Thyroid Disease in Chronic Hepatitis C Infection Treated With Combination Interferon-a and Ribavirin: Management Strategies and Future Perspective

ObjectiveHepatitis C virus (HCV) infection is one of the major epidemics afflicting young people in both developed and developing countries. The most common endocrine disorder associated with this infection, especially in conjunction with interferon-α (IFN-α)-based therapy, is thyroid disease (TD). This review examines the development of TD before, during, and after the completion of treatment with combination IFN-α and ribavirin (RBV) for chronic HCV infection. We also summarize the current understanding of the natural history of the condition and propose management and follow-up guidelines.MethodsPubMed was searched up to June 30, 2011 for English-language publications that contained the search terms “hepatitis C virus,” “chronic hepatitis C,” “HCV,” “thyroid disease,” “thyroiditis,” “autoimmunity,” “inter-feron-alpha,” and “ribavirin.” Additional publications were identified from the reference lists of identified papers. The included studies were original research publications and included combination IFN-α and RBV use in patients that developed TD.ResultsThe prevalence of TD before combination IFN-α and RBV therapy ranges from 4.6 to 21.3%; during therapy, 1.1 to 21.3%; and after therapy, 6.7 to 21.3%. The most common TD is thyroiditis. Thyroid function testing (TFT) frequency and diagnostic criteria for various thyroid conditions are not standardized, and many of the existing studies are retrospective.ConclusionPatients undergoing this therapy should be assessed with a standardized protocol to appropriately detect and manage developed TD. Based on the currently available literature, we recommend that patients receiving combination interferon-α and RBV therapy undergo monthly thyrotropin (TSH) level testing. (Endocr Pract. 2013;19:292-300)     

PEG-IFN Alpha but Not Ribavirin Alters NK Cell Phenotype and Function in Patients with Chronic Hepatitis C

Background

Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown.

Methods

Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells.

Results

Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56^bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load.

Conclusions

PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.     

Hepatitis C virus RNA replication in human stellate cells regulates gene expression of extracellular matrix-related molecules

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, including chronic hepatitis, fibrosis, and cirrhosis. Fibrosis often develops in HCV-infected livers and ultimately leads to cirrhosis and carcinoma. During fibrosis, hepatic stellate cells (HSC) play important roles in the control of extracellular matrix synthesis and degradation in fibrotic livers. In this study, we established a subgenomic replicon (SGR) cell line with human hepatic stellate cells to investigate the effect of HCV RNA replication on HSC. Isolated SGR clones contained HCV RNA copy numbers ranging from 10⁴ to 10⁷ per μg total RNA, and long-term culture of low-copy number SGR clones resulted in markedly increased HCV RNA copy numbers. Furthermore, HCV RNA replication affected gene expression of extracellular matrix-related molecules in both hepatic stellate cells and hepatic cells, suggesting that HCV RNA replication and/or HCV proteins directly contribute to liver fibrosis. The HCV RNA-replicating hepatic stellate cell line isolated in this study will be useful for investigating hepatic stellate cell functions and HCV replication machinery.     

Host-based ribavirin resistance influences hepatitis C virus replication and treatment response

Many individuals infected with hepatitis C virus (HCV) develop a chronic infection, and of those who are treated with pegylated interferon and ribavirin (RBV), many do not respond. While the nucleoside analog RBV improves treatment outcome, and will likely be an important component of therapy with next-generation viral inhibitors, RBV's mechanism is controversial. Most of RBV's proposed mechanisms require RBV import into cells. Therefore, we explored whether host-based RBV resistance develops through reduced cellular uptake, akin to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on HCV replication in cultured hepatoma Huh7.5 liver cells and whether RBV resistance develops in HCV patients. When Huh7.5 cells were exposed to RBV, resistance developed through reduced RBV uptake via the ENT1 nucleoside transporter and antiviral efficacy was reduced. The uptake defect in RBV-resistant cells was specific to RBV, since transport of another ENT1 substrate, cytidine, was unaffected. Importantly, RBV uptake significantly declined in HCV patient peripheral blood mononuclear cells (PBMCs) following 4 weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance and suggest that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance.     

ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection

Background/ObjectiveGenetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV.ResultsIn total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04–0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64–1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024).ConclusionGenetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently.     

Interferon and Ribavirin Combination Treatment Synergistically Inhibit HCV Internal Ribosome Entry Site Mediated Translation at the Level of Polyribosome Formation

Purpose

Although chronic hepatitis C virus (HCV) infection has been treated with the combination of interferon alpha (IFN-α) and ribavirin (RBV) for over a decade, the mechanism of antiviral synergy is not well understood. We aimed to determine the synergistic antiviral mechanisms of IFN-α and RBV combination treatment using HCV cell culture.

Methods

The antiviral efficacy of IFN-α, RBV alone and in combination was quantitatively measured using HCV infected and replicon cell culture. Direct antiviral activity of these two drugs at the level of HCV internal ribosome entry site (IRES) mediated translation in Huh-7 cell culture was investigated. The synergistic antiviral effect of IFN-α and RBV combination treatment was verified using both the CalcuSyn Software and MacSynergy Software.

Results

RBV combination with IFN-α efficiently inhibits HCV replication cell culture. Our results demonstrate that IFN-α, interferon lambda (IFN-λ) and RBV each inhibit the expression of HCV IRES-GFP and that they have a minimal effect on the expression of GFP in which the translation is not IRES dependent. The combination treatments of RBV along with IFN-α or IFN-λ were highly synergistic with combination indexes <1. We show that IFN-α treatment induce levels of PKR and eIF2α phosphorylation that prevented ribosome loading of the HCV IRES-GFP mRNA. Silencing of PKR expression in Huh-7 cells prevented the inhibitory effect of IFN-α on HCV IRES-GFP expression. RBV also blocked polyribosome loading of HCV-IRES mRNA through the inhibition of cellular IMPDH activity, and induced PKR and eIF2α phosphorylation. Knockdown of PKR or IMPDH prevented RBV induced HCV IRES-GFP translation.

Conclusions

We demonstrated both IFN-α and RBV inhibit HCV IRES through prevention of polyribosome formation. The combination of IFN-α and RBV treatment synergistically inhibits HCV IRES translation via using two different mechanisms involving PKR activation and depletion of intracellular guanosine pool through inhibition of IMPDH.     

The Absence of Thyroid Disease in an Australian Hepatitis C Cohort Treated With Triple Combination Therapy: A Paradigm Shift

Objective: To assess the prevalence of thyroid disease in triple combination therapy with interferon (IFN)-α, ribavirin (RBV), and protease inhibitors (boceprevir and telaprevir) for the treatment of chronic hepatitis C virus (HCV) infection in an Australian hepatitis C cohort. Also, to compare with those who received dual RBV and IFN in the past.Methods: A preliminary, retrospective, and nested case control study of thyroid disease in patients who underwent triple combination therapy for chronic HCV infection compared with dual therapy at a major tertiary referral hospital center. Fifty-nine patients were treated with such therapy at the Hunter New England Area Hepatitis C Treatment Center. Of these, 38 were treated with boceprevir and 21 with telaprevir. All had genotype 1 HCV infection. The main outcome measures included (1) the prevalence of thyroid disease (TD), including hyperthyroidism and hypothyroidism, and (2) thyroid outcome comparison with patients who had received dual therapy.Results: There was no case of TD detected for the entire duration of therapy with triple anti-HCV therapy. There was a significant absence of TD in the protease inhibitor–treated group.Conclusion: No case of TD was detected during the treatment of HCV patients with protease inhibitor–based triple therapy. The reasons for this are unclear. Larger studies are necessary to confirm this finding.Abbreviations: CV = coefficient of variation fT₃ = free triiodothyronine fT₄ = free thyroxine HCV = hepatitis C virus IFN-α = interferon-alpha PI = protease inhibitor RBV = ribavirin TD = thyroid disease TSH = thyroid-stimulating hormone TTX = thyrotoxicosis     

Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA

Ribavirin (RBV), used in combination with alpha interferon to treat hepatitis C virus (HCV) infections, is a guanosine nucleotide analog that can increase the error rate of viral RNA-dependent RNA polymerases, imbalance intracellular nucleotide pools, and cause toxicity in many cell types. To determine potential mechanisms of RBV resistance during HCV RNA replication, we passaged HCV replicon-containing cell lines in the presence of increasing concentrations of RBV. RBV-resistant, HCV replicon-containing cell lines were generated, and the majority of RBV resistance was found to be conferred by changes in the cell lines. The resistant cell lines were defective in RBV import, as measured by [(3)H]RBV uptake experiments. These cell lines displayed reduced RBV toxicity and reduced error accumulation during infection with poliovirus, whose replication is known to be sensitive to RBV-induced error. For one RBV-resistant isolate, two mutations in the replicon RNA contributed to the observed phenotype. Two responsible mutations resided in the C-terminal region of NS5A, G404S, and E442G and were each sufficient for low-level RBV resistance. Therefore, RBV resistance in HCV replicon cell lines can be conferred by changes in the cell line or by mutations in the HCV replicon.     

CD100 Up-Regulation Induced by Interferon-α on B Cells Is Related to Hepatitis C Virus Infection

Objectives

CD100, also known as Sema4D, is a member of the semaphorin family and has important regulatory functions that promote immune cell activation and responses. The role of CD100 expression on B cells in immune regulation during chronic hepatitis C virus (HCV) infection remains unclear.

Materials and Methods

We longitudinally investigated the altered expression of CD100, its receptor CD72, and other activation markers CD69 and CD86 on B cells in 20 chronic HCV-infected patients before and after treatment with pegylated interferon-alpha (Peg-IFN-α) and ribavirin (RBV) by flow cytometry.

Results

The frequency of CD5⁺ B cells as well as the expression levels of CD100, CD69 and CD86 was significantly increased in chronic HCV patients and returned to normal in patients with sustained virological response after discontinuation of IFN-α/RBV therapy. Upon IFN-α treatment, CD100 expression on B cells and the two subsets was further up-regulated in patients who achieved early virological response, and this was confirmed by in vitro experiments. Moreover, the increased CD100 expression via IFN-α was inversely correlated with the decline of the HCV-RNA titer during early-phase treatment.

Conclusions

Peripheral B cells show an activated phenotype during chronic HCV infection. Moreover, IFN-α therapy facilitates the reversion of disrupted B cell homeostasis, and up-regulated expression of CD100 may be indirectly related to HCV clearance.     

Prediction of effect of pegylated interferon alpha-2b plus ribavirin combination therapy in patients with chronic hepatitis C infection

Treatment with pegylated interferon alpha-2b (PEGIFN) plus ribavirin (RBV) is standard therapy for patients with chronic hepatitis C. Although the effectiveness, patients with high titres of group Ib hepatitis C virus (HCV) respond poorly compared to other genotypes. At present, we cannot predict the effect in an individual. Previous studies have used traditional statistical analysis by assuming a linear relationship between clinical features, but most phenomena in the clinical situation are not linearly related. The aim of this study is to predict the effect of PEG IFN plus RBV therapy on an individual patient level using an artificial neural network system (ANN). 156 patients with HCV group 1b from multiple centres were treated with PEGIFN (1.5 μg/kg) plus RBV (400-1000 mg) for 48 weeks. Data on the patients' demographics, laboratory tests, PEGIFN, and RBV doses, early viral responses (EVR), and sustained viral responses were collected. Clinical data were randomly divided into training data set and validation data set and analyzed using multiple logistic regression analysis (MLRs) and ANN to predict individual outcomes. The sensitivities of predictive expression were 0.45 for the MLRs models and 0.82 for the ANNs and specificities were 0.55 for the MLR and 0.88 for the ANN. Non-linear relation analysis showed that EVR, serum creatinine, initial dose of Ribavirin, gender and age were important predictive factors, suggesting non-linearly related to outcome. In conclusion, ANN was more accurate than MLRs in predicting the outcome of PEGIFN plus RBV therapy in patients with group 1b HCV.     

Pre-Existing HCV Variants Resistant to DAAs and Their Sensitivity to PegIFN/RBV in Chinese HCV Genotype 1b Patients

BackgroundThe efficacy of direct-acting antiviral agents (DAAs) could be attenuated by the presence of resistance-associated variants (RAVs). The aim of this study was to investigate the natural prevalence of RAVs among Chinese HCV genotype 1b patients and analyze the efficacy of pegylated interferon (PegIFN)/ribavirin (RBV) therapy in patients with and without RAVs at baseline.MethodsDirect sequencing of the HCV NS3, NS5A and NS5B regions was performed in baseline serum samples of 117 DAAs-naïve subjects infected with HCV genotype 1b. The efficacy of PegIFN/RBV therapy in patients with and without RAVs at baseline was analyzed by comparing the response rates between patients with RAVs and patients with wild type virus.ResultsThe incidence of RAVs was 8.00% (8/100) in the NS3 region (T54S, n = 1, 1.00%; R117H, n = 5, 5.00%; S122T, n = 1, 1.00%; S174F, n = 1, 1.00%), 29.91% (32/107) in the NS5A region (L28M, n = 12, 11.21%; R30Q, n = 10, 9.35%; L31M, n = 1, 0.93%; P58S, n = 4, 3.74%; Y93H, n = 8, 7.48%) and 98.15% (106/108) in the NS5B region (L159F, n = 1, 0.93%; C316N, n = 103, 95.37%; A421V, n = 6, 5.56%). The response rates to PegIFN/RBV treatment did not differ between patients with or without RAVs in the NS5A region.ConclusionsPre-existing RAVs, including key RAVs, were detected in Chinese DAAs-naïve patients infected with HCV genotype 1b. IFN-based therapy could be a good option for patients with RAVs, especially key RAVs, at baseline.     

Impaired Expression of Type I and Type II Interferon Receptors in HCV-Associated Chronic Liver Disease and Liver Cirrhosis

Purpose

Chronic Hepatitis C Virus (HCV)-infected patients with liver cirrhosis (LC) respond poorly to interferon-alpha (IFN-α) and ribavirin (RBV) combination therapy, but the reason for this is unclear. We previously reported that HCV-infection induces endoplasmic reticulum (ER) stress and autophagy response that selectively down regulates the type I IFN-α receptor-1 (IFNAR1) and RBV transporters (CNT1 and ENT1), leading to IFN-α/RBV resistance. The goal of this study is to verify whether an increase in ER stress and autophagy response is also associated with the reduced expression of IFNAR1 and RBV transporters in chronic HCV-infected patients.

Methods

Primary human hepatocytes (PHH) were infected with cell culture grown HCV particles (JFH-ΔV3-Rluc). HCV replication was confirmed by the detection of viral RNA by RT-qPCR and HCV-core protein by Western blotting. The ER stress and autophagy response and expression of IFN receptors and RBV transporters in HCV infected PHH and liver tissues derived from patients were measured by Western blotting.

Result

HCV infection of PHH showed impaired expression of IFNAR1, IFNγR1 (Type II IFN receptor) and RBV transporters but not IL10Rβ (Type III IFN-λ receptor). ER stress markers (BiP, IRE1α and peIF2α) and autophagy response (LC3II, Beclin 1 and ATG5) were induced in HCV infected chronic liver disease (CLD) and LC patients. Liver biopsies (CLD) show a 50% reduced expression of IFNAR1 and RBV transporters. Furthermore, the expression of IFNAR1 and RBV transporters was impaired in almost all LC patients.

Conclusion

HCV infection induces ER stress and autophagy response in infected PHH and chronically infected liver tissues. The expression of IFNAR1, IFNγR1 and RBV transporters were significantly impaired in CLD and cirrhotic livers. Our study provides a potential explanation for the reduced response rate of IFN-α and RBV combination therapy in HCV infected patients with liver cirrhosis.     

Kinetic response of wild and mutant core codon 70 strains of HCV genotype 1b to pegylated interferon-α and ribavirin therapy

Background

Amino acid (aa) 70 substitution (R70Q/H) in the core protein of hepatitis C virus (HCV) genotype 1b has been shown to be one of the key factors in determining resistance for pegylated interferon-α plus ribavirin combination therapy (PEG-IFNα/RBV). But the exact mechanisms remain unclear. The aim of this study was to investigate the dynamic response of wild and mutant core codon 70 strains to PEG-IFNα/RBV treatment.

Methods

One hundred twelve Chinese patients with chronic HCV 1b infection were enrolled and received a standard protocol of 48 weeks of PEG-IFNα/RBV therapy and 24 consecutive weeks of follow-up. Serial blood samples were obtained at pretreatment baseline, and again at weeks 2, 4, 8, 12, and 24 during therapy for the quantification of 70R and 70Q/H strains. Dynamic characteristics and association with early virological response (EVR), sustained virological response (SVR) and IL28B genotypes were analyzed.

Results

Of the 112 patients enrolled in this study, 93.8 % (105/112) were infected with mixture of 70R and 70Q/H strains before treatment. The 70Q/H strain was dominant in 20.5 % of patients. 42.9 % of patients with dominant 70Q/H exhibited EVR versus 88.6 % of patients with dominant 70R (P?<?0.001). Furthermore, 35.0 % of patients with dominant 70Q/H exhibited SVR versus 77.4 % with dominant 70R (P?<?0.001). However, regardless of the dominant strain, virological response types or the IL28B SNP genotypes, 70Q/H strains always exhibited the same response to treatment as the 70R strains and the percentage of HCV harboring the 70Q/H substitution did not change significantly during treatment.

Conclusions

Although the ratio of 70Q/H to 70R is related to the virological response, 70Q/H strains always exhibited the same response as the 70R strains during PEG-IFNα/RBV treatment. Substitution of R70Q/H alone is not enough to lead to resistance to therapy. Positive selection for 70Q/H induced by IFNα was not observed.

     

Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C

The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy.     

Hepatitis C virus resistance to interferon therapy: an alarming situation

Hepatitis C virus is presently a major public health problem across the globe. The main objective in treating hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). Interferon-α (IFN-α) and pegylated interferon (PegIFN) in combination with Ribavirin (RBV) are the choice of treatment nowadays against chronic hepatitis C. There are several mechanisms evolved by the hepatitis C virus that facilitate the persistence of virus and further lead the patient’s status as non responder. Various factors involved in patient’s lack ofresponse to the therapy include: (1) viral factors, (2) host factors, (3) molecular mechanisms related to the lack of response and (4) social factors. Herein we have made an attempt to summarize all the related predictors of drug resistance in one article so that the future polices can be planned to overcome this obstacle and potential therapies can be designed by considering these factors.     

Pretreatment Predictors of Response to PegIFN-RBV Therapy in Egyptian Patients with HCV Genotype 4

BackgroundEgypt has the highest prevalence of a difficult to treat chronic hepatitis C virus (HCV), genotype 4. Pretreatment factors could guide individualization of therapy which aids in treatment optimization and interleukin IL28B gene polymorphism has been shown to closely relate to HCV treatment response. Polymorphisms in genes encoding inhibitors of T-cell response, which have role in disease progression as Programmed Cell Death 1 (PD-1), and Cytotoxic T-Lymphocytes Antigen-4 (CTLA-4), could be candidate markers predicting treatment response.MethodsThis cohort study consisted of 200 chronic HCV genotype 4 infected patients treated with PegIFN α-2a and RBV in 2 hepatology centers. Genotyping of the polymorphisms in the IL28B gene region (rs12979860), PD1.3 (rs11568821) and CTLA-4 (rs231775) was performed on DNA collected from each patient using TaqMan^® genotyping assay. Groups were classified according to response into sustained virological responders (SVR), or non-responders (NR). A multivariate logistic regression analysis was used to identify potential markers, host pretreatment clinical and viral predictive factors including viral load, insulin resistance, and alpha fetoprotein (AFP) related to treatment response.ResultsOur results showed that in a multivariate analyses IL28B C/C genotype was the most significant predictor for SVR (OR = 10.86; p<0.0001) followed by AFP (OR = 0.915; p = 0.001) then CTLA-4/G genotypes (OR = 1.948; p = 0.022). However, PD-1.3/A genotypes and platelets count were significantly related to response in univariate analysis only (OR = 1.973; p = 0.023; OR = 1.007; p = 0.009 respectively).ConclusionIL28B SNP, AFP level, and CTLA-4 SNP could be used in conjunction to predict treatment response in HCV genotype 4 infected Egyptian patients.     

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.     

Anti-interferon-α neutralizing antibody induced telaprevir resistance under the interferon-α plus telaprevir treatment in vitro

Although the development of anti-interferon (IFN)-α neutralizing antibodies (NAbs) is likely to be a common clinical problem for patients with various diseases treated with IFN, anti-IFN-α NAb has been exceptionally considered to have no clinical significance in the treatment of chronic hepatitis C with pegylated IFN-α (Peg-IFN-α). However, we recently clarified that the presence of NAb was associated with a non-response to the Peg-IFN plus ribavirin (RBV) therapy. In this study, we used the HCV-replicon system with genotype 1b, and investigated the role of anti-IFN-α NAb in the response to telaprevir (TVR)-containing new antiviral therapy for hepatitis C virus (HCV). Anti-IFN-α NAb-positive sera specifically inhibited the anti-HCV effects of IFN-α, without any effect on the activity of IFN-β in vitro. The NAb-positive sera also inhibited the IFN-α-dependent induction of interferon-stimulated genes, MxA and OAS-1, in a dose-dependent manner. Although TVR monotherapy decreased the HCV-RNA in vitro, the HCV-RNA was increased again with the development of TVR-resistant mutations. When IFN-α was administrated with TVR, the replication of HCV was continuously suppressed for more than a month. However, in the presence of anti-IFN-α NAb-positive sera, even when IFN-α was combined with TVR, the levels of HCV-RNA exhibited a time-course similar to that with TVR monotherapy, and HCV with TVR-resistant mutations emerged. In conclusion, our findings suggest that the presence of IFN-α NAb decreases the antiviral effects of IFN-α and may be related to the development of TVR-resistant mutated viruses.     

Cytokines genes polymorphisms in chronic hepatitis C: Impact on susceptibility to infection and response to therapy

BackgroundCytokines play a key role in the regulation of immune responses. In hepatitis C virus infection, the production of abnormal cytokine levels appears to contribute in the progression of the disease, viral persistence, and affects response to therapy. Cytokine genes polymorphisms located within the coding/regulatory regions have been shown to affect the overall expression and secretion of cytokines. The aim of the study was to evaluate the association of of IL28B rs12979860, TGF-β1-509, TNF-α 308, and IL-10-1082 polymorphisms with the susceptibility to hepatitis C virus genotype 4 infection and response to pegylated interferon-α and ribavirin therapy.MethodsIL28B, TGF-β1 and TNF-α genes polymorphisms were genotyped using polymerase chain reaction (PCR)-based restriction fragment length polymorphism assay while IL-10 gene polymorphism was detected by sequence specific primer-PCR in 220 healthy individuals and 440 hepatitis C infected patients (220 sustained virological response and 220 non-responder to combination therapy).ResultsIL28 B CT and TT, TGF-β1 CT and TT and TNF-α AG and AA genotypes were significantly associated with susceptibility to hepatitis C infection and response to therapy. While no association was found between IL-10 gene polymorphism and susceptibility to HCV infection and response to treatment.ConclusionsThese results suggested that inheritance of IL28B CT and TT, TGF-β1 CT and TT and TNF-α AG and AA genotypes which appear to affect the cytokine production may be associated with susceptibility to HCV infection and resistance to combined antiviral therapy.