Ribavirin Treatment Response Research Articles

MBL2 Genetic Variants in HCV Infection Susceptibility, Spontaneous Viral Clearance and Pegylated Interferon Plus Ribavirin Treatment Response.

Hepatitis C is disease that damages the liver, and it is caused by the hepatitis C virus (HCV). The pathology became chronic in about 80% of the cases due to virus persistence in the host organism. The standard of care consists of pegylated interferon plus ribavirin; however, the treatment response is very variable and different host/viral factors may concur in the disease outcome. The mannose-binding protein C (MBL) is a component of the innate immune system, able to recognize HCV and consecutively activating the immune response. MBL is encoded by MBL2 gene, and polymorphisms, two in the promoter region (H/L and X/Y) and three in exon 1 (at codon 52, 54 and 57), have been described as functionally influencing protein expression. In this work, 203 Italian HCV patients and 61 healthy controls were enrolled and genotyped for the five MBL2 polymorphisms mentioned above to investigate their role in HCV infection susceptibility, spontaneous viral clearance and treatment response. MBL2 polymorphisms were not associated with HCV infection susceptibility and with spontaneous viral clearance, while MBL2 O allele, O/O genotype, HYO haplotype and DP combined genotype (all correlated with low or deficient MBL expression) were associated with sustained virological response. Moreover, a meta-analysis to assess the role of MBL2 polymorphisms in HCV infection susceptibility was also performed: YA haplotype could be associated with protection towards HCV infection.

IL28B rs12980275 polymorphism shows association with response to treatment in Pakistani patients with chronic hepatitis C.

The aim of this study was to describe the genetic characteristics of Pakistani patients infected with hepatitis C virus (HCV) in relation to IL28B polymorphisms and its association to interferon and ribavirin treatment response. A total of 220 patients, infected with HCV were enrolled, out of which 100 were responders and 120 were nonresponders. The whole blood samples were collected to extract viral RNA and genomic DNA. PCR following the restriction fragment length polymorphism method was used to genotype IL28B rs12979860, rs8099917, and rs12980275 polymorphisms. Liver biopsies and HCV genotyping were performed in nonresponder patients. The rs12980275 AA genotype exhibited significant correlation to treatment response and was found in 62% of the responders and 37.5% of nonresponder patients, whereas AG genotype was noticed frequently in the nonresponder group (P < 0.0001). The rs12979860 CT and rs8099917 TT genotypes were found in 74% and 66% of the responders as compared to 58.3% and 50.8% in nonresponder patients (P = 0.001 and P = 0.032) respectively. HCV 3a genotypes were detected in 50.8% of the nonresponder patients. No significant association was detected between liver biopsy findings and IL28B SNPs (P > 0.05). The results showed the significant association of rs12980275 polymorphism with treatment response in HCV patients followed by rs12979860 and rs8099917. This is the first report describing the association of rs12980275 with response to HCV treatment from Pakistan. These findings may help in predicting the outcome of pegylated interferon and ribavirin treatment in HCV patients, and may reduce the side effects and cost of treatment in predicting non-responder patients.

SVR 24 (Sustained Virologic Response) with Current DAA HCV Therapy (Pegylated Interferon alpha 2a/2b, Ribavirin, Telaprevir [TVR]/Boceprevir [BOC]) in Naive and Prior Interferon and Ribavirin Treatment Response (PR)

Purpose: To confirm SVR 24 rates reported in registration DAA HCV therapy trials with TVR/BOC based on naive and patient's treatment history with pegylated interferon and ribavirin (PR). Methods: Retrospective data review of patients considered for G1 DAA HCV therapy from 2011-2013. Ninety of the 139 patients identified in the database met criteria after DAA HCV therapy initiation and SVR 24 analysis. The other 49 patients have not yet completed therapy. Results: The mean age of the 90 patients was 56, with 47 males and 43 females. Ethnic distribution was as follows: 38 (42%) patients were Caucasian, 34 (37%) patients were African-American, 13 were Hispanics (14%), and four were Asians, who represented 4% of the total cohort. Seven of these patients were after a solid organ transplant (Six after liver transplant and one after a simultaneous liver and kidney transplant. Seventy-one (78%) were genotype 1a. All 90 patients were analyzed based on the following characteristics from prior pegylated and interferon treatment (PR): Relapser, non-responder, null responder, unknown treatment response, and naïve to HCV therapy. Concurrently, advanced stages of liver fibrosis (stage 3-4) were evaluated in each of these sub-groups to determine its impact on SVR 24. SVR 24 rates were highest for relapsers, which was (N=19) 68%, non-responders had an SVR24 of (N=17) 24%, null -responders had 4 (0%) SVR. The patients who were in the naïve group had a low SVR (N=35) 37%. There were 15 patients who had no knowledge of their prior PR therapy or had no records supporting their PR, who also had a low SVR24 of 29%. Fourteen patients completed shorter duration (RGT-Response guided therapy) of therapy 24/28 weeks, based on TVR/BOC as the DAA agent. Twenty-six of the 90 patients discontinued DAA HCV therapy from either physical side effects or emotional side effects of therapy. Seven of these patients stopped prior to starting TVR/BOC because of lack of interferon responsiveness (<1 log decline at Week 4) (Table 1).Table: Table. Prior HCV Treatment (PR) and SVR 24 (%) with DAA HCV TherapyConclusion: Relapsers had the highest SVR 24 rates; advanced stage 3-4 fibrosis did not alter the SVR 24 rates in this group. This finding of SVR 24 is lower, but consistent with registration trials for TVR and BOC. The whole cohort of 90 patients had a larger proportion of African Americans (37%), 50% of patients had stage 3-4 fibrosis, and the majority of patients represented genotype 1a (78%), which are not representative of the registration trials of TVR/BOC. These factors contribute negatively to SVR24. We plan on further multivariate analysis of our data to quantify statistical significance of viral factors, host factors, and compliance as determinants of lower SVR 24 rates in the whole cohort, naive, and each sub-group treated with prior PR. Disclosure - Abdullah Mubarak, MD- Speaker Vertex, Merck, Salix.

Serum autoantibodies positivity prevalence in patients with chronic HCV and impact on pegylated interferon and ribavirin treatment response

Prevalence of serum autoantibodies in chronic hepatitis C (HCV) patients is higher than that in the general population. Interferon may induce autoimmune manifestations in patients treated with peg-interferon and ribavirin. Effect of autoantibody seropositivity and treatment response are limited and controversial. To detect the prevalence of serum autoantibodies in patients with chronic HCV and impact on histopathology and treatment response. Retrospective study including 3673 Egyptian chronic HCV naïve patients enrolled in the Egyptian national programme for HCV treatment with pegylated interferon and ribavirin in the years 2007-2010. Antinuclear antibody (ANA) was determined by ELISA considered positive with a titre ≥ 1:40 by indirect immunofluorescence. ANA-positive patients pre treatment workup including serum aminotransferases, thyroid profile and liver biopsy, follow-up during treatment and sustained virological response (SVR) were assessed compared to ANA-negative patients. Serum ANA was positive in 1.6% of the studied patients. There were no statistically significant differences concerning the demographic, biochemical and histopathological data in ANA positive and negative patients. SVR was comparable between ANA-positive and ANA-negative patients (67.8% and 61.3% respectively). Follow-up treatment; ANA-positive patients' did not experience statistically significant haematological complications, flare-up of serum transaminases, thyroid dysfunction. No systemic autoimmune disorders developed during follow-up. ANA positivity is not a factor in chronic HCV disease progression and does not affect the treatment response. Pegylated interferon and ribavirin therapy is safe and effective in autoantibodies-positive chronic HCV patients with no need for further follow-up or worry during the treatment in absence of systemic autoimmune disorders.

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.

Genetic Factors and Hepatitis C Virus Infection

It is now possible to comprehensively screen the human genome for genetic variation that influences the outomes of human disease and pharmacotherapy. The most opular approach remains the genome-wide association tudy (GWAS), in which many hundreds of thousands of enetic markers, representing common variation across he genome, are tested for association with disease. Two uccess stories of the GWAS era are reviewed here: the iscoveries of the association between interleukin-28B IL28B) polymorphism and peginterferon(pegIFN) and ribavirin (RBV) treatment response for genotype 1 HCV, as well as spontaneous clearance of acute HCV infection, and the association between inosine triphosphatase (ITPA) variation and RBV-induced hemolytic anemia. The discovery that IL28B variation is associated with the response to treatment with peginterferon alfa (pegIFN) and ribavirin (RBV) for genotype 1 hepatitis C virus (HCV) was made by 4 independent groups in late 2009 and early 2010.1–4 All identified single nucleotide polymorphisms SNPs) that tag a haplotype block on chromosome 19 spaning IL28B, coding for IFN3, and which strongly predict the outcomes for treatment of chronic genotype 1 HCV infection. Individuals who carry the good response variant have an approximately 2-fold higher rate of sustained virological response (SVR) (Table 1). The top discovery SNPs identified in the GWAS included rs129798601 and rs80999171–4 (note that rs12979860 was only included on the enotyping chip used for the Ge study; rs8099917 was included n the genotyping chips used in all 4 studies). A more compreensive discussion of GWAS methodology is detailed in Manoio et al,5 Pearson et al,6 and Hardy et al.7 In most populations, these 2 SNPs are in strong linkage disequilibrium and are similarly informative, the exception being individuals of African American ancestry, where rs12979860 is more closely associated with treatment outcome. The frequency of the good response allele differs according to ethnic background; it is more common in individuals of Asian Caucasian Hispanic African ancestry.1,8 IL28B allele frequency explains much of the difference in treatment response rates that have been observed between different populations. The good response variant was also noted to be less common among individuals chronically infected with HCV than healthy controls,1 consistent with geetic selection. IL28B variation was subsequently found to be ssociated with spontaneous clearance of HCV infection as ell.4,8–10 The effect size is similar, with patients carrying the ood response variant being 2-fold more likely to naturally clear cute infection. IL28B polymorphism is strongly associated with the iral kinetics of IFN response, where the major influence f the good response variant is to enhance phase 1 deline,11 increasing the rates of critical on-treatment milestones and decreasing relapse (Table 1).12 IL28B genotype is the strongest pretreatment predictor of IFN responsiveness.12 Once treatment has been started, on-treatment iral decline remains the strongest predictor of viral clearnce. Patients carrying the good response IL28B variant re more likely to achieve week-4 rapid virological reponse and week-12 complete early virological response, ut once these milestones have been achieved, SVR rates re high regardless of IL28B genotypes (Table 1). IL28B enotyping and on-treatment viral kinetics can therefore e considered complementary, one being informative prereatment, the other requiring a trial of treatment. The association between IL28B genotype and pegIFN nd RBV treatment response has been considered in a umber of different clinical scenarios. IL28B genotype is relevant to the outcomes of pegIFN and RBV treatment for genotype 1 HCV patients co-infected with human immunodeficiency virus, with similar effect size to that seen in HCV monoinfection.13 It is also relevant to the treatment of genotype 1 HCV in patients after orthotopic liver transplantation.14,15 Both donor and recipient IL28B genotypes have an additive influence on IFN treatment

The Interferon Signaling Pathway Genes as Biomarkers of Hepatitis C Virus Disease Progression and Response to Treatment

Hepatitis C virus is an ever-increasing worldwide health problem with over 350,000 individuals succumbing to hepatitis C virus-related liver diseases each year. The ability to determine the outcome of an acute-phase illness may be useful in terms of implementing treatment strategies; however, to date, the predictive associations in the literature have centered around candidate gene analysis. Much greater advancements have been made in describing biomarkers from the activation of the host innate immune response, such as the interferon system, for prediction of treatment outcome in chronic hepatitis C with the advent of genome-wide association studies. Recent times has seen a major breakthrough in the field with the description of the IL28B genotype as an independent association factor for pegylated IFN-α2b/ribavirin treatment response. The ability to couple this with other easily measured biomarkers such as the interferon-stimulated gene CXCL10, serum concentration may make this predictive marker set very useful in the clinical setting.

Risk score based PEG Interferon alpha 2b and Ribavirin treatment response estimation model for genotype 1 chronic hepatitis C patients

Attempt to create simple practical algorithm for prospective assessment of PEG interferon/ribavirin related treatment response in individuals with chronic hepatitis C (CHC) basing on the risk factors defined prior to the treatment initiation. Retrospective assessment of 45 female and 39 male previously untreated CHC patients aged 20 to 73 years, with genotype 1, undergoing standard treatment with PEG-IFNa2b+RBV was performed. For the final analysis 78 patients were included (38 effectively treated and 40 treatment failures). Thirty-six sustained virological response (SVR) related factors, which were routinely measured before treatment initiation were compared (including physical, biochemical, serologic and histopathologic). From this group the risk factors of the highest predictive value for treatment failure were selected. Cut-off values for statistical significance were defined for each parameter, with risk score (RS) calculated and compared in the group with and without SVR. Seven factors related to treatment failure were identified: HCV>600000 IU/L, blood platelet count <150000/ul, GGTP>45 IU/ml, total serum protein<7.8 g/dl, glycaemia>105 mg/dl, detectable HBc IgG antibodies and cirrhosis. In the group with RS 1 the likelihood of SVR was 70% (p<0.028), while in patients with RS 3 the response was reduced to 23.8% (p<0.016), with no SVR achieved among patients with RS >3. Low risk score (0-2) is associated with high probability of treatment success with scores >3 predictive for treatment failure. The presented model is a simple tool for prediction of treatment success for clinical use before PegIFN/RBV treatment initiation among genotype 1 CHC patients.

IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C

Polymorphisms in the region of the interleukin (IL)28B gene have been associated with pegylated-interferon (PEG-IFN) and ribavirin treatment response mainly in genotype 1 HCV infections. However, there are few data on HCV genotype 4 (HCV-4) infection. We evaluated, in a unique well-characterized cohort of HCV-4 patients, the association of IL28B polymorphism with response to treatment or liver disease severity. This study included 164 HCV-4 patients from different ethnic groups (Egyptian, European, and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. Free DNA extracted from all the 164 patient's serum samples was analyzed by direct sequencing of the SNP rs12979860 of IL28B. Genetic and bio-clinical features from patients having sustained virological response (43 SVR patients) and from those who did not respond to treatment or had a relapse after the end of the treatment (39 NR patients) were compared. IL28B polymorphism was compared between the 78 patients with mild fibrosis (Metavir score F0-F1) and the 82 with advanced fibrosis (F2-F4). Our data showed a better treatment response rate of the C allele of the IL28B gene SNP rs12979860 (p=0.0008). The response rates were 81.8%, 46.5%, and 29.4% for genotype CC, CT, and TT, respectively. No significant relationship was found between rs12979860 and the severity of the disease. The SNP rs12979860 is strongly associated with SVR in patients infected with HCV-4, but not with liver disease severity. Analysis of IL28B genotype might be used to guide treatment for these patients.

A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4+CD25+CD127low/−FoxP3+ T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment

Resolution of hepatitis C virus (HCV) infection requires a complex interplay between innate and adaptative immune responses. The role of lymphocyte subpopulations during combined antiviral treatment remains to be defined. This study was conducted to assess the effect of pegylated interferon-alpha2a (pegIFN-α2a) and ribavirin treatment on peripheral blood lymphocytes, mainly on CD81 expression on B cells and CD4(+) CD25(+) CD127(low/-) FoxP3(+) regulatory T cells (Tregs) in patients with chronic HCV infection. Thirty-five patients with chronic HCV infection who started pegIFN-α2a and ribavirin treatment were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained at baseline before treatment (BT), mid-treatment (MT), the end of treatment (ET) and 24weeks post-treatment (PT). During combined antiviral treatment, a significant decrease in the percentage of CD3(+) , CD8(+) , CD3(+) gamma/delta (γδ)(+) , CD19(+) lymphocyte subpopulations and Tregs was observed. There was also a significant increase in the percentage of the CD4(+) lymphocyte subpopulation and in CD81 expression levels on CD19(+) B cells when BT was compared with ET (all P<0.05). Seventeen patients were nonresponders (NR) and 18 had a sustained virological response (SVR). At baseline, NR patients had higher CD81 expression levels on CD19(+) B cells (P=0.017) and a higher Tregs percentage (P=0.025) than SVR patients. Our results suggest that immunomodulation fluctuates during antiviral treatment and that percentage CD81 expression levels on B cells and Tregs might be useful as an immunological prognostic factor for pegIFN-α2a and ribavirin treatment response in chronic HCV infection.

Peginterferon Alfa-2b and Ribavirin Treatment Response among Hispanic Veterans with Chronic Hepatitis C Genotype 1

Peginterferon Alfa-2b and Ribavirin Treatment Response among Hispanic Veterans with Chronic Hepatitis C Genotype 1