IL28B Rs12979860 CC Research Articles

Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP‐C and PROPEL studies

The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C). We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin. Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1). Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.

HCV RNA viral load is independent from CD4 cell count and plasma HIV RNA viral load in immunocompetent HIV-HCV co-infected patients: a 3-years follow-up study.

BackgroundHCV RNA viral load is an important predictor of sustained virological response and, recently, a significant correlation with liver fibrosis was described. We investigated on possible influence of clinical and viro-immunological variables on HCV viral load in HIV-HCV co-infected patients over a study time of three years (2009-2012).MethodsWe retrospectively enrolled 98 adult patients with a diagnosis of chronic HIV infection in 2009, a diagnosis of chronic HCV infection with a detectable plasma HCV RNA in 2009 and 2012, HCV therapy-naïve or with failed and stopped antiviral treatment before June 2008. The following variables were recorded: age, gender, HCV genotype, IL28B rs12979860 CC genotype, HCV treatment status, advanced liver fibrosis diagnosis, antiretroviral therapy, CD4+ cell count, HCV viral load, HIV RNA (plasma HIV-1 RNA levels were measured from blood samples every three months at least). The correlation was established using linear regression analysis, analysis of variance and Fisher’s exact test. Comparisons between groups were performed using Fisher’s exact test, the independent samples t-test and the t-test for paired data, as appropriate, for continuous variables. A mixed mode (ME) maximum likelihood linear regression model was constructed to evaluate the dependence of HCV viral load.ResultsHCV RNA levels did not change significantly from 2009 to 2012 (from 3924650 ± 5320177 IU/ml to 3085128 ± 3372347 IU/ml, p = 0.13); the CD4+ count increased significantly (from a mean of 576 to a mean of 654, p = 0.003). Using linear regression, a positive correlation was observed for HCV load and genotype 1 (p = 0.002), nonresponder status (p = 0.04) and with interleukin 28B CC allele (p = 0.05). Other studied covariates failed to reach a significant correlation.ConclusionsThe HCV RNA load, a known pretreatment predictor of response to antiviral therapy, was independent of the two main parameters of HIV disease, plasma HIV RNA and CD4 cell count, over an observation time of 3 years in patients with recovered or spontaneously maintained immunocompetence.

Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection

HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment. We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance. Plasma apolipoprotein H (ApoH) levels were significantly higher in patients who achieved spontaneous clearance or responded to pegylated-interferon/ribavirin therapy. Strikingly, patients carrying the IL28B rs12979860 CC SNP correlated with the plasma concentration of ApoH in all three cohorts. Both ApoH and IL28B CC SNP were associated with HCV clearance in univariate analysis. Additional multivariate analysis revealed that the association between IL28B and HCV clearance was closely linked to that of Apo H and HCV clearance, suggesting that both belong to the same biological pathway to clearance. The association between IL28B CC SNP and ApoH was not observed in healthy individuals, suggesting that early post-infection events trigger differential ApoH expression in an IL28B allele dependent manner. This relationship identifies ApoH as the first induced protein quantitative trait associated with IL28B, and characterises a novel host factor implicated in HCV clearance.

1039-LBP: Influence of IL28B (rs12979860) polimorphisms and KIR genes in spontaneous clearance of hepatitis C virus in a multi-ethnic population from Rio de Janeiro (Brazil)

Aim IL-28B (rs12979860) SNP and KIR genes were investigated as candidates for susceptibility to persistent HCV infection or HCV clearance in a sample of Rio de Janeiro (Brazil) population. Methods The PCR-rSSO was employed to identify KIR genes and pseudogenes and 207 chronic hepatitis C (CHC) patients and 45 spontaneously recovered (SR) individuals. Also, IL28B (rs12979860) single nucleotide polymorphism was typed by real-time PCR. Results The carrier frequency (CF) of the following KIR genes was higher in SR compared to CHC: KIR2DL2 (73.3% vs. 46.4%; p = 0.001, OR = 0.33), KIR2DS1 (48.9% vs. 28.0%, p = 0.006, OR = 0.4), KIR3DS1 (46.7% vs. 26.1%, p = 0.006, OR = 0.4). In addition, rs12979860 CC genotype was more frequent in SR (62.2%) than CHC (27.5%; p = 0.0001, OR = 0.2) and this effect was influenced by the presence of some specific genes – KIR2DL2 (44.4% vs. 13.0%, p = 0.0001, OR = 0.2), KIR3DS1 (20.0% vs. 8.2%, p = 0.01, OR = 0.4) and KIR2DS1 (24.4% vs. 8.7%, p = 0.003, OR = 0.3) as well as the absence of some other genes – KIR3DS1 (42.2% vs. 19.3%, p = 0.001, OR = 0.3), KIR2DS1 (37.8% vs. 18.8%, p = 0.005, OR = 0.4) and KIR2DS5 (37.8% vs. 17.9%, p = 0.003, OR = 0.4). Multivariate analysis revealed that IL-28B CC genotype ( p = 0.0001, OR = 5.0, 95%CI = 2.3–11.2), KIR2DL2 ( p = 0.0008, OR = 7.8, 95%CI = 2.3–27.0) and KIR2DS1 ( p = 0.004, OR = 4.5, 95%CI = 1.6–13.3) genes were associated with spontaneous recovery. Conclusions IL28B rs12979860 CC genotype associated with diverse KIR genes strongly enhances spontaneous resolution of HCV infection. These findings support a role for natural killer (NK) cell activation in clearance of HCV, partially mediated by IL28B effect among individuals of Rio de Janeiro (Brazil) population.

P1125 PHARMACOKINETIC-RESPONSE ANALYSIS OF FALDAPREVIR IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HCV GENOTYPE-1 INFECTION: A POOLED ANALYSIS OF TWO PHASE III TRIALS

constrained countries for the foreseeable future. There are currently limited data on the use of BOC + PegIFN alfa-2a/RBV in treatmentnaive patients. Methods: Treatment-naive G1-infected patients with/without cirrhosis received 4 weeks PegIFN alfa-2a/RBV lead-in followed by BOC 800mg tid plus PegIFN alfa-2a/RBV. Treatment was stopped if HCVRNA ≥100 IU/mL at Week 12 or detectable at Week 24. This interim analysis explores factors predictive of qualification for an abbreviated 28-week regimen in non-cirrhotic patients. Results: 144 non-cirrhotic patients were included (88% G1b, 21% IL28B rs12979860 CC, 42% IL28B rs8099917 TT and 7% transition-to-cirrhosis). Overall, 118 patients (82%) had a ≥1 log10 drop in HCVRNA at Week 4 and 128 (89%) achieved ontreatment virological response (HCVRNA <15 IU/mL) at Week 24. A total of 84/144 (58%) patients achieved undetectable HCVRNA at Weeks 8 and 24 and therefore qualified for the shorter 28week treatment. MLR was used to explore the association between the following baseline factors and qualification for 28-weeks’ abbreviated treatment; G1 subtype, HCVRNA, age, weight, BMI, gender, IL28B genotype rs12979860/rs8099917 and fibrosis stage. Using backward elimination, factors remaining significant were G1a, lower HCVRNA, IL28B rs12979860 CC and rs8099917 TT genotype and no cirrhosis. SVR12 data will be presented at EASL.

Host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients.

Previous studies have suggested that host genetic polymorphisms may affect virological response to pegylated-interferon and ribavirin (PEG-IFN/ ribavirin) therapy in chronic HCV infection. IL28B and MxA are the most intensively studied genes in Chinese Han population. The current research is to summarize published data and evaluate the overall association of meaningful SNPs in these two genes with virological response to interferon-based therapy. Literature search was performed in online database and a systematic review was conducted based on the search results. Meaningful single nucleotide polymorphisms (SNPs) were summarized and analyzed for odds ratio (OR) and 95% confidence intervals (95% CI). Data manipulation and statistical analyses were performed by using STATA 12.0 and Review Manager version 5.1. Eighteen papers were included for final data analysis. Three SNPs of IL28B and two SNPs of MxA were found to be associated with higher sustained virological response (SVR) to interferon therapy. The ORs and 95% CIs of each variant were: IL28B rs8099917 TT (OR: 4.35, 95% CI: 3.10∼6.12), IL28B rs12979860 CC (OR: 5.37, 95% CI: 3.95∼7.31), IL28B rs7248668 CC (OR: 3.50, 95% CI: 2.30∼5.35), MxA rs2071430 GT (OR: 2.03, 95% CI: 1.31∼3.13), and MxA rs17000900 AC/AA (OR: 1.82, 95% CI: 1.17∼2.83). The genotypes of IL28B rs8099917, rs12979860, rs7248668, MxA rs2071430, and MxA rs17000900 were strong SVR predictors for PEG-IFN/ ribavirin -treated HCV patients in Han Chinese population. Our findings suggest that host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients.

Association of polymorphisms in interleukin-18 and interleukin-28B genes with outcomes of hepatitis B virus infections: a meta-analysis.

Several polymorphisms in the interleukin-18 (IL-18) and nterleukin-28B (IL-28B) genes have been reported to influence hepatitis B virus (HBV) infection. However, the published findings have been conflicting. We conducted meta-analyses of randomized, controlled trials to address the association of IL-18 or IL-28B polymorphisms and the outcomes of HBV infection. Weipu, Wanfang, CNKI, MEDLINE, PubMed, EMBASE, and Cochrane Library databases were employed to search for citations using the MeSH terms as "interleukin-18"/"interleukin-28B" AND "HBV" AND "gene" AND "polymorphism" without any restriction in language and publication year. Meta-analysis was conducted by RevMan 5.0 software. The results showed that the IL28B rs8099917 AA genotype (AA vs AC + CC: odds ratio (OR) = 0.63, 95 % confidence interval (CI) = 0.46-0.87) was associated with a decreased risk of hepatocellular carcinoma (HCC). Carriage of IL28B rs12979860 CC genotype was associated with an increased risk for developing liver cirrhosis among patients with HBV infection (CC vs CT + TT: OR = 1.39, 95 % CI = 1.04-1.85). Further well-designed large studies are warranted to confirm the mechanisms by which these are involved in these outcomes of HBV infection.

IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection

In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients.

Prevalence of IL‐28B and ITPA genotypes in Chinese Han population infected persistently with hepatitis C virus genotype 6 or HCV‐1

The geographic distribution, demographics, epidemiology, host factors, and clinical characteristics of persistent HCV-6 infection in China need further characterization. This multicenter study enrolled 63 patients with persistent HCV-6 infection and 63 patients with persistent HCV-1 infection as controls. Blood biochemistry, quantitation of HCV RNA levels, and identification of host IL-28B genotypes (rs12979860, rs8099917, and rs12980275) and ITPA genotype (rs1127354) were performed to estimate potential variability in host factors that may affect response to treatment. The mean HCV-6 RNA level (3.8E6 IU/ml) was significantly higher than that in patients infected with HCV-1 (1.7E6 IU/ml; P < 0.001). Patients persistently infected with HCV-6 had a high prevalence of IL-28B rs12979860 CC genotype (92.1%), rs8099917 TT genotype (93.7%), and rs12980275 AA genotype (90.5%). Their prevalence in patients infected with HCV-1 was only modestly lower (82.5%, 84.1%, and 82.5%, respectively; P > 0.05). The inosine triphosphate pyrophosphatase (ITPA) SNP rs1127354 CC genotype was present in 66.7% of patients infected with HCV-6, comparable to that of patients infected with HCV-1 (65.1%; P > 0.05). There were no differences in the liver function, proportion of hepatic cirrhosis patients or patients with increased serum glucose between these two groups. Persistent HCV-6 infection in Chinese Han is found mainly in the southern China. Chinese Han with chronic HCV-1 or HCV-6 infection have IL-28B genotypes, suggesting responsiveness to interferon-based pharmacotherapy. Most patients (67%) possess the ITPA genotype associated with susceptibility to ribavirin-induced hemolysis. The routes of transmission for HCV-6 genotype were more diversified than HCV-1 genotype. The outbreak of HCV-6 infection through blood transfusion progressed faster than HCV-1.

1021-LB

Aim IL28B and KIR genes with their HLA-C groups ligands were investigated as candidates for persistent HCV infection or HCV clearance in a sample of Rio de Janeiro (Brazil) population. Methods The (rSSO-PCR) was employed to identify KIR genes and pseudogenes and HLA alleles in 181 chronic hepatitis C (CHC) patients, 45 spontaneously recovered (SR), and 214 blood donor healthy individuals (BD). Also, IL28B single nucleotide polymorphisms (SNPs) rs12979860, rs12980275 and rs8099917 were typed by real-time PCR in all groups (CHC = 217 individuals; SR = 45; BD = 191). Results The carrier frequency of KIR2DL2 is higher in SR (73.3%) compared to CHC (55.6%; p = 0.005) and BD (48.9%; p = 0.04) and KIR2DL5 is lower in CHC (46.8%) vs BD (63.3%; p = 0.002). KIR3DS1 was decreased in CHC (24.2%) than SR (46.7%; p = 0.005) and BD (38.3%; p = 0.005). The frequencies of KIR genes and their HLA-C group ligands were significantly different among CHC vs. SR (KIR2DL2/3+C1, p Conclusions We confirmed that KIR2DL2 and KIR3DS1 are associated in resolution of Hepatitis C virus infection and KIR2DL5 with chronic hepatitis. The imbalance between activating and inhibitory KIR and HLA ligands may explain, at least in part, the pathogenesis of the HCV infection. IL28B rs12979860 CC and rs12980275 AA genotype strongly enhances spontaneously resolution of HCV infection. These findings support a role for natural killer (NK) cell activation in clearance of HCV, partially mediated by IL28B among individuals of Rio de Janeiro (Brazil) population.

Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection

A substantial proportion of patients with chronic hepatitis C virus infection treated with pegylated interferon α/ribavirin fail to achieve sustained virological response (SVR). Since growing evidence suggests that innate immunity may influence treatment responses, we examined natural killer (NK) cell phenotypic and functional changes during standard antiviral therapy. Expression of several NK-cell regulatory molecules was evaluated by flow cytometry in 37 consecutive patients with chronic HCV infection at baseline and at different time points during and after discontinuation of treatment. Cytokine production was evaluated by intracellular staining. Cytolytic potential was assessed as degranulation and as antibody-dependent cytotoxicity. Baseline frequencies of CD56(dim) NK cells and perforin content were significantly higher, whereas CD16 expression was lower in SVR vs. non-responder subjects. Analysis by linear regression for repeated measures during the first 12 weeks showed significantly increased frequencies of activated (CD69(+)) NK cells in rapid virological responders (RVR) and identified a typical NK cell profile associated with SVR, featuring higher NK perforin content, lower CD16 expression, and higher proportion of CD56(dim)/CD16(-) cells. Moreover, SVR patients displayed higher natural and antibody-dependent NK cell cytotoxicity. IL28B rs12979860 CC homozygosis was significantly associated with SVR, independently of NK-cell phenotype and function. Different NK-cell phenotypic and functional features, in patients with chronic hepatitis C treated with standard therapy, were observed between non-responder vs. SVR patients, suggesting a potential role of NK cells in the response to treatment.

Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation

IL28B single nucleotide polymorphisms are strongly associated with spontaneous HCV clearance and treatment response in non-transplant populations. A DDX58 single nucleotide polymorphism is associated with the antiviral response of innate lymphocytes. We aimed at evaluating the associations of donor and recipient IL28B (rs12979860 and rs8099917) and DDX58 (rs10813831) genotypes with severity of HCV recurrence after liver transplantation. In a case-control study of 523 liver transplantation recipients with HCV, we matched severe with mild recurrent HCV based on 2-year clinical and histologic follow-up. A total of 440 liver transplantation recipients (severe, n=235; mild, n=205) with recipient DNA and 225 (severe, n=123; mild, n=102) with both recipient and donor DNA were analyzed. IL28B [rs12979860, non-CC (vs. CC) and rs8099917, non-TT (vs. TT)] in the recipient-only analysis had higher risk of severe recurrent HCV [OR 1.57 and 1.58, p<0.05]. However, for the 225 with donor and recipient DNA, IL28B rs12979860 CC (vs. non-CC) and rs8099917 TT (vs. non-TT) and DDX58 rs10813831 non-GG (vs. GG) were associated with more (not less) severe recurrent HCV. The greatest risk of severe recurrent HCV was for rs12979860 CC donors in non-CC recipients (OR 7.02, p <0.001, vs. non-CC donor/recipient) and for rs8099917 TT donors in non-TT recipients (OR 5.78, p=0.001, vs. non-TT donor/recipient). These associations persisted after controlling for donor age, donor race, and donor risk index. IL28B and DDX58 single nucleotide polymorphisms that are favorable when present in the non-transplant setting or in the recipient are unfavorable when present in a donor liver graft.

Impact of IL-28B polymorphisms on pegylated interferon plus ribavirin treatment response in children and adolescents infected with HCV genotypes 1 and 4

IL-28B polymorphisms are predictors of response to therapy in adults infected with hepatitis C. We do not know whether they are markers of response to therapy in children and adolescents. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the IL-28B gene could influence the probability of response to therapy compared with other known baseline prognostic factors and correlate with clinical findings in pediatric patients infected with hepatitis C virus (HCV) genotypes 1 or 4. We determined three SNPs of IL-28B (rs12979860, rs12980275, and rs8099917) in 82 patients with chronic HCV infection treated with pegylated interferon alpha and ribavirin (peg-IFNα/RBV). Treatment response and clinical data were analyzed. Overall, sustained virological response (SVR) was achieved by 45 % of patients infected with difficult-to-treat HCV genotypes 1 and 4. Except for IL-28B polymorphisms, there was no association of SVR with any other clinical data. IL-28B rs12979860 CC [odds ratio (OR), 6.81; p = 0.001] and rs8099917 TT (OR, 3.14; p = 0.013) genotypes were associated with higher SVR rates. IL-28B rs12980275 was not significantly associated with SVR (p = 0.058). Only the distribution between CC and CT–TT genotypes of rs12979860 significantly differentiated patients achieving early virological response (EVR) (OR, 10.0; p = 0.011). Children with the rs12979860 CC genotype had significantly higher baseline viral load compared with CT–TT patients (p = 0.010). In children and adolescents chronically infected with HCV genotypes 1 and 4, IL-28B rs12979860 and rs8099917 polymorphisms were the only predictors of response to peg-IFN/RBV.

Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals

BackgroundIL28B polymorphism is recognized as one of the most prominent predictors of hepatitis C spontaneous and treatment-induced clearance. Interestingly, the favorable genotypes of IL28B are found to be more frequent in Asian ethnicity than Caucasian and African populations, respectively. A few studies reported that there is a mysterious association between the IL28B polymorphism and the hepatitis C virus (HCV) genotype in patients with chronic hepatitis C but they did not give any reason for this phenomenon.ObjectivesThe foremost purpose of this study was to compare the distribution of IL28B genotypes between Iranian healthy individuals and patients with chronic hepatitis C.Patients and MethodsIn this study, 921 patients with chronic hepatitis C and 142 healthy individuals were included. The IL28B rs12979860 and rs8099917 polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.ResultsThe frequency of IL28B rs12979860 CC, CT, and TT genotypes in chronic hepatitis C patients was 38%, 48.8%, and 13.2% and in healthy individuals was 43.7%, 48.6%, and 7.7%. Also, the frequency of IL28B rs8099917 TT, GT, and GG genotypes in chronic hepatitis C patients was 58.3%, 37.1%, and 4.6% and in healthy individuals was 64.1%, 32.4% and 3.5%. The differences in the distribution of IL28B rs12979860 and rs8099917 genotypes between patients with chronic hepatitis C and healthy individuals were not statistically significant. When we compared the distribution of IL28B genotypes between the healthy group and the HCV infected patients by HCV genotype, we found 9.8% higher frequency of rs12979860 CC genotype in the healthy individuals than HCV genotype 1 infected patients (P = 0.03) however there was no significant difference in the distribution of rs12979860 genotypes between the healthy and HCV genotype 3 infected groups (P = 0.46).ConclusionsIt seems that the impact of IL28B polymorphism on the spontaneous clearance of HCV genotype 1 is more prominent than HCV genotype 3 which results in the observation of higher rs12979860 C allele frequency in chronic hepatitis C patients with HCV genotype 3 than HCV genotype 1.

Spontaneous clearance of hepatitis C infection after liver transplantation from IL28B rs12979860 CC donors

Genetic polymorphisms adjacent to IL28B have been previously associated with spontaneous clearance of hepatitis C virus (HCV) and a higher rate of sustained virological response to interferon-based treatment in HCV genotype 1-infected patients. A recent study has shown that patients with the CC genotype of the rs12979860 single nucleotide polymorphism upstream from the IL28B gene are more likely to clear HCV spontaneously relative to the CT or TT genotype. In the liver transplant cohort, HCV recurs almost universally in patients with detectable HCV RNA at the time of transplantation. The spontaneous clearance of HCV infection after transplant is very rare. We report two cases of spontaneous clearance of HCV genotype 1 infection after liver transplantation from homozygous IL28B CC donors. This finding may be explained by alterations in the host immune responses to HCV after transplantation with a CC donor liver, which has potential implications for donor selection in HCV-positive recipients.

Interleukin-28B polymorphisms on the SVR in the treatment of naïve chronic hepatitis C with pegylated interferon-α plus ribavirin: A meta-analysis

There are accurate but inconclusive data on the association between single nucleotide polymorphisms (SNPs) of interleukin (IL)-28B and sustained virological response (SVR) in chronic hepatitis C (CHC). This meta-analysis aimed to derive a more precise estimation of the effects of IL-28B SNPs locus (rs12979860 and rs8099917) on SVR in naïve CHC patients receiving pegylated interferon alpha (PEG-IFN-α) plus ribavirin. Literature search was conducted up to June, 2011, in PubMed, EMBASE and Cochrane Database of Systematic Reviews. A total of 36 studies involving 10912 cases with CHC receiving PEG-IFN-α plus ribavirin met the inclusion criteria. Analyses were stratified either by ethnicity or genotype of hepatitis C virus. In genotype 1/4 patients, rs12979860 CC was associated with high SVR in CHC patients (Caucasian: odds ratio (OR), 4.567; 95% confidence interval (CI), 3.826–5.452; Asian: OR, 4.033; 95%CI, 3.050–5.333; African American: OR, 4.297; 95%CI, 2.168–8.515; Hispanics: OR, 4.350; 95%CI, 2.817–6.717) but had no effect in genotype 2/3. In Caucasian (genotype 1/4: OR, 2.542; 95%CI, 2.108–3.065; genotype 2/3: OR, 1.363; 95%CI, 1.020–1.820) and Asian (genotype 1/4: OR, 5.214; 95%CI, 3.694–7.360; genotype 2/3: OR, 1.785; 95%CI, 1.095–2.910), rs8099917 TT was associated with high SVR in both genotype 1/4 and 2/3. Meta-regression showed that in Caucasians with CHC genotype 1/4, gender male might contribute to the effect of rs12979860 on SVR but advanced fibrosis might weaken this effect. Furthermore, in Asians with CHC genotype 1/4, high baseline viral load and advanced fibrosis might also undermine the effect of rs8099917 on SVR. This meta-analysis suggested that IL-28B rs12979860 CC and rs8099917 TT were associated with high SVR rate in CHC genotype 1/4. In CHC genotype 2/3, rs8099917 TT carriers also had higher SVR.

HCV RNA levels in a multiethnic cohort of injection drug users: Human genetic, viral and demographic associations

In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV enzyme immunoassay were tested for HCV viremia by a branched-chain DNA assay. HCV genotype was determined by sequencing the HCV nonstructural 5B protein region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1,701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). Human immunodeficiency virus type 1 (HIV-1) prevalence was 13.9%. The overall median HCV RNA level was 6.45 log(10) copies/mL. In unadjusted analyses, higher levels were found with older age, male gender, African-American ancestry, hepatitis B virus infection, HIV-1 infection, and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotypes 3 or 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype, and IL28B rs12979860 genotype were all independently associated with HCV RNA. The level of HCV viremia is influenced by a large number of demographic, viral, and human genetic factors.

Factors That Predict Response of Patients With Hepatitis C Virus Infection to Boceprevir

Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors. Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a ≥ 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a <1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed. In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥ 1 log(10) decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR. The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥ 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B.

Meta‐analysis: IL28B polymorphisms predict sustained viral response in HCV patients treated with pegylated interferon‐α and ribavirin

Interleukin (IL) 28B single nucleotide polymorphisms can predict sustained virological response (SVR) in hepatitis C virus (HCV) patients following pegylated interferon-alpha (PEG IFN-α) and ribavirin treatment. To design a meta-analysis to determine IL28B genotypes', rs12979860 CC and rs8099917 TT, correlation with SVR in PEG IFN-α/ribavirin-treated HCV patients. Meta-analysis was performed in 17 studies of rs12979860 CC vs. CT/TT and 17 of rs8099917 TT vs. TG/GG. Odds ratios (OR) and confidence intervals (95% CI) were calculated by fixed- or random-effects models. Heterogeneity, sensitivity analysis and publication bias were also assessed. Of 4252 Asian, Caucasian and African HCV patients analysed for rs12979860, SVR was more frequent in CC (vs. CT/TT; OR = 4.76, 95% CI: 3.15-7.20). Moreover, CC was associated with SVR for HCV genotype-1 or -4 infections (OR(genotype 1) = 5.52, 95% CI: 3.74-8.15; OR(genotype 4) = 8.11, 95% CI: 4.13-15.93), regardless of ethnicity. Of 4549 Caucasian and Asian HCV patients analysed for rs8099917, SVR was more frequent in TT (vs. TG/GG; OR = 3.31, 95% CI: 2.39-4.59). Moreover, TT was associated with SVR for HCV-1 (OR(genotype 1) = 4.28, 95% CI: 2.87-6.38). Rs8099917 TT predictive value was stronger in Asians (OR(Asians) = 8.09, 95% CI: 5.63-11.61; OR(Caucasians) = 3.00, 95% CI: 2.03-4.45). Ethnicity stratification revealed that rs8099917 TT had slight predictive value in Asian HCV-2/3 patients (OR = 1.99, 95% CI: 1.09-3.62). IL28B rs12979860 CC and rs8099917 TT are strong SVR predictors for PEG IFN-α/ribavirin-treated HCV-1 patients, regardless of ethnicity. In HCV-2/3, rs12979860 CC has no SVR predictive value, but rs8099917 TT was slightly associated with SVR in Asians.

Apolipoprotein-E and hepatitis C lipoviral particles in genotype 1 infection: Evidence for an association with interferon sensitivity

Hepatitis C virus (HCV) interacts with apolipoproteins B (apoB) and E (apoE) to form infectious lipoviral particles (LVP). Response to peginterferon is influenced by interferon-stimulated genes (ISGs) and IL28B genotype. LDL cholesterol (LDL-C) also predicts interferon response, therefore we hypothesised that LVP may also be associated with interferon sensitivity. LVP (HCV RNA density ≤1.07 g/ml) and 'non-LVP' (d >1.07 g/ml) were measured in 72 fasted HCV-G1 patients by iodixanol density gradient ultracentrifugation and the LVP ratio (LVP/LVP+non-LVP) was calculated. Fasting lipid profiles and apolipoproteins B and E were measured. Interferon-gamma-inducible protein 10 kDa (IP10), a marker of ISGs, was measured by ELISA. Complete early virological response (EVR) was associated with lower apoE (23.9±7.7 vs. 36.1±15.3 mg/L, p=0.013), higher LDL-C (p=0.039) and lower LVP ratios (p=0.022) compared to null responders. In multivariate linear regression analysis, apoE was independently associated with LVP (R(2) 19.5%, p=0.003) and LVP ratio (p=0.042), and negatively with LDL-C (p<0.001). IP10 was significantly associated with ApoB (p=0.001) and liver stiffness (p=0.032). IL28B rs12979860 CC was associated with complete EVR (p=0.044), low apoE (CC 28±11 vs. CT/TT 35±13 mg/L, p=0.048) and higher non-LVP (p=0.008). Logistic regression analysis indicated that patients with high LVP ratios were less likely to have EVR (odds ratio 0.01, p=0.018). In HCV-G1, interferon sensitivity is characterised by low LVP ratios and low apoE levels in addition to higher LDL-C and IL28B rs12979860 CC. Null-response is associated with increased LVP ratio. The association of apoE and LVP with peginterferon treatment response suggests that lipid modulation is a potential target to modify interferon sensitivity.