interleukin-28B Genotype Research Articles

Impact of IL-28B gene polymorphism on chronic hepatitis-C patients progression with diabetes and non-diabetes

BackgroundChronic hepatitis C (CHC) is a silent viral infection; however, elevated mortality and morbidity rates are noted in Egypt due to its adverse effects. The augmented incidence of diabetes in patients with viral C infection may be owing to glucose intolerance, high BMI, senility, and inherited factors.Purpose of the studyLittle information is available about the connection between interleukin-28B (IL-28B) genotype in disease progression among CHC patients with diabetes. Thus, we aimed to assess the association between IL-28B genotype (rs12979860) in CHC with type 2 diabetes mellitus (T2DM) versus those without diabetes in disease progression among Egyptian patients.ResultsCC genotype was significantly lower in diabetics than in non-diabetics (13.7% vs. 36.3%). While (CT/TT) were significantly higher in diabetics than in non-diabetics (CT 58.8% vs. 43.7%), (TT 27.5% vs. 20%) (p = 0.03) and likewise alleles (p = 0.04). Multivariate logistic regression analysis was significant with viral load p < 0.001, alanine aminotransferase (ALT) p < 0.001, genotype CC versus TT p = 0.04 & T2DM p = 0.03.ConclusionCC genotype might be used as a protective factor and TT genotype as a risk factor in disease progression among CHC patients with T2DM. Additionally, viral load, ALT & T2DM might interplay as predictors of disease severity. Detecting the genetic factors can be helpful in predicting and preventing the complications of diabetes associated with the hepatitis C virus (HCV).

Сatamnestic data on the effect of interferon therapy on the course of combined HIV/HCV-infection

Aim: catamnestic analysis of the effectiveness of antiviral therapy for chronic hepatitis C in combination with HIV infection.Materials and methods. A retrospective study included 145 patients with combined HCV/HIV infection for 8±0,43 years.Results. 55% of patients received antiviral therapy for chronic hepatitis with pegylated interferons and ribavirin. The frequency of achieving a stable virological response is 73%. Persistent virological response with favorable Il-28B genotypes was detected in 85% of cases, with unfavorable genotypes less frequently — in 63% (p=0,028); the relapse rate is 27%. The level of HIV RNA viral load and the frequency of patients with secondary diseases was higher in patients with natural HCV/HIV infection with favorable interleukin-28B genotypes compared to other comparison groups (р&lt;0,05).Conclusion. The course of chronic hepatitis C after therapy was more positive with favorable Il-28B genotypes. HIV infection was more severe in the absence of antiviral therapy for chronic hepatitis C.

Association between interleukin 28B polymorphism and sustained virological response to sofosbuvir plus daclatasvir in chronic hepatitis C genotype 4 Egyptian patients

Sofosbuvir has been approved as the first nonstructural protein 5Bpolymerase inhibitor with pan-genotypic activity against the hepatitis C (HCV) virus. Daclatasvir is a first-in-class hepatitis C virus nonstructural protein 5A replication complex inhibitor. We aimed to evaluate the usefulness of the reference single nucleotide polymorphism (rs12979860) interleukin 28B (CC genotype) for predicting sustained virological response to sofosbuvir plus daclatasvir in Egyptian patients infected with HCV-4. Samples were collected at week zero. One hundred and thirty-one patients who reached the end of treatment (at week 12) were divided into three groups, according to their interleukin 28B genotype: Group A included 31 patients (CC genotype), group B included 79 patients (CT genotype) and group C had 21 patients (TT genotype). All patients received treatment for 3months in the form of sofosbuvir plus daclatasvir with ribavirin (in case of cirrhotic patients) or without ribavirin (in case of non-cirrhotic patients). Sustained virological response rate was significantly higher in patients with IL28B (CC genotype) vs. (non-CC genotype) (100 vs.88%) (p<0.0001).These patients also showed lower rates of post-treatment relapse and non-response, compared with the CT and TT patients (0% vs. (7.59% and 28.5%, respectively) (p<0.0001). Also, patients with CC genotype showed higher sustained virological response than non-CC genotypes on both cirrhotic (100% vs. 68.75%) and non-cirrhotic patients (100% vs. 91.66%) (p≤0.0001). Our results suggest that IL28B genotype contributes to the prediction of response to sofosbuvir plus daclatasvir.

PNPLA3 polymorphisms are associated with raised alanine aminotransferase levels in hepatitis C virus genotype 3

Background and study aimsHepatitis C virus (HCV) infection is one of the leading causes of end-stage liver diseases. This study aimed to determine the association between polymorphisms in interleukin 28B (IL28B), PNPLA3, toll-like receptor 7 (TLR7), nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and retinoic inducible gene-I (RIG-I) and HCV genotype and clinical presentation in an Indian population. Patients and methodsA total of 500 patients with chronic HCV were enrolled in 19 centres across India. Genomic DNA was extracted from whole blood samples, and single nucleotide polymorphisms (SNPs) for IL28B, PNPLA3, TLR7, NOD2 and RIG-I genes were genotyped by real-time PCR using a TaqManSNP genotyping assay. ResultsThe mean age of the patients was 45 + 13 years, and the most common genotype observed was HCV genotype 3 (54%), followed by genotype 1 (24%). Although the allelic frequencies of TLR7, NOD2 and RIG-I were in significant disequilibrium in HCV patients compared with those in controls, the PNPLA3 polymorphism correlated significantly with higher viral load and alanine aminotransferase (ALT) levels in genotype 3 patients. Patients with PNPLA3 CG/GG genotypes, along with IL28B genotype CC, had higher levels of ALT than those with other genotypes. ConclusionThese results indicate that PNPLA3 polymorphisms are associated with higher ALT levels in HCV genotype 3 patients in India and can help in identifying people who are at greater risk of developing HCV-associated liver diseases.

IL-28B variant as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy.

Single-nucleotide polymorphisms (SNPs) of the interleukin-28B (IL-28B) gene are associated with the effectiveness of interferon therapy for chronic hepatitis C infection. Whether the IL-28B genotype affects the course of treatment and the outcomes of patients with advanced hepatocellular carcinoma (HCC) is unknown. We detected the IL-28B SNP (rs8099917) using TaqMan PreDesigned SNP Genotyping Assays to assess the effects of the IL-28B genotype on treatment efficacy and prognosis of patients with advanced HCC treated with hepatic arterial infusion chemotherapy (HAIC) between September 2003 and January 2015. The study included 154 patients who received HAIC to treat advanced HCC, among which 27 (17.5%) had the minor genotype, IL-28B rs8099917 TG or GG, and the others had the major genotype, IL-28B rs8099917 TT. The objective response rates of patients with the minor or major genotype were 51.9% and 29.1% (P=0.022), respectively. Multivariate analysis revealed that the minor genotype remained associated with the response to HAIC (odds ratio, 2.620; P=0.026). The median overall survival of patients with major or minor genotypes was 14.1 and 16.9months, respectively, and the overall survival of patients with the major genotype was significantly shorter than that of patients with the minor genotype (P=0.027). Multivariate analysis revealed that the major genotype was an independent, unfavorable prognostic factor (hazard ratio, 1.720; P=0.024). Consistent results were obtained in selected populations after propensity score matching analysis. The IL-28B SNP (rs8099917) will serve as a useful predictor of the outcomes of patients with advanced HCC treated with HAIC.

Correlation between female sex, IL28B genotype, and the clinical severity of bronchiolitis in pediatric patients.

BackgroundSingle-nucleotide polymorphisms (SNPs) that impact on the differential expression of interleukin 28B (IL28B) are implicated in the progression of viral-induced diseases. In this prospective longitudinal cohort study, we evaluated the association between IL28B SNPs rs12979860 and rs8099917 and the clinical outcome of bronchiolitis in pediatric patients.MethodsA total of 682 infants suffering from bronchiolitis, categorized based on the final clinical outcome as mild or severe, were genotyped for IL28B SNPs rs12979860 and rs8099917.ResultsWhen infants were categorized exclusively based on the final clinical outcome, no association was established between IL28B SNPs and the severity of bronchiolitis. However, when stratified by sex, the homozygotes for the minor alleles of rs12979860 (T) and rs8099917 (G) were associated with a mild disease in girls but not in boys.ConclusionSNPs rs12979860 and rs8099917 correlate with the severity of bronchiolitis and display a sex bias, where GG rs8099917 and TT rs12979860 genotypes are associated with a mild disease in girls but not in boys. These findings suggest that innate immunity and female sex links with the outcome of the diseases induced by respiratory viruses, such as RSV.

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.

Detection of residual HCV-RNA in patients who have achieved sustained virological response is associated with persistent histological abnormality

BackgroundWhether achieving sustained virological response (SVR) in patients with hepatitis C attains complete elimination of hepatitis C virus (HCV) is unknown, because occult HCV infection (OCI), defined as the detection of HCV-RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum HCV-RNA, may occur. We thus investigated the prevalence and clinical relevance of OCI. MethodsSubjects from three hospitals who had achieved serum HCV clearance, including 60 of Direct-acting antiviral agents (DAAs) induced SVR, 50 of pegylated interferon plus ribavirin (PR) induced SVR, and 30 of spontaneous resolution, were subjected to detect HCV-RNA in liver by robust RNAscope assay and PBMC by qPCR. Paired liver biopsies at baseline and at SVR24 were analyzed. ResultsOCI was detected in 16 of 140 subjects (11.4%), with 15.0% in DAA-based group, 10.0% in PR group and 6.7% in spontaneously resolved group. In DAA-based subgroups, the incidence of OCI was gradually increased in group of solely DAA(s) therapy, combining DAA and PR therapy and combining DAA and ribavirin therapy. OCI is more frequent in patients with genotype 3. No correlation between baseline viral load, interleukin-28B genotype, baseline transaminases, post-SVR transaminases and OCI were found. However, OCI was significantly linked with severity of fibrosis and active inflammation at post-SVR, even considering basal fibrosis status. In addition, both the magnitude and the frequency of fibrosis regression were lower in patients with OCI than in those without OCI. In the multivariate analysis, PR therapy was identified an independent negative prognostic factor for both hepatic inflammation (P = .022) and fibrosis regression (P = .015). Importantly, we found HCV relapse in one of the OCI patients at 48 weeks after the end of PR treatment. ConclusionsHCV-RNA can persist in hepatocytes and/or PBMC in a certain of patients who achieved spontaneous or treatment-induced HCV RNA clearance from serum and associated with persistent histological abnormality. Our findings provide new insights into cure of HCV and could influence the following-up scenario after SVR.

Comparative Study of Interleukin 28B Gene in Genotype 3 Chronic Hepatitis C Patients Before and After Treated With Interferon/Pegylated in Sindh

Chronic hepatitis C (HCV) caused by hepatitis C (HCV) virus, approximately estimated 170-200 million individuals in the world including Pakistan having 10 million HCV infected . The effective available treatment option is a combination of Pegylated interferon (PegIFN) and Ribavirin (RBV) . Recently Genome wide association studies (GAWAS)supporting two single nucleotide polymorphism SNPs adjacent interleukin 28B gene associated with spontaneous and treatment induced clearance of HCV patients. The aim of the present study was to analysis the impact of response associated interleukin 28B(IL28B) single nucleotide polymorphism (SNPs) rs12979860, rs8099917 in different treatment interval with one month (RVR) and after end of treatment (SVR) with Pegylated Interferon(PEG IFN) and Ribavirin in Hepatitis C genotype 3 patients. The present study enrolled 200 HCV RNA positive genotype 3 patients having both SNPs (rs12979860, rs8099917) were analyzed by Real Time Polymerase Chain Reaction (RT-PCR). The frequency distribution of IL28B genotypes were investigated by SNIPs (rs12979860 and rs8099917) in HCV RNA positive genotype 3 patients in Pakistani population

Elevated serum levels of adiponectin and interlukin-28B after IFN/RIB therapy in hepatitis C virus-infected patients.

The interleukin 28B (IL28B) genotype is associated with changes of lipid metabolism in patients infected with hepatitis C virus (HCV). The association of steatosis with serum levels of adiponectin in chronic hepatitis C (CHC) patients has also been documented. This study aimed for the evaluation of serum levels of IL28B and adiponectin as well as the association of IL28B SNPs with different clinicopathological parameters in HCV-infected patients. All 142 HCV-infected patients received peg-interferon plus ribavirin. Detection of rs8099917 and rs12979860 IL-28B genotypes was done with specific primers. Serum IL28 and adiponectin levels were measured using commercial ELISA kits. Higher levels of both IL28 and adiponectin were found in patients. In Genotype 3a (G3a) -infected patients, IL28 and adiponectin serum levels were significantly higher than those infected with G1a. A correlation was found between increasing levels of AST and ALT in G3a-infected patients and the decrease in IL28 and adiponectin serum levels, respectively, in contrast to G1a-infected patients. Higher levels of both IL28 and adiponectin were associated with both CT allele of rs12979860 and TT allele of rs8099917 in patients in comparison with corresponding alleles in controls. In contrast to other studies, this study showed higher serum adiponectin levels in HCV-infected patients compared to that in healthy controls. This finding is possibly due to adiponectin resistance caused by down-regulation of adiponectin receptors or tumorigenic effects of adiponectin. Our genotype-based analyses revealed, at least in part, the involvement of the viral factors in the outcome of HCV infection.

IL-28B genetic variation, gender, age, jaundice, hepatitis C virus genotype, and hepatitis B virus and HIV co-infection in spontaneous clearance of hepatitis C virus.

Spontaneous viral clearance observed in some patients is one of the variants of the hepatitis C virus (HCV) infection natural history. We aimed to look at the complexity of factors affecting the spontaneous clearance of HCV (SC HCV). A total of 357 anti-HCV positive patients (309 with chronic hepatitis C and 48 patients with SC HCV) were included into the study. We studied the effects of the interleukin-28B (IL-28B) gene polymorphism, gender, age, the routes of virus transmission, past hepatitis C with jaundice, HCV genotype, and hepatitis B virus (HBV) and HIV co-infection on the outcome of HCV infection. Based on the study results, the SC HCV was found in 48 individuals (13.4%). The most significant positive factors affecting the SC HCV included IL-28B single nucleotide polymorphism (SNP) rs12979860 (CC) and SNP rs8099917 (TT) (OR 4.03, p<0.001) and (OR 3.14, p<0.002), female gender (OR 2.72, p<0.001), young age (OR 2.30, p<0.008), and past history of jaundice (OR 5.12, p<0.001). The markers of a past HBV infection were found significantly more often in SC. Positive predictors of the SC HCV include favorable IL-28B genotype, female gender, young age, a history of jaundice, markers of a past HBV infection, the absence of HIV infection, but not the viral genotype.

Detection of Residual HCV RNA in Patients Who Have Achieved Sustained Virological Response Is Associated with Persistent Histological Abnormality

Background: Whether achieving sustained virological response (SVR) in patients with hepatitis C attains complete elimination of hepatitis C virus (HCV) is unknown, because occult HCV infection (OCI), defined as the detection of HCV-RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum HCV-RNA, may occur. We thus investigated the prevalence and clinical relevance of OCI. Methods: Subjects from three hospitals who had achieved serum HCV clearance, including 60 of Direct-acting antiviral agents (DAAs) induced SVR, 50 of pegylated interferon plus ribavirin (PR) induced SVR, and 30 of spontaneous recovery, were subjected to detect HCV-RNA in hepatocytes and PBMC. Paired liver biopsies at baseline and post-SVR were analyzed. Results: OCI was detected in 16 of 140 subjects (11.4%), with 15.0% in DAA-based group, 10.0% in PR group and 6.7% in spontaneously resolved group. OCI is more frequent in patients with genotype 3. No correlation between baseline viral load, interleukin-28B genotype, baseline transaminases, post-SVR transaminases and OCI were found. However, OCI was significantly linked with severity of fibrosis at post-SVR, even considering basal fibrosis status. In addition, both the magnitude and the frequency of fibrosis regression were lower in patients with OCI than in those without OCI. In the multivariate analysis, PR therapy was identified an independent negative prognostic factor for both hepatic inflammation (P = 0.022) and fibrosis regression (P = 0.015). Conclusions: HCV-RNA can persist in hepatocytes and/or PBMC in a certain of patients albeit achieving serum resolution of hepatitis C and associated with persistent histological abnormality. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (NNSFC) (No. 81673654) (to J.Zhao); NNSFC (No. 31770186) (to Y. Wang); NNSFC (No. 81802020) (to Y. Wang); and the National S&T Major Project for Infectious Diseases (No. 2017ZX10302201001007) (to J.Zhao). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was done in accordance with the ethical principles of the Declaration of Helsinki as revised in 2013 and was approved by the Ethics Committee by each institution’s human research committee, Peking University People’s Hospital, the first Hospital of Jilin University and Chinese PLA General Hospital. Informed consent was obtained from all participants prior to enrolment. Written informed consent was received from participants prior to inclusion in the study.

IL-28B rs12979860 polymorphism affect the course of chronic hepatitis and the development of HCC in Egyptian patients with hepatitis C type 4

ABSTRACTBackground: A single nucleotide polymorphism (SNP) in the interleukin 28B (IL28B) gene may alter the trajectory of hepatitis C virus (HCV) chronic infection. Several studies have sought to determine a link between IL28B rs12979860 SNP and the development of HCV-related hepatocellular carcinoma (HCC), but with variable results, and consensus is awaited. We hypothesised that IL28B rs12979860 SNP is linked to HCC in patients with HCV type 4.Methods: IL28B genotyping of 300 patients with HCV-related fibrosis (n = 100), cirrhosis (n = 100) and HCC (n = 100) was carried out and the results were analysed to determine the association between the IL28B genotype and clinical outcome.Results: In IL28B TT genotype carriers, the proportions of moderate/severe fibrosis, advanced cirrhosis (Child B-C) and HCC (50%, 84% and 60.2%, respectively) were higher (p < 0.05) than in CC/CT (4.3%, 46% and 23%, respectively). IL-28B SNP was linked significantly (p < 0.05) with cirrhosis progression and HCC advanced stages. Moreover, HCC advanced Child, Okuda and CLIP stages were associated with T allele carriage (73.9%, 82.6% and 78.3% vs. 44.2%, 50.6% and 46.8% in CC/CT). The percentage of large tumour size (> 3cm) increased (p = 0.028) in TT genotype carriers (81.8% vs.52.6% in CC/CT).Conclusion: IL-28B rs12979860 TT genotype is more prevalent in patients with advanced fibrosis, cirrhosis and HCC stages. Thus, it seems to be associated with poor outcomes in chronic HCV patients and to augment the risk of developing HCC.

Hepatitis C Virus Elimination is Not Attained in a Certain of Immunocompetent Patients Who Achieved Sustained Viral Response to Direct-Acting Antiviral Agents

Background: Direct-acting antiviral agents (DAAs) have opened a new era for treating chronic hepatitis C virus (HCV) infection. However, whether DAA induced SVR attains real cure and complete eradication of HCV RNA is unknown, because occult HCV infection (OCI), as defined the detection of HCV RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum of HCV RNA, may occur despite SVR and the clinical significance is yet to be established. We thus investigated the prevalence and provisional outcome of OCI in patients who achieved spontaneous or therapy-induced resolution of hepatitis C. Methods: Chronic HCV subjects from three tertiary hospitals who had achieved serum viral clearance, including 60 of DAAs treatment, 50 of pegylated interferon plus ribavirin (PR) treatment, and 30 of spontaneous recovery, were subjected to detect HCV RNA in hepatocytes by in suit hybridization as well as in PBMC by PCR. Liver function testes, HCV genotypes, and paired liver biopsies of pre- and post-treatment for each patient were acquired for comparison analysis. Findings: 16 of 140 subjects (11·4%) were found to have OCI, with the highest (15·0%) rate in DAA-based treated subjects, 10·0% in PR treated subjects and 6·7% in spontaneously resolved cases. Rates of OCI were 16·7% and 11·1% among patients with PR-free regimen and PR-based regimen, respectively. The existence of intermediate negative strand of HCV genome in all PBMCs of OCI patients suggested ongoing viral replication. The occurrence of OCI is more frequent in patients with genotype 3 HCV but less in patients with genotype 1. No correlation between baseline HCV viral load, interleukin-28B genotype, baseline transaminases, post transaminases and occurrence of OCI was found. While notably, OCI patients had more advanced liver fibrosis and active inflammation at both baseline and post- treatment. In addition, fibrosis scores were significantly decreased after SVR only in patients without OCI (P <0·001), but not in OCI subjects (P = 0·385). Patients with OCI have less incidence of fibrosis regression than in those without OCI after SVR. Importantly, we found two cases of HCV reactivation in OCI patients during 48 weeks to three-year follow up. Interpretation: HCV RNA can persist as ongoing replicative virus after treatment-induced or spontaneous serum resolution of hepatitis C, with highest incidence in patients with PR-free regimen induced SVR. The existence of OCI is associated with persistent pathological abnormality and likely to result in HCV relapse. Funding Statement:This study is supported by grants from National Natural Science Foundation of China (NNSFC) (No. 81673654) (to J.Zhao); NNSFC (No. 31770186) (to Y. Wang); the National S&T Major Project for Infectious Diseases (No. 2017ZX10302201001007). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: This study was done in accordance with the ethical principles of the Declaration of Helsinki as revised in 2013 and was approved by the Ethics Committee by each institution’s human research committee. Informed consent was obtained from all participants prior to enrollment. All patients were recruited from three tertiary hospitals, Peking University People’s Hospital, the first Hospitalof Jilin University and Beijing 302 hospital.

Association of killer cell immunoglobulin-like receptors with spontaneous clearance of hepatitis C virus in the Chinese population.

Natural killer (NK) cells are critical components in innate immune response to viral infection. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating the balance of activation or inhibitory function of NK cells. However, the association of KIRs with the spontaneous clearance of hepatitisC virus (HCV) remains unclear in the Chinese population. A total of 407 HCV-seropositive voluntary blood donors were recruited, including 203 with spontaneous viral clearance and 204 with chronic infection. The presence of KIR genes was detected individually by polymerase chain reaction with sequence-specific primers. Data of HLA and interleukin-28B (IL28B) genotypes were extracted from our previous study. Our results showed that KIR2DL2, 2DS2, 2DL2/2DL3, and 2DL5A-/2DL5B+ were more frequent in subjects with HCV clearance than those with chronic infection (odds ratio [OR], 1.640, p=0.034; OR, 1.664, p=0.032; OR, 1.636, p=0.040; and OR, 2.601, p=0.012, respectively). Multivariate logistic regression analysis showed that KIR2DL5A-/2DL5B+ associated with HCV clearance (OR, 2.448, p=0.027), independent of sex, IL28B, and other KIRs. In contrast, KIR2DL3/2DL3 (OR,0.610, p=0.034) as well as 2DL3/2DL3+HLA-C1 or C1C1 (OR, 0.580, p=0.017; and OR, 0.639, p=0.025, respectively) was found associated with chronic HCV infection. The presence of the homozygous KIR2DL3 with or without its HLA ligand increased the OR of developing chronic HCV infection in the context of IL28B. In this study we identified KIR2DL5A-/2DL5B+ associated with HCV spontaneous clearance, while KIR2DL3/2DL3, 2DL3/2DL3+HLA-C1, or C1C1 associated with chronic infection. Our study highlighted the fact that the roles of KIR and KIR-HLA contributed to the control of HCV infection by innate immune responses.

The role of biochemical variations and genotype testing in determining the virological response of patients infected with hepatitis C virus

Background:In hepatitis C virus (HCV), infection viral and IL28B genotype along with many clinical and biochemical factors can influence response rates to pegylated interferon plus ribavirin (Peg-IFN-a/R) therapy and progression to chronic hepatitis C (CHC).Aims:The present study was conducted to determine the effect of biochemical and risk factors on treatment outcome in CHC patients in relation to their viral and host genotype.Settings and Design:The present study was a prospective Pe- IFN efficacy study consisting of Peg-IFN-a/R therapy for 24–48 weeks including 250 HCV infected patients.Materials and Methods:Biochemical parameters were determined by Beckman Coulter AU680 automated analyzer. HCV and Interleukin 28B (IL28B) genotyping were carried out by polymerase chain reaction-restriction fragment length polymorphism and viral load was determined by quantitative real-time PCR.Results:Wild outnumbered the variant genotypes in rs12979860, rs12980275, and rs8099917 SNP of IL28B gene. Sustained virological response (SVR) SVR and viral genotype were significantly associated with age, hepatic steatosis, low-grade varices, and serum aspartate transaminase levels (at the end of treatment) (P < 0.05). In addition, SVR was significantly influenced by body mass index (BMI), insulin resistance, serum low-density lipoprotein , and ferritin levels (P < 0.05). Viral genotype 1 infected patients had higher serum cholesterol and triglyceride levels (P < 0.05).Conclusions:Although the IL28B sequence variation is the major factor that can influence response rates to antiviral therapy, viral and biochemical factors also have a definite role to play in the diagnosis, etiology, and treatment outcome in HCV-infected patients.

Identification of IL-28B Genotype Modification in Hepatocytes after Living Donor Liver Transplantation by Laser Capture Microdissection and Pyrosequencing Analysis.

The aim of this study is to elucidate the biogenetic modification of donor and recipient interleukin-28B (IL-28B) genotypes in liver graft biopsies after living donor liver transplantation (LDLT) for chronic hepatitis C virus- (HCV-) related, end-stage liver disease. Fifty liver graft biopsies were collected from recipients during LDLT treatment for HCV-related, end-stage liver disease. DNA was extracted from all 50 liver tissues, and the IL-28B single-nucleotide polymorphisms (SNPs) rs8099917 and rs12979860 were studied for allelic discrimination by real-time PCR analysis. Blood samples were obtained from donors and recipients on postoperative day 0 (POD0), POD7, and POD30. We randomly selected five liver biopsies and isolated the hepatocytes by laser capture microdissection (LCM) to evaluate genotype modifications resulting from LDLT. After LDLT, the IL-28B SNP rs8099917 was identified not only in the liver graft biopsies and donors' sera (TT = 41 : 43; GT = 9 : 5; GG = 0 : 2), but also in liver graft biopsies and recipients' sera on POD0 (TT = 41 : 44; GT = 9 : 4; GG = 0 : 2), POD7 (TT = 41 : 30; GT = 9 : 18; GG = 0 : 2), and POD30 (TT = 41 : 29; GT = 9 : 19; GG = 0 : 2). A significant difference was observed between the rs8099917 allele frequencies of liver graft biopsies and recipients' sera on POD30 (p = 0.039). In addition, a significant difference was also noted between the rs12979860 allele frequencies of liver graft biopsies and donors' sera (CT = 49 : 39; TT = 1 : 10) (p = 0.012) and of liver graft biopsies and recipients' sera on POD0 (CT = 49 : 39; TT = 1 : 11) (p = 0.002), POD7 (CT = 49 : 42; TT = 1 : 8) (p = 0.016), and POD30 (CT = 49 : 41; TT = 1 : 9) (p = 0.008). This phenomenon was confirmed by pyrosequencing of hepatocytes isolated by LCM. Following LDLT, the TT-to-GT IL-28B genotype modification predominated in rs8099917, and the CC-to-CT modification predominated in rs12979860. In conclusion, these modified phenomena suggested that the selected donor with a predictable and favourable IL-28B genotype will not confer a benefit on the recipient in the living donor liver transplantation setting.

Relationship between antibodies to hepatitis C virus core+1 protein and treatment outcome.

BackgroundIt has been suggested that hepatitis C virus (HCV) core+1 protein plays a crucial role in the viral life cycle, potentially affecting liver cirrhosis and the development of hepatocellular carcinoma.MethodsTo investigate its relationship with the outcome of HCV standard combination therapy with peginterferon-α plus ribavirin, we screened 139 consecutive HCV patients (119 with chronic HCV infection and 20 who spontaneously cleared HCV) for the presence of anti-core+1 antibodies (Abs). In addition, liver fibrosis was determined by FibroScan in all but one patients.ResultsTwenty-nine patients were cirrhotic (stiffness >12.5 kPa, F4 METAVIR), all of them with mild liver cirrhosis (Child-Pugh score A). Eighty-six of 139 patients were treatment-experienced with standard combination therapy. Fifty of them had achieved a sustained virological response, while 36 were non-responders. The prevalence of anti-core+1 Abs in patients with chronic HCV infection was 22.69% (27/119 patients): 18% (9/50 patients) in responders and 36.11% (13/36 patients) in non-responders (P=0.050). Five (17.24%) of the 29 cirrhotic patients and 22 (24.72%) of the 89 non-cirrhotic patients were positive for anti-core+1 Abs (P=0.405). Furthermore, the presence of anti-core+1 Abs correlated with the poor response interleukin (IL) 28B genotype TT (P=0.040). No correlation between spontaneous clearance and anti-core+1 Abs was observed (P=0.088).ConclusionThe presence of anti-core+1 Abs might be correlated with the poor response IL28B TT genotype and may negatively affect the outcome of standard combination treatments in HCV patients, suggesting that core+1 may play a biological role in the course of HCV infection.

Influence of IL28B and MxA gene polymorphisms on HCV clearance in Han Chinese population.

The high rate of chronic hepatitis C (CHC) was one of the key issues of global public health concern. Interferon (IFN)-λ relevant genes were in the antiviral treatment pathway, not only influenced hepatitis C virus (HCV) spontaneous clearance, but also affected the IFN-mediated viral clearance. The aim of this study was to identify the association of interleukin 28B (IL28B), myxovirus resistance A (MxA) gene polymorphisms with HCV spontaneous clearance and therapeutic response in Chinese CHC patients. IL28B and MxA gene genotypes were detected among 231 CHC carriers, 428 subjects with HCV spontaneous clearance and 662 CHC patients with pegylated IFN-α and ribavirin (pegIFN-α/RBV) treatment. Patients with MxA rs2071430 TT genotype were more likely to develop HCV infection chronicity (additive model: odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.48, P = 0.042). IL28B rs1298075 variant genotypes (additive model: OR 0.58, 95% CI 0.34-0.98, P = 0.040) and MxA rs17000900 variant genotypes (additive model: OR 0.54, 95% CI 0.30-0.99, P = 0.048) were less likely to achieve a sustained virological response. The life table indicated that patients with IL28B rs1298075 AG genotype were slower to achieve a viral load 106 copies/ml (all P < 0.05). This study illustrated that the carriage of IL28B rs12980275 AA had a positive effect on treatment response to pegIFN-α/RBV among Chinese CHC patients.