Performance of the tetra-primer PCR technique compared to PCR-RFLP in the search for rs12979860 (C/T) and rs8099917 (T/G) single nucleotide polymorphisms (SNPs) in the IFNL4 gene / Desempenho da técnica tetra-primer PCR em relação a PCR-RFLP na pesquisa de polimorfismos de nucleotídeos únicos (SNPs) rs12979860 (C/T) e rs8099917 (T/G) no gene IFNL4

Single nucleotide polymorphisms (SNPs, rs12979860 e rs8099917) in the Interferon Lambda 4 gene (IFNL4, formerly IFNL3and/or IL28B) has been associated with failure in the innate immune response, sustained virological response in hepatitis C, and HTLV-1-associated myelopathy (HAM) development. To search for these polymorphisms several methodologies can be employed, such as sequencing, real-time or quantitative polymerase chain reaction (qPCR), restriction fragment length polymorphism analysis in PCR products (PCR-RFLP), and tetra-primer PCR. The present study compared the performance of the tetra-primer PCR in relation to the PCR-RFLP, both optimized in the Research HTLV Laboratory of the Center of Immunology of Instituto Adolfo Lutz in São Paulo. One hundred DNA samples obtained from patients of STD/Aids Reference Centre in São Paulo, previously analyzed for IL28B SNPs by PCR-RFLP were selected for analysis, after confirming that they represent all IL28B SNPs patterns described in the literature. The results obtained showed concordance between the PCR-RFLP and the tetra-primer PCR SNPs results, and because of the low cost, easy to perform, and minor employment of biological specimen and reagents, the tetra-primer PCR is of choice to be used in routine. (AU)

Polimorfismos de nucleotídeos únicos (single nucleotide polymorphisms, SNPs rs12979860 e rs8099917) no gene que codifica o Interferon Lambda 4 (IFNL4, antigamente IFNL3 e/ou IL28B) têm sido associados às falhas na resposta imune inata e resposta virológica sustentada na hepatite C, e a mielopatia associada ao HTLV-1 (HTLV-1-associated myelopathy, HAM). A pesquisa destes polimorfismos pode empregar diversas metodologias: sequenciamento, reação em cadeia da polimerase em tempo real ou quantitativa (quantitative polymerase chain reaction, qPCR), análise de fragmentos de restrição enzimática em produtos de PCR (restriction fragment length polymorphism in PCR products, PCR-RFLP) e a tetra-primer PCR. Este estudo comparou o desempenho da tetra-primer PCR em relação a PCR-RFLP, ambas otimizadas no Laboratório de Pesquisa em HTLV do Centro de Imunologia do Instituto Adolfo Lutz de São Paulo. Foram selecionadas 100 amostras de DNA obtidas de pacientes do Centro de Referência e Treinamento em DST/Aids de São Paulo cujos SNPs na IL28B foram anteriormente determinados por PCR-RFLP e representaram todos os perfis descritos em literatura. Os resultados obtidos mostraram concordância entre elas, e pelo fato da tetra-primer PCR ter menor custo, ser de fácil execução, empregar menos tempo, insumos e material biológico, é a técnica de escolha para uso em rotina. (AU)

Inhibitory effects of IL-28B in a mouse model of colitis and its mechanism / 中华微生物学和免疫学杂志

Objective:To investigate the effects of IL-28B in a mouse model of dextran sulfate sodium (DSS)-induced colitis and to analyze the possible mechanism.Methods:Thirty-five male C57BL/6 mice were randomly divided into the following groups with seven mice in each group: control group, DSS group and three IL-28B groups (1.25 μg, 2.5 μg and 5 μg). The mice in the DSS group and IL-28B groups were fed with 2.5% DSS solution and from day 3, the IL-28B groups were given intraperitoneal injection of corresponding IL-28B every day and the DSS group was treated with PBS. During the experiment, the disease activity index (DAI) was evaluated daily. On day 8, the mice were sacrificed and peripheral blood, spleen, mesenteric lymph node and colon samples were collected. The colon samples were observed, measured in length and stained with HE, and histopathological scores were calculated based on HE staining. Changes of immune cells in different samples were detected by flow cytometry. ELISA was used to detect the expression of IL-12, IL-10, IL-1β, IL-6, IL-4 and IL-13 in serum and colon tissues.Results:Compared with the DSS group, the IL-28B group (2.5 μg) had lower DAI scores [(9.40±1.67) vs (3.50±1.73), P<0.01], less shortening of the colon [(5.16±0.61) cm vs (6.91±0.60) cm, P<0.01] and significantly lower histopathological scores [(7.33±0.58) vs (4.33±0.58), P<0.01]. Moreover, compared with the DSS group, the IL-28B group (2.5 μg) showed decreased macrophages in the peripheral blood [(21.39±3.21)% vs (15.63±2.98)%, P<0.05] and spleen [(3.03±0.28)% vs (2.05±0.48)%, P<0.05], and significantly increased mean fluorescence intensity of M2 macrophages in the colon [(1 361.00±293.40) vs (2 074.00±87.61), P<0.05]. IL-12 expression in colon tissues and IL-1β expression in serum were reduced, and IL-10, IL-4 and IL-13 expression in colon tissues was significantly increased in the IL-28B group (2.5 μg) as compared with those in the DSS group [IL-12: (31.72±6.92) pg/mg vs (5.41±3.41) pg/mg; IL-1β: (48.01±16.13) pg/ml vs (12.27±6.26) pg/ml; IL-10: (184.70±46.82) pg/mg vs (444.30±157.80) pg/mg; IL-4: (2.23±0.27) pg/mg vs (3.64±0.80) pg/mg; IL-13: (11.79±0.99) pg/mg vs (22.59±1.92) pg/mg; all P<0.05]. Conclusions:IL-28B might alleviate the severity of acute enteritis in mice by increasing the secretion of IL-4 and IL-13, regulating macrophage differentiation and modulating the expression of inflammatory factors.

Prevalence of hepatitis C virus infection and the IL28B genotype polymorphism among blood donors and high-risk populations

INTRODUCTION@#To study the prevalence of hepatitis C virus (HCV) infection in blood donor (BD), haemodialysis (HD) and intravenous drug user (IVDU) populations in Singapore and assess the IL28B polymorphism if HCV positive.@*METHODS@#The BD population were healthy volunteers, the HD population were patients who were on haemodialysis for at least six months of follow-up between January 2009 and December 2014. IVDU population was from inmates at halfway houses who consented.@*RESULTS@#Between 2011 and 2014, of 161,658 individuals who underwent screening prior to blood donation, 95 (0.059%) were positive for HCV. Of the 42 sera available, common genotypes (GTs) were GT-3 (47.6%) and GT-1 (31.0%). Of 1,575 HD patients, 2.2% were anti-HCV positive. The HCV GT distribution was HCV GT-1 (32.4%), HCV GT-3 (20.5%) and GT-6 (8.8%). 83 halfway house inmates were screened. Of the 47 IVDUs, 36.2% were anti-HCV positive with predominant GT-3 (%). IL28B polymorphism was noted to be CC predominantly 85.3%.@*CONCLUSION@#Prevalence of HCV infection has decreased in both the BD and HD populations. However, it remains high in the IVDU population. GT-1 remains the most common in the HD population; however, GT-3 infection is now more common among the BD population in Singapore. IL28B - CC is the predominant variant among the HCV-infected individuals in Singapore.

The long-term efficacy of PEG-IFN in treatment of chronic hepatitis C with IL28B rs12979860 C/C genotype / 西安交通大学学报(医学版)

Objective To investigate the long-term efficacy of PEG-IFN alpha-2a (PEG-IFNα-2a)plus ribavirin (RBV)in treatment of chronic hepatitis C (CHC)patients with IL28B single nucleotide polymorphisms (SNPs)rs12979860 C/C type in different HCV genotypes.Methods A prospective study was conducted on 38 CHC patients from our hospital's Infection Department from March 2011 to September 2015.The patients were treated with PEG-IFNα-2a/RBV for 48 weeks.A 42-month follow-up of patients was performed after withdrawal of treatment.The main paramenters to value the efficacy were liver function,blood lipids,and sustained virological response (SVR).Results In the CHC patients with IL28B SNP rs12979860 C/C type,the rate of SVR in patients with antiviral therapy had no significant difference between groups 1b and 2a (73.33% and 95.65%,respectively, P＞0.05).After anti-HCV therapy,liver function indices such as ALT,AST,TBIL,TC,TG and HDL all significantly improved in the two groups (all P＜0.05).However,there was no difference in biochemical indices (ALT,GGT,bilirubin,blood lipids)between the two groups (all P＞0.05).Conclusion In CHC patients with IL28B SNP rs12979860 C/C type,the long-term efficacy of PEG-IFNα-2a/RBV is good.IFN-based antiviral therapy has a higher SVR rate,and liver function and lipid metabolism can be significantly improved.

Profile of HIV subtypes in HIV/HBV- and HIV/HCV-coinfected patients in Southern Brazil

Abstract INTRODUCTION: HIV and viral hepatitis infections are major causes of chronic disease worldwide and have some similarities with regard to routes of transmission, epidemiology, front barriers faced during access of treatment, and strategies for a global public health response. The objective was to describe the HIV-1 subtypes, viral tropism and single-nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) from a case series of HIV/viral hepatitis coinfected patients from southern Brazil. METHODS: Clinical and epidemiological data were evaluated by a review of medical records. Periodic blood draws were taken to determine the viral and host characteristics. RESULTS: This study included 38 patients with HIV/HBV or HIV/HCV coinfection; the median age was 49 years. Thirty-seven (97.4%) were on antiretroviral therapy, 32 (84.2%) had an undetectable viral load, a median CD4+ T-cell count of 452 cells/mm3. HIV-1 subtyping showed 47.4 and 31.6% of patients with subtypes C and B, respectively. Analysis of viral co-receptor usage showed a predominance of the R5 variant (64.7%), with no significant difference between the subtypes. Twenty patients with HIV/HCV coinfection were eligible to receive HCV therapy with pegylated-interferon-alpha plus ribavirin, and 10/20 (50%) of them achieved sustained virological response. SNPs of IL28B were evaluated in 93.3% of patients with HIV/HCV coinfection, and 17 (60.7%) presented the CC genotype. CONCLUSIONS: In the present case series, a higher frequency of HIV subtype C was found in coinfected patients. However such findings need to be prospectively evaluated with the inclusion of data from regional multicenter analyses.

Function of the IL28B gene in Hepatitis B virus infection / 生物工程学报

Hepatitis B virus (HBV) that causes Hepatitis B with a high chronic rate, could lead to hepatic cirrhosis and hepatocellular carcinoma. The IL28B gene belongs to a new interferon family λ and its genetic polymorphisms are identified to be associated with treatment effect and viral clearance. The purpose of this review is to discuss the role of the IL28B gene in treatment response and viral clearance of HBV-infected individuals, and further to reveal the mechanisms. This review could provide a theoretical basis for personalized medicines of HBV patients.

Association of interleukin‑28B rs12979860 and rs8099917 polymorphisms with sustained viral response in hepatitis C virus genotype 1 and 3 infected patients from the Indian subcontinent.

Background: Polymorphisms of the IL28B gene (rs12979860 and rs8099917) have been shown to impact treatment responses in hepatitis C virus (HCV) infected patients. The association of these polymorphisms with sustained viral response (SVR) has been studied in HCV genotype 3 infected patients in India, but not in genotype 1. Objectives: This study aimed to determine the association of IL28B gene polymorphisms and other host and viral factors with treatment response in patients with HCV genotype 1 and 3 infection. Materials and Methods: DNA from 42 HCV‑infected patients on antiviral therapy was analysed for the IL28B polymorphisms using polymerase chain reaction‑restriction fragment length polymorphism (PCR‑RFLP). Bidirectional sequencing was performed on a subset of samples for verification of PCR‑RFLP results. Information on age, weight, height, diabetic status, pre‑treatment viral load and alanine aminotransferase (ALT) levels was obtained from clinical records. The IL28B genotypes and the other factors were analysed for their association with SVR. Results: The frequency distribution of rs12979860 CC/CT/TT genotypes was found to be 66.7%, 26.2% and 7.1%, respectively. For rs8099917 genotype, the TT/GT/GG distribution was 73.8%, 21.4% and 4.8%, respectively. SVR was seen in 61.9% of cases (55.6% in genotype 1 and 62.5% in genotype 3). CC genotype at rs12979860 and TT genotype at rs8099917 were significantly higher in responders (P = 0.013 and 0.042, respectively). Lower baseline ALT and rapid viral response were also found to be associated with SVR. On logistic regression analysis, CC genotype at rs12979860 emerged as the most powerful predictor of treatment response. Conclusion: IL28B polymorphisms are strong predictors of SVR in patients from the Indian subcontinent infected with HCV genotype 3 and genotype 1.

Association between the IL28B rs12979860 POLYMORPHISM and therapy response in patients infected with genotype 1 of hepatitis c virus in central Brazil

Single nucleotide polymorphisms (SNPs) upstream of the IL28B gene have been associated with the spontaneous clearance of hepatitis C virus (HCV) and with a sustained virological response (SVR) to HCV infection treatment. This study aimed to investigate the association between IL28B SNP rs12979860 and SVR in patients with hepatitis C in Central Brazil. A total of 101 HCV genotype 1 mono-infected chronic patients treated with pegylated interferon and ribavirin (PEG-IFN/RBV) were studied in the City of Goiânia, Central Brazil. Analysis of rs12979860 showed that the most prevalent genotype was CT (57.4%), followed by CC (23.8%) and TT (18.8%). An overall SVR rate of 28.7% (95% CI: 20.4-38.7) was found in the study population. In a multivariate analysis, only IL28B rs12979860 CC genotype (OR: 3.77; 95% CI: 1.13-12.60; p = 0.031) was associated with SVR. These findings show that IL28B SNP rs12979860 is a strong predictor of SVR in the PEG-IFN/RBV treatment in patients infected with genotype 1 of HCV in Central Brazil

Association of IL28B Genotypes and Baseline Serum Interferon-γ-Inducible-Protein-10 Levels with Treatment Response in Hepatitis C Virus Patients in China

BACKGROUND/AIMS: Several studies have demonstrated that serum interferon-γ-inducible-protein-10 (IP-10) levels at baseline and single nucleotide polymorphisms (SNPs) near the IL28B gene were associated with viral response and treatment outcomes. Our purpose was to assess the combination of pretreatment IP-10 levels with IL28B SNPs as predictors of treatment response to pegylated interferon α-2a plus ribavirin in patients infected with genotype 1 hepatitis C virus in China. METHODS: Seventy-two patients with chronic hepatitis C without fibrosis/cirrhosis were enrolled in the study. The virologic parameters and baseline serum IP-10 levels were determined. IL-28B genotypes were determined by sequencing. RESULTS: In this cohort, serum baseline IP-10 levels lower than 426.7 pg/mL could predict rapid virological response/sustained virological response (SVR). Patients carrying favorable IL28B SNP genotypes had higher SVRs than did those carrying unfavorable variants (IL28B rs12979860, p=0.002; IL28B rs8099917, p=0.020). Combining both baseline IP-10 and IL28B SNPs could improve the prediction of SVR in favorable allele carriers of IL28B, rs12979860 CC and rs8099917 TT. Serum baseline IP-10 levels and IL28B genotypes were independent predictors of SVR. CONCLUSIONS: Our study shows that the combination of baseline serum IP-10 levels and the determination of IL28B SNPs increase the predictability of SVR rates in this cohort.

Meta Analysis of the Association of Polymorphism in IL-28B Gene and Virological Response to Interferon in HBeAg-positive Chronic Hepatitis B / 中国医科大学学报

Objective To explore the association between the polymorphism in IL-28B gene and the interferon virological response in HBeAg-posi-tive chronic hepatitis B patients. Methods A literature search was performed on PubMed,web of Science,China Bio Medicine(CBM)and wan-Fang database. The references was screened with the inclusion and exclusion criteria,and then data were extracted and methodological quality of the studies was judged. Statistical analysis was carried out with RevMan 5.3 and STATA 11.0. Results Totally 7 publications were recruited for the study,including 1 345 patients. The meta-analysis showed that there was no significant difference of interferon response between HBeAg-positive chronic hepatitis B patients with rs8099917TG/GG alleles and rs8099917TT alleles (P= 0.20). There was no statistical difference between Rs12979860CC and CT/TT allele for the sustained virological response(P=0.75). Conclusion Our current meta-analysis suggests that there was no correlation of rs8099917,rs12979860 polymorphism in IL-28B with the sustained virological response to interferon in HBeAg-positive chronic hepatitis b.

Correlation study of interleukin-28B rs12978960 genetic polymorphism and the retreatment efficacy of peginterferon/ribavirin in chronic hepatitis C genotype 1 b relapsers / 中华传染病杂志

Objective To investigate the virological response in hepatitis C virus (HCV)genotype 1b relapsers after 48 weeks of peginterferon/ribavirin (peg-IFN/RBV)combination retreatment,and to explore the predictive value of interleukin (IL )-28B rs12978960 genetic polymorphismon virological response.Methods From 2012 to 2014,genotype 1b chronic hepatitis C (CHC)relapsers in He′nan Provincial People′s Hospital were retreated with combined peg-IFN/RBV for 48 weeks and followed up for 24 weeks off-treatment.Host IL-28B genetic polymorphism was detected.Predictive factors associated with virological response and sustained virological response (SVR)were analyzed.Independent-samples t test was conducted in continuous variables,whileχ2 test or Fisher exact probability test was conducted in counts data.Results A total of 61 patients finished 48 weeks of peg-IFN/RBV combination therapy and were further followed up for 24 weeks off-treatment.Mean age was (46.7 ±12.4)years.Thirty-seven patients (60.7%)were male and 49 were rs12978960 CC genotype.After 48 weeks of retreatment with peg-IFN/RBV and 24 weeks of off-treatment follow-up,40 patients (65 .6%)achieved SVR.Rapid virological response (RVR)and SVR of younger patients were both significantly higher than those of older patients (100.0% vs 67.4% and 85 .0% vs 47.6%,respectively;both P =0.006).IL-28B rs12978960 genotype was predictive to RVR and SVR.Patients with RVR and SVR had higher carriage rates of IL-28B rs12978960 CC genotype compared with those without RVR and SVR (both P <0.05 ).Patients with CC genotype had higher rates of RVR (34.1 % vs 0;χ2 = 10.625 ,P =0.006 ),end-of-treatment virological response (84.1 % vs 70.6%;χ2 =5 .563,P =0.039 )and SVR (77.3% vs 35 .3%;χ2 =9.572,P =0.007)than those with CT/TT genotype.However,there were no statistical differences of extended RVR (34.1 % vs 29.4%;χ2 =0.122,P =0.809)and early virological response (79.5 % vs 82.3%;χ2 =0.612,P =0.964).Conclusions Retreatment with antiviral therapy is necessary in CHC patients with genotype 1b. IL-28B rs12978960 genetic polymorphism is predictive to the SVR of retreatment,especially for patients without RVR,which will provide individualized treatment and optimize the treatment strategy.

Correlation of IL-28B gene polymorphism and natural outcome of hepatitis C / 中国免疫学杂志

Objective:To explore the association between interleukin(IL)-28B single nucleotide polymorphisms and natural outcome of hepatitis C virus.Methods:The IL-28B rs12979860 locus was genotyped in 266 HCV infected volunteer blood donors(107 spontaneous cleared and 159 chronic infection) and 97 healthy controls using Sanger sequencing assay.The difference in rs12979860 genotypes and allele frequencies between the six groups(107 spontaneous cleared and 159 chronic infection,266 HCV infection and 97 healthy controls,159 chronic infection and 97 healthy controls) were analyzed by statistics.Results:159 HCV chronic infection,107 spontaneous cleared and 97 healthy controls,were shown more CC genotype,accounting for 83.6%,95.3%and 86.6%,respectively, while the CT genotype accounted for 16.4%,4.7%and 13.4%respectively.No TT genotype was found.The CC/CT genotype was not significant difference between HCV infection and healthy controls,chronic infection and healthy controls(χ2=0.204,P=0.652;χ2=0.406,P=0.524),but between chronic infections and spontaneous clearance had statistically significant(χ2=8.474,P=0.004),the frequence of C allele in spontaneous cleared was higher than HCV chronic infection(χ2=7.949,P=0.005).Conclusion: The gene polymorphism of IL-28B rs12979860 is not related to HCV susceptibility,but there are differences in chronic infection and spontaneous cleared,showing the C allelic in favor of HCV spontaneous cleaed.

Tendencia preliminar del polimorfismo rs12979860 il28b en la población mestiza venezolana / Preliminary tendency of rs12979860 il28b polymorphism in the mestizo Venezuelan population

Introducción: El polimorfismo de un solo nucleótido (SNP) rs12979860 en el gen IL28B del cromosoma 19 que codifica al interferón (IFN)-λ-3, se asocia con respuesta viral sostenida a la terapia combinada de IFN-α pegilado y ribavirina en pacientes con virus de hepatitis C (VHC) genotipo 1. La diferencia alélica de este polimorfismo difiere entre grupos étnicos. Objetivo: Comparar las frecuencias alélicas (FA) y genotípicas (FG) del SNP rs12979860 del gen IL28B entre individuos sanos y pacientes con VHC mestizos venezolanos. Material y métodos: De 34 pacientes con VHC genotipo 1 investigados para este polimorfismo, solamente 19 eran venezolanos de tercera generación, a quienes comparamos con 19 individuos sanos conocidos mestizos. La determinación del polimorfismo se realizó mediante el ensayo TaqMAN SNP empleando el sistema de PCR-tiempo real. Resultados: El alelo más prevalente en la población sana fue el alelo silvestre C (55%) y en los pacientes la frecuencia fue igual para el alelo C y para el alelo mutado T (50%) sin diferencia significativa entre las dos poblaciones. El genotipo predominante fue el heterocigoto (C/T) en pacientes y en controles (80% y 58%) evidenciándose mayor valor en el primer grupo pero no llegando a ser significativo. Predominando en controles vs pacientes se aprecian los genotipos homocigotos C/C (26% vs 10%) y T/T (16% vs 10%). Conclusión: La tendencia preliminar apunta al genotipo heterocigoto C/T del gen IL28B como el más frecuente en la población mestiza venezolana.

Introduction: Single-nucleotide polymorphism (SNP) rs12979860 in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-λ-3 are associated with sustained viral response to combined therapy with pegylated IFN-α and ribavirin in patients with hepatitis C virus (HCV) genotype 1. Allelic difference from this polymorphism varies among ethnic groups. Objective: To compare allelic frequencies (AF) and genotypes frequencies (GF) of SNP rs12979860 of the IL28B gene between healthy individuals and mestizos Venezuelan HCV patients. Material and Methods: From 34 patients with HCV genotype 1 investigated for this polymorphism only 19 were third generation mestizo Venezuelan patients who were compared to 19 healthy individuals known mestizos. SNP determination was carried-out by TaqMAN SNP assay employing real-time PCR system. Results: Most prevalent allele in the healthy population was the C wild (55%) while in patients similar frequency was found for C allele or the mutant allele (50% each) with no significant difference. The heterozygote genotype (C/T) was predominant in patients and controls (80% and 58%) with a higher value for the former group but without significance. Homozygote genotypes were more prevalent in controls vs. patients: C/C (26% vs. 10%) and T/T (16% vs. 10%). Conclusion: Preliminary tendency points-out that heterozygote genotype C/T from the IL28B gene is the most frequent in the Venezuelan mestizo population.

Prediction value of IL-28B gene polymorphism on antiviral curative effect in patients with chronic hepatitis B / 国际检验医学杂志

Objective To investigate the role of IL-28B gene on the antiviral curative effect in the patients with chronic hepatitis B.Methods 205 HBeAg-positive patients treated with the antiviral therapy of pegylation interferon(PEG-IFN)were detected the IL-28B rs12980275 and rs12979860 genotypes by TapManSNP genotyping assay and the relationship between the IL-28B genotypes and HbeAg seroconversion at end of treatment was analyzed.Results Among 205 cases,6 cases of genotype were uncertainty,the frequencies of IL-28B genotypes in other 199 cases were 77%,19%,5% for AA,AG,GG genotypes at rs12980275 and 76%,20%, 4%,for CC/CT/TT genotypes at rs12979860 respectively.The IL-28B polymorphisms were significantly correlated with the HbeAg seroconversion at the end of PEG-IFN treatment (P =0.001).In rs12979860 genotype,by the HBV genotyp,age,HBV lev-el,ALT and the combined therapy,the odds ratio (OR)of AA versus AG/GG was adjusted to 3.16 by HbeAg seroconversion.The similar result also obtained for the rs12980275 genotype.The IL-28B genotype was also associated with the HBsAg clearance.Con-clusion The IL-28B gene polymorphism is associated with the antiviral curative effect in the patients with HBeAg positive chronic hepatitis B.

Myxovirus resistance, osteopontin and suppressor of cytokine signaling 3 polymorphisms predict hepatitis C virus therapy response in an admixed patient population: comparison with IL28B

OBJECTIVES: Suppressor of cytokine signaling 3, myxovirus resistance protein and osteopontin gene polymorphisms may influence the therapeutic response in patients with chronic hepatitis C, and an association with IL28 might increase the power to predict sustained virologic response. Our aims were to evaluate the association between myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 gene polymorphisms in combination with IL28B and to assess the therapy response in hepatitis C patients treated with pegylated-interferon plus ribavirin. METHOD: Myxovirus resistance protein, osteopontin, suppressor of cytokine signaling 3 and IL28B polymorphisms were analyzed by PCR-restriction fragment length polymorphism, direct sequencing and real-time PCR. Ancestry was determined using genetic markers. RESULTS: We analyzed 181 individuals, including 52 who were sustained virologic responders. The protective genotype frequencies among the sustained virologic response group were as follows: the G/G suppressor of cytokine signaling 3 (rs4969170) (62.2%); T/T osteopontin (rs2853744) (60%); T/T osteopontin (rs11730582) (64.3%); and the G/T myxovirus resistance protein (rs2071430) genotype (54%). The patients who had ≥3 of the protective genotypes from the myxovirus resistance protein, the suppressor of cytokine signaling 3 and osteopontin had a greater than 90% probability of achieving a sustained response (p<0.0001). The C/C IL28B genotype was present in 58.8% of the subjects in this group. The sustained virological response rates increased to 85.7% and 91.7% by analyzing C/C IL28B with the T/T osteopontin genotype at rs11730582 and the G/G suppressor of cytokine signaling 3 genotype, respectively. Genetic ancestry analysis revealed an admixed population. CONCLUSION: Hepatitis C genotype 1 patients who were responders to interferon-based therapy had a high frequency of multiple protective polymorphisms in the myxovirus ...

Response to treatment in Brazilian patients with chronic hepatitis C is associated with a single-nucleotide polymorphism near the interleukin-28B gene

A single-nucleotide polymorphism (SNP) upstream of interleukin (IL)28B was recently identified as an important predictor of the outcome of chronic hepatitis C patients treated with pegylated interferon plus ribavirin (PEG-IFN/RBV). The aim of this study was to investigate the association between the IL28B gene polymorphism (rs12979860) and virological response in chronic hepatitis C patients. Brazilian patients (n = 263) who were infected with hepatitis C virus (HCV) genotype 1 and were receiving PEG-IFN/RBV were genotyped. Early virological response (EVR) (12 weeks), end-of-treatment response (EOTR) (48 weeks), sustained virological response (SVR) (72 weeks) and relapse were evaluated using conventional and quantitative polymerase chain reaction (PCR) assays. The frequency of the C allele in the population was 39%. Overall, 43% of patients experienced SVR. The IL28B CC genotype was significantly associated with higher treatment response rates and a lower relapse rate compared to the other genotypes [84% vs. 58% EVR, 92% vs. 63% EOTR, 76% vs. 38% SVR and 17% vs. 40% relapse rate in CC vs. other genotypes (CT and TT), respectively]. Thus, the IL28B genotype appears to be a strong predictor of SVR following PEG-IFN/RBV therapy in treatment-naïve Brazilian patients infected with HCV genotype 1. This study, together with similar research examining other SNPs, should help to define adequate protocols for the treatment of patients infected with HCV genotype 1, especially those with a poor prognosis.

The Impact of Inosine Triphosphatase Variants on Hemoglobin Level and Sustained Virologic Response of Chronic Hepatitis C in Korean

Two variants of the inosine triphosphatase (ITPA: rs1127354, rs7270101) gene cause ITPA deficiency and protect against the hemolytic toxicity of ribavirin. We investigated the clinical significance of ITPA variants in Korean patients treated with pegylated interferon (PEG-IFN) plus ribavirin. Of the 133 patients, 108 were CC and 25 were non-CC at rs1127354 (groups A and B, respectively). On the other hand, at rs7270101 all 133 were AA. The mean values of Hemoglobin (Hgb) after 4, 8, and 12 weeks of treatment in groups A and B were 12.2 and 14.0, 11.8 and 13.2, and 11.5 and 12.9, respectively (P=0.001, 0.036, 0.036). Sustained virologic response (SVR) was achieved in 67.8% (40/59) of genotype 1 patients and in 75% (27/36) of non-genotype 1 patients. Regarding ITPA variants, SVR was achieved by 66% and 80% of genotype 1 (P=0.282), and by 78% and 71% (P=0.726) of non-genotype 1. SVR was not significantly different in groups A and B. In conclusion, non-CC at rs1127354 without involvement of rs7270101 is strongly associated with protection from ribavirin-induced anemia, however, ITPA genotype is not associated with SVR.

A single nucleotide polymorphism, rs129679860, in the IL28B locus is associated with the viral kinetics and a sustained virological response in a chronic, monoinfected hepatitis C virus genotype-1 Brazilian population treated with pegylated interferon-ribavirin

Single nucleotide polymorphisms (SNPs) in the interleukin (IL)28B locus have been associated with a sustained virological response (SVR) in interferon-ribavirin (IFN-RBV)-treated chronic hepatitis C virus (HCV)-infected patients in European and African populations. In this study, the genotype frequency of two IL28B SNPs (rs129679860 and rs8099917) in a cohort of chronic HCV-monoinfected patients in Brazil was evaluated and the SNP sufficient to predict the treatment response outcome was determined. A total of 66 naïve genotype-1 chronic HCV-infected patients were genotyped and the associated viral kinetics and SVR were assessed. The overall SVR was 38%. Both the viral kinetics and SVR were associated with rs129679860 genotypes (CC = 62% vs. CT = 33% vs. TT = 18%, p = 0.016). However, rs8099917 genotypes were only associated with SVR (TT = 53% vs. TG = 33% vs. GG = 18%; p = 0.032). In this population, the analysis of a single SNP, rs12979860, successfully predicts SVR in the IFN-RBV treatment of HCV.

Efficacy of peginterferon and ribavirin is associated with the IL28B gene in Korean patients with chronic hepatitis C

BACKGROUND/AIMS: Sustained virologic response (SVR) for the treatment of chronic hepatitis C (CHC) may differ with ethnicity due to differences in genetic traits. This study evaluated the efficacy of peginterferon and ribavirin, and the association between IL28B genotypes and the treatment efficacy in Korean CHC patients. METHODS: This was a retrospective cohort study using data from medical records. Eighty-five CHC patients were eligible for assessment of the efficacy of antiviral therapy, and 47 patients were available for an IL28B genetic study, which was performed using the Multiplex tetra-primer PCR method for rs12979860. RESULTS: Overall, the early virologic response rate was 87.1%: 84.9% in HCV genotype 1 and 90.6% in genotype 2. The overall end-of-treatment virologic response rate was 81.2%: 75.5% in genotype 1 and 90.6% in genotype 2. The overall SVR rate was 81.2%: 75.5% in genotype 1 and 90.6% in genotype 2. For rs12979860, the frequencies of polymorphisms were 89% for the CC type, 11% for the CT type, and 0% for the TT type. Their overall SVR rate was 87% (39/47): 90.5% (38/42) for the CC type and 20% (1/5) for the CT type. For genotype 1, SVR rates were 88% (21/24) for the CC type and 0% (0/4) for the CT type. Multivariate analysis revealed that the IL28B-CC type was a good predictor for SVR. CONCLUSIONS: The SVR of the combination therapy in Koreans was higher than that observed in Western countries. This finding might be attributable to the high prevalence of IL28B-CC type among Koreans, which may be a good predictor of SVR.