the allelic (TT+CT vs CC, P=0.32) nor in the recessive model (TT vs CT+CC, P=0.79). Contrarily, in the PPD group, T allele (TT+CT vs CC) had a protective effect, OR 0.4 (95% CI 0.2-0.8, P=0.008). Further risk factors of PPD were age <55years and valganciclovir prophylaxis, whereas the risk factors of OPD were age <55years, cyclosporine A therapy and pre-transplant CMV serostatus (donor +/recipient -). IL28B rs12979860 T allele carriers had a lower risk of CMV PPD.

PS1469 IL28B GENE POLYMORPHISMS INFLUENCE ON THE RESPONSIVENESS AND TOLERABILITY OF IFN‐Α IN PATIENTS WITH MPN

Background:Interferon‐α (IFN‐α) provides several benefits to myeloproliferative neoplasms (MPNs) patients and leads 35% of its experienced a good molecular response. Both newly diagnosed and previously treated patients with polycythemia vera (PV) exhibit high hematologic response rates, and some of these patients achieve molecular responses [Kiladjian J‐J., et al., 2016]. Nevertheless, IFN‐α therapy is often accompanied by serious side effects, which forces some patients to refuse treatment. Only one scientific team [Lindgren M., et al., 2012, 2018] previously published data demonstrating the effect of IL28B gene polymorphisms on the success of interferon therapy in MPNs.Aims:Evaluate the prognostic impact of IL28B rs12979860 and rs8099917 on IFN‐α treatment response and toxicity in patients with MPNs.Methods:35 patients were investigated: 18 with polycythemia vera, 12 with essential thrombocythemia and 5 with primary myelofibrosis. All patients were treated with IFN‐α (three times weekly). DNA from whole blood samples was isolated using «DNAsorb‐B» (Central Research Institute for Epidemiology, Russia). The rs12979860 and rs8099917 SNPs genotyping was determined by pyrosequencing on a PyroMark Q24 instrument. Allele burden JAK2 V617F was determined using «Myeloscreen JAK2» («Formula of gene Ltd», Russia). Hematologic response was evaluated using the European Leukemia Net criteria. The quantitative values are given as a median and 25% and 75% percentiles.Results:The JAK2 V617F allele burden after 60 months of IFN‐α therapy was significantly reduced in samples of patients with polycythemia vera in the presence of a “strong” TT/CC variant of the haplotype IL28B (13; 8.4–24.4) compared with other variants of polymorphism of these gene (57; 44,3–67,0). The average duration of therapy to failure due to side effects of IFN‐α was also 2–3 times shorter (p &lt; 0.05) in patients with a TT/CC haplotype. The therapeutic impact of IFN‐α in patients with MPN involve IL28B signaling pathways. This is the second independent confirmation of the data by Lindgren et al.Summary/Conclusion:Genotype evaluation of IL28B can be useful for predicting the effectiveness of interferon therapy in MPNs.image

IL-28B genotypes as predictors of long-term outcome in patients with hepatitis C-related severe liver injury.

Patients with severe fibrosis or cirrhosis are at high risk for liver-related complications, even after successful antiviral treatment and/or regression of fibrosis. These are the first published results concerning the role of IL-28B genotypes as predictors of the durability of sustained virological response (SVR) and long-term outcome, in patients with baseline severe fibrosis and cirrhosis caused by hepatitis C (HCV) infection. Genetic testing for three different single nucleotide polymorphisms (SNP) near the IL28B gene, rs12979860, rs12980275 and rs8099917, was performed in 42 patients with HCV-related advanced fibrosis and cirrhosis, who achieved SVR after successful interferon-based treatment. Baseline clinical and laboratory parameters were analysed, as well as IL28B genotype association with late virological relapse, fibrosis progression and clinical outcomes. The most prevalent genotypes in all three tested SNP positions were: CCrs12979860 genotype in 69% of patients, GTrs8099917 in 78.6% and GGrs12980275 in 47.6% of patients. The presence of IL28B CCrs12979860 genotype was identified as a negative predictor of late virological relapse. Further analysis did not confirm the association of other IL28B genotypes with the progression of fibrosis and clinical outcomes. Varying long-term prognosis in patients with HCV-related severe fibrosis and cirrhosis is due to multiple interactions between host genetic factors, virus and environment. These are first published results demonstrating the significance of IL28B CCrs12979860 genotype as a negative predictor of late virological relapse. A further investigation concerning genetic factors is necessary to identify patients under risk for late relapse, complications and unfavorable outcomes, so that they can be reevaluated and offered new treatment options.