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Introduction: Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naïve or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy., Material and Methods: We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon-free treatment with DAA±RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients., Results: A significant association was observed between presence of anti-E1E2 and HCV viral load<6log10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level., Conclusions: The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (<6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background and Aims: We previously showed that pre-treatment serum anti-E1E2 predicted hepatitis C virus (HCV) RNA viral kinetics (VKs) and treatment outcome in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (Peg-IFN/RBV) double therapy. Here, we determined whether baseline anti-E1E2 was correlated with the on-treatment VK and could predict virological outcome in treatment-experienced HCV-infected cirrhotic patients receiving protease inhibitor-based triple therapy., Methods: Sera from 19 patients with HCV genotype 1 infection and compensated cirrhosis who failed to respond to a prior course of Peg-IFN/RBV were selected at time 0 before starting triple therapy with boceprevir or telaprevir. We assessed patients with sustained viral response 12 weeks after the end of triple therapy (SVR12) by analyzing VKs at weeks 4, 12, 24, 36, 48 (end of treatment) and 60., Results: Patients baseline characteristics were similar to the well-defined CUPIC cohort (age, HCV subtype, baseline viremia, and treatment history). Among the 19 patients, 11 achieved an SVR12. Fifteen patients were positive for pre-treatment anti-E1E2 and all of them achieved SVR12. Moreover, anti-E1E2 and SVR12 correlated with prior response to IFN/RBV therapy (relapse, partial or null response)., Conclusions: Baseline anti-E1E2 could be considered as a new biomarker to predict SVR12 after triple therapy in this most difficult-to-treat population. These results warrant further validation on larger cohorts including patients receiving highly effective direct-acting antivirals to explore whether this test could help in better defining treatment duration for these very costly molecules., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma. Current therapy based on pegylated-interferon-α (PEG-IFN) and ribavirin (RBV) combination has limited efficacy and is poorly tolerated. Disease progression is highly variable and pre-therapeutic prediction of response to treatment remains difficult. Although viral kinetics proved most useful to monitor duration of therapy, other predictors would be helpful to identify patients with the best chance of subsequent treatment response prior initiation of antiviral therapy (double or triple therapy). The predictive power of IL28B polymorphism is well-recognized and has become the reference biomarker for clinicians in patients treated with double therapy. The combination of serum IP-10 and IL28B SNPs increases predictive value of treatment response. Recently, anti-E1E2 antibodies appear to closely correlate with therapeutic outcome and predict the complete elimination of HCV. They may represent a new relevant prognostic biomarker of double therapy response. Since the introduction of triple therapy including protease inhibitors (telaprevir/boceprevir), the major priority is to help patients who failed on double therapy, and there is now an urgent need for robust pre-therapeutic predictors of response to better select the patients to treat. Indeed, the relevance of IL28B polymorphism and IP-10 serum concentration are limited in triple therapy. Many new drugs are currently under investigation and there is hope that effective and well-tolerated IFN-free regimens may become a part of future therapy. In this context, this will help to identify the most powerful predictive marker and/or to assess the benefit of anti-E1E2 in decision to treat., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Unique serum anti-E1E2 antibodies were shown to be associated with spontaneous recovery or predictive of sustained virological response (SVR) in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (PEG-IFN/RBV) therapy. The objectives were to establish the relationship between pretreatment anti-E1E2 titres and HCV RNA kinetics during PEG-IFN/RBV therapy, and to examine whether the combined determination of interleukin (IL)28B rs12979860 and rs8099917, pretreatment inducible protein (IP)-10 levels and/or anti-E1E2 improved the prediction of SVR., Methods: Sera from 26 treatment-naive consecutive HCV patients treated with PEG-IFN/RBV for 48 weeks were analysed. Serum anti-E1E2 titres and pretreatment IP-10 levels were measured by enzyme-linked immunosorbent assays. The IL28B variants were determined using genotyping real-time polymerase chain reaction method. Viral decline was measured at weeks (W) 4 and 12 and SVR assessed 6 months after the end of therapy., Results: Baseline anti-E1E2 titres were correlated with HCV RNA decline at W4 and W12 and were highly predictive of SVR with 100% of patients negative for anti-E1E2 failing to achieve SVR. Receiver operating characteristic curve analyses indicate that the best prediction of SVR (AUC 0.990) was obtained with the combination of anti-E1E2 and IP-10 levels. Predictive values were better than those obtained with IP-10 alone or in combination with IL28B variants., Conclusions: Pretreatment serum anti-E1E2 response predicts HCV RNA clearance kinetics and treatment outcome. The combination of anti-E1E2 and IP-10 significantly improved the prediction of treatment response. This warrants further investigation and validation on larger cohorts of patients in the context of new therapeutic strategies.

Background & Aims: Therapy for chronic hepatitis C (CHC) has limited efficacy, adverse effects, and high costs. Cohort and vaccine-based preclinical studies have indicated the importance of T-cell-based immunity in controlling viral infection. TG4040 is a recombinant poxvirus vaccine that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase I clinical trial to assess the safety, immunogenicity, and early antiviral efficacy of TG4040 in patients with CHC., Methods: In an open-label, dose-escalating study, patients with mild CHC (genotype 1) were assigned to 3 groups of 3 patients each; they received subcutaneous injections of 10⁶, 10⁷, or 10⁸ plaque-forming units of TG4040 on study days 1, 8, and 15. Six additional patients were given the highest dose of vaccine (10⁸ plaque-forming units). Patients were followed for 6 months after the last injection. T-cell-based and antibody responses and levels of HCV RNA were measured., Results: All 3 doses of TG4040 were well tolerated, without serious adverse events. Vaccine-induced HCV-specific cellular immune responses were observed in 5 of the 15 patients (33%). A transient decrease in circulating levels of HCV RNA, from -0.52 log₁₀ to -1.24 log₁₀, was observed in 8 patients; in 5 patients, the lowest level of HCV RNA was observed on day 37, after the first injection. The most pronounced decrease in viral load occurred in 2 patients, who also had marked vaccine-induced T-cell responses., Conclusions: In patients with CHC, the viral-vector-based vaccine TG4040 had a good safety profile, induced HCV-specific cellular immune responses, and reduced viral load. This vaccine should be investigated in further clinical studies, in combination with standard of care., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test., Methods: Two separate cohorts of HCV patients (Brussels, Belgium/Hannover, Germany) were retrospectively analyzed. Only patients with a fibrosis Ishak or METAVIR score of F0-F1 at baseline were included. Patients were classified as progressors if they showed an increase ≥2 fibrosis stages at the second histological evaluation after a follow-up ≥5years. The CRS was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis., Results: In Brussels, 12/25 patients progressed (48%); similarly in Hannover, 16/31 (52%) patients progressed. In both sample sets, the CRS was significantly associated with fibrosis progression (p=0.050 in Brussels; p=0.018 in Hannover). The ELF test was only a significant predictor in Hannover (p=0.015). In multivariate analysis the CRS remained the only variable associated with fibrosis progression (odds-ratio=2.23, 95%CI 1.21-4.11 p=0.01)., Conclusions: Although conducted on a limited number of patients, this study in two independent centres confirms that the CRS predicts fibrosis progression in initially mild CHC., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n = 229]; Hannover, Germany [n = 171]; Lyon, France [n = 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P = 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P = 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P = 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P = 0.875) and did not influence clinical or biological variables., Conclusion: The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Hepatitis C virus (HCV) infections pose a growing challenge to health care systems. Although chronic HCV infection begins as an asymptomatic condition with few short-term effects, it can progress to cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and death. The rate of new HCV infections is decreasing, yet the number of infected people with complications of the disease is increasing. In the United States, people born between 1945 and 1964 (baby boomers) are developing more complications of infection. Men and African Americans have a higher prevalence of HCV infection. Progression of fibrosis can be accelerated by factors such as older age, duration of HCV infection, sex, and alcohol intake. Furthermore, insulin resistance can cause hepatic steatosis and is associated with fibrosis progression and inflammation. If more effective therapies are not adopted for HCV, more than 1 million patients could develop HCV-related cirrhosis, hepatic decompensation, or HCC by 2020, which will impact the US health care system. It is important to recognize the impact of HCV on liver disease progression and apply new therapeutic strategies., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Therapy of chronic hepatitis C presently achieves 60% of sustained virological response, with clear on improvement of liver histology. Failure to eradicate HCV infection does not mean that the patient is non-responsive to therapy and indeed most patients improve biochemically and histologically. The objective of maintenance therapy is therefore to reduce fibrosis progression and its complications. Meta-analysis of 4 registration pivotal trials revealed that 40% of patients who failed to clear HCV at the end of therapy, improved histologically. 3 large long term prospective studies in mostly advanced patients have also addressed the issue of maintenance therapy: HALT-C, COPILOT, EPIC 3. Interim analysis at 2 years of the COPILOT study in particular reveals that only 20% patients receiving low dose peg-interferon versus 39% in the placebo colchicine group reached complication end points. Prospective and retrospective studies, controlled or not, do also indicate a significant trend towards reduced incidence of HCC in patients receiving long term interferon therapy. Potent new anti-HCV small molecules will soon become available and will undoubtedly increase dramatically the cure rate. It is critical therefore for the moment to protect as many patients as possible from irreversible deterioration.

Background & Aims: The impact of interferon (IFN) treatment on the occurrence of complications related to hepatitis C virus (HCV)-related cirrhosis is debated because the majority of studies are retrospective. We designed a randomized controlled trial comparing the efficacy of prolonged IFN alfa-2a treatment vs nontreatment on complication-free survival in patients with compensated HCV cirrhosis., Methods: A total of 102 patients (mean age, 60.5 +/- 9.5 y; male/female ratio, .82) with biopsy examination-proven HCV cirrhosis, Child-Pugh score A, who were hepatocellular carcinoma (HCC) free, and had at least 1 risk factor of complications were randomized to receive IFN or no therapy for 24 months., Results: During the follow-up evaluation, the complication rate was 24.5%: HCC occurred in 12 and decompensation unrelated to HCC occurred in 13 patients. The number of HCC patients was similar in both groups. The probability of complication-free survival was not significantly different between treated and untreated patients (98% and 72.3% vs 90% and 70.7% at 12 and 24 mo, respectively, P = .59). The median time until complication occurrence was 17.1 months in the treated group vs 13.6 months in the untreated group (P = .2)., Conclusions: This randomized controlled trial showed that a 2-year course of IFN has little or no impact on complication-free survival in patients with high-risk compensated HCV cirrhosis.

HCV particles were isolated from the plasma of chronically infected patients. The virus was analysed by sucrose density gradient centrifugation. The fractions were tested for viral RNA, core antigen and envelope proteins by using a monoclonal antibody directed against the natural E1E2 complex (D32.10). Two populations of particles containing RNA plus core antigen were separated: the first with a density of 1.06-1.08 g/ml did not contain the envelope proteins; the second with a density between 1.17 and 1.21 g/ml expressed both E1 and E2 glycoproteins. Electron microscopy of the enveloped population after immunoprecipitation with D32.10 showed spherical particles with a rather featureless surface and with a diameter around 40 nm. Immuno-gold staining gave evidence that the E1E2 complex was indeed positioned at the surface of these particles.

We report the case of a 56 year-old woman with post-transfusion chronic hepatitis C who presented with a severe ALT flare up associated with a rapid progression of liver fibrosis during interferon alpha 2b therapy. Several hypotheses were considered to explain the etiology of this ALT flare: there was no viral super infection by other hepatotropic viruses, no toxic hepatitis, no metabolic disease, and no other specific liver diseases could be identified. HLA typing showed a specific profile A1 B8 DR3 (risk factor of auto-immunization during interferon alpha therapy) with antinuclear antibodies and anti smooth muscle antibodies. This case suggests that auto-immunization induced by interferon alpha should be investigated in case of ALT flare that is not followed by an HCV breakthrough.

To clarify whether some of the functions of B lymphocytes could be affected during hepatitis C virus (HCV) infection, phenotypic characteristics of B lymphocytes from HCV-infected patients and their capacity to differentiate into immunoglobulins (Ig)-secreting cells were studied. B lymphocytes differentiation was investigated for patients untreated and non-responders (n=9), treated and non-responders (n=6), responders (n=6), long-term responders (n=9) to therapy and seronegative controls (n=14) following in vitro stimulation with S. aureus strain Cowan I mitogen. HCV sequences in purified B lymphocytes were detected by RT-PCR. It was found that HCV-patients harbor a similar mean percentage of B cells and a normal level of naïve B cells (% IgM+/IgD+ cells=79.7 +/- 15.4 for untreated non-responders, 57.1 +/- 22.9 for treated non-responders, 44.3 +/- 29.1 for responders, 75.7 +/- 16 for long-term responders) as compared with controls. It was also found that peripheral blood mononuclear cells (PBMCs) of patients or controls produced similar amounts of IgG, A, and M in vitro. A total of 57% of untreated non-responders versus 17% of treated non-responders were able to produce HCV-specific antibodies. Interestingly, B lymphocytes from PBMCs able to secrete anti-HCV antibodies contained HCV positive strand RNA, although no systematic detection of the negative strand was found. These data suggest that signaling through the B cell receptor (BCR) in B lymphocytes of HCV-infected patients appears normal whatever their response to therapy. The capacity to secrete HCV-specific IgG seemed to be linked to the presence of positive strand RNA rather than virus replication., (Copyright 2004 Wiley-Liss, Inc.)

The aim of this retrospective study was to determine the predictive value of alanine aminotransferase (ALT) levels for histologic findings in patients with chronic hepatitis C virus (HCV) infection. Data on 864 HCV RNA-positive patients were collected. ALT values were obtained at the time of biopsy (before treatment), and normal ALT values were defined as normal values obtained at serial evaluations during a 6-month period. Histologic results were scored using the METAVIR system. Among all patients, 99% of those with elevated ALT levels had a score of at least F1 (positive predictive value [PPV], 99%) and 88% had a score greater than A1F1. Among patients with persistently normal ALT values, 65% had a score of at least F1 (negative predictive value [NPV], 35%) and 26% had a score greater than A1F1. The receiver operating characteristics analysis indicates that the ALT threshold for the best compromise sensitivity-specificity was about 2.25 times the upper limit of normal (ULN). In conclusion, almost all HCV RNA-positive patients with elevated ALT levels have some degree of fibrosis. However, an important proportion of patients with persistently normal ALT levels also show some histologic signs of fibrosis; the degree of fibrosis is usually mild but is sometimes more marked, and in rare cases cirrhosis may be present. In this subset of patients, the indication of liver biopsy and the potential benefit of therapy need to be further evaluated. These results suggest the need to revisit the algorithm for liver biopsy practice.