Clinical and histopathological changes in different KIR gene profiles in chronic HCV Romanian patients.

Hepatitis C virus (HCV)-infected individuals may have a faster progression of liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development when influenced by host, viral and environmental factors. Hepatitis C virus disease progression is also associated with genetic variants of specific killer cell immunoglobulin-like receptors (KIRs) and genes of the major histocompatibility complex (MHC). The aim of the present study was to correlate clinical, virologic and biochemical parameters and to evaluate the possible influence of KIR genes and their HLA class I ligands in patients infected with hepatitis C virus. The present study analysed a total of 127 chronic HCV-infected patients for various biochemical and genetics factors that can influence disease progression and prognosis. Liver function parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), direct bilirubin (DB), alpha-fetoprotein (AFP), HCV RNA levels and fibrosis indices were analysed using well-established biochemical methods. At the same time, KIR and HLA genotyping was performed using a polymerase chain reaction sequence-specific primer technique. Analysis of HLA class I and HLA ligands revealed that HLA-C*12:02 and HLA-A3 and HLA-A11 were positively associated with the F3-F4 fibrosis group (p = .026; OR = 8.717, CI = 1.040-73.077; respectively, p = .047; OR = 2.187; 95% CI = 1.066-4.486). KIR2DL2-positive patients had high median levels of AST after treatment and direct bilirubin levels when compared to KIR2DL2-negative patients (p = .013, respectively, p = .028). KIR2DL2/KIR2DL2-C1C1 genotype was associated with increased AST, ALT and GGT levels. A higher GGT level was also observed in KIR2DS2-C1-positive patients when compared to KIR2DS2-C1-negative patients. The present research demonstrates several links between specific clinical, virologic and biochemical parameters and the expression of KIR genes and their HLA ligands in HCV-infected patients. These connections should be taken into account when considering disease development and treatment.

Maintenance interferon therapy in chronic hepatitis C patients who failed initial antiviral therapy: A meta-analysis.

OBJECTIVES: To evaluate the effect of pegylated interferon maintenance therapy in patients with chronic hepatitis C who failed initial antiviral therapy. METHODS: This is a meta-analysis of 6 randomized controlled trials that met the eligibility criteria. In all, 2438 chronic hepatitis C patients who failed to achieve sustained virologic response after initial treatment with pegylated interferon and ribavirin (antiviral therapy nonresponders or relapsers) were enrolled; 1237 patients received maintenance therapy (Maintenance group) and 1201 received no treatment (Observation group). RESULTS: The pooled analyses found that patients in the Maintenance group had a significantly higher rate of normal alanine aminotransferase than did patients in the Observation group (pooled odds ratio [OR] 4.436, 95% confidence interval [CI] 1.225-16.064, P = .023), but there was no significant difference between the 2 groups in the incidence of hepatocellular carcinoma (pooled OR 0.872, 95% CI 0.501-1.519, P = .630), or the mortality rate (pooled OR 1.564, 95% CI 0.807-3.032, P = .185). CONCLUSIONS: Interferon-based maintenance therapy in patients with chronic hepatitis C who failed initial antiviral therapy improved liver inflammation as indicated by blood chemistry (alanine aminotransferase).

Occurrence of hepatocellular carcinoma 24 years after successful interferon therapy in a patient with chronic hepatitis C: a case report.

An 82-year-old man presented with hepatocellular carcinomas (HCCs) 24 years after achieving a sustained virological response (SVR) to an interferon for hepatitis C. His hepatic fibrosis stage was F1 when he was treated at 58 years. He was followed-up by annual blood tests and abdominal ultrasonography or computed tomography. After the IFN treatment, he had drunk approximately 100 g of ethanol. Serum aspartate aminotransferase and gamma-glutamyl transpeptidase levels had been elevated since 2012. To investigate the possible factors that affect hepatocarcinogenesis over 10 years after achieving an SVR, we reviewed the literature. Of 39 reported patients, 26, as well as ours, had one or more lifestyle-related factors, including body mass index ≥ 25 kg/m2, diabetes mellitus, impaired glucose tolerance, hepatosteatosis, or alcohol consumption. In our patient, aging and daily alcohol consumption might have triggered the development of HCCs.

The Correlation between miR-122 and Lipoprotein Lipase Expression in Chronic Hepatitis C Patients.

Chronic HCV infection is strictly associated with host lipid/lipoprotein metabolism disorders. The study aimed to analyze the relationship between viral load, lipid profile, IFNγ, and the expression of miR-122 and LPL in the liver and PBMCs. Sera, PBMCs, and matching liver biopsies from 17 chronic hepatitis C patients were enrolled in this study. Collected data shows that liver (not PBMCs) miR-122 expression is positively correlated with HCV RNA load and IFNγ and reversely with LPL expression in CHC patients. Presented, for the first time, in this study, the reverse correlation of miR-122 and LPL expression in liver; miR-122 and LPL seem to be important factors of CHC infection.

The MTHFR polymorphism affect the susceptibility of HCC and the prognosis of HCC liver transplantation

Background. Methylenetetrahyfrofolate reductase (MTHFR) is the key enzyme for one carbon and folate metabolism. Previous studies have drawn different conclusions about the relationship between the mutation of MTHFR and hepatocellular carcinoma (HCC) occurrence. MTHFR polymorphisms' influence on liver transplantation for HCC recurrence has yet not been reported. Aim of this study was to clarify the impact of MTHFR polymorphism on hepatocarcinogenesis and the prognosis of liver transplant recipient with HCC. Methods. This study enrolled 244 HCC patients and 487 healthy individuals in Chinese Han population to analyze the influence of MTHFR polymorphism on HCC susceptibility first. Furthermore, this research choose another 100 donors’ and 104 recipients’ specimens to detect the association between polymorphism of MTHFR and post-transplant HCC recurrence. Result. rs1801131 polymorphism A to C was associated with the occurrence of HCC in Chinese Han population (p < 0.05), especially in age exceeding 50 years (p < 0.01). No association was observed with rs1801133 polymorphism and HCC occurrence. The mean tumor-free survival for recipients with donor liver graft rs1801133 C to T variants was shorter than CC type (12.63 ± 3.84 vs 22.43 ± 4.74 months, p < 0.05). Multivariate analysis revealed that Donor rs1801133 and Hangzhou criteria were two independent prognostic factors for tumor-free survival (p < 0.05). Neither donor rs1801131 polymorphism nor recipients’ MTHFR polymorphisms was associated with HCC recurrence. Conclusion. This study demonstrated that MTHFR polymorphism was associated with HCC occurrence and post-transplant HCC recurrence. rs1801131 mutation A to C is a valuable molecular biomarker for predicting HCC occurrence in Chinese Han population. Donor MTHFR rs1801133 C to T polymorphism could present as a promising prognostic biomarkers for HCC recurrence in liver transplant recipients (AU)

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Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis.

BACKGROUND Hepatitis C virus (HCV) infection and metabolic diseases including nonalcoholic steatohepatitis (NASH) exhibit a complex interplay. Although free fatty acid-mediated apoptosis is a prominent feature of NASH, the impact of HCV infection on hepatocyte lipotoxicity has remained largely unexplored. The study aimed at identifying whether infection by HCV affected the apoptotic pathway in hepatocytes during fatty acid assault. MATERIAL AND METHODS OR6 cells, which are derived from human hepatocellular carcinoma Huh-7 cells and harbor a full-length HCV RNA genome replication system, were treated with palmitate. Apoptosis was examined by 4',6-diamidino-2-phenylindole staining. Activation and expression of JNK, Bim, cIAP-1, and Mcl-1 were examined by immunoblotting. mRNA expression of CHOP, a major player in endoplasmic reticulum stress-mediated apoptosis, was assessed by real-time PCR. RESULTS Palmitate-induced hepatocyte apoptosis was significantly enhanced in OR6 cells compared to cured cells, in which the HCV genome had been eradicated by treatment with interferon-α. Although basal expression of CHOP mRNA was enhanced in OR6 cells compared to cured cells, it was similarly upregulated in both cell lines following palmitate treatment. Notably, palmitate-induced JNK phosphorylation was accentuated in OR6 cells compared to cured cells. Inhibition of JNK with SP600125 attenuated palmitate-induced apoptosis. Palmitate-mediated upregulation of BH3-only protein Bim, which acts downstream of JNK, was also enhanced in OR6 cells compared to cured cells. In contrast, Mcl-1 and cIAP-1 were equally reduced in OR6 cells and cured cells following palmitate treatment. CONCLUSIONS These findings suggest that during lipoapoptosis, HCV infection may enhance hepatocyte toxicity by increasing JNK phosphorylation.

Involvement of Ornithine Carbamoyltransferase in the Progression of Chronic Hepatitis C and Liver Cirrhosis.

Background: The involvement of serum ornithine carbamoyltransferase (OCT) in the progression of chronic hepatitis and liver cirrhosis is unclear. Methods: A total 256 patients with chronic hepatitis C and 5 healthy controls were examined. Serum OCT concentrations were measured by enzyme-linked immunosorbent assay. Serum OCT concentrations were compared with serum cytokine and chemokine levels, and with disease severity and development of hepatocellular carcinoma (HCC). Results: The median OCT concentrations were 21.8 ng/ml for healthy controls, 36.7 ng/ml for F0 stage disease, 48.7 ng/ml for F1 stage, 77.9 ng/ml for F2 stage, 104.8 ng/ml for F3 stage, and 121.4 ng/ml for F4 stage. OCT concentrations were correlated with aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet counts, indocyanine green retention rate at 15 min, prothrombin times, the molar ratio of branched chain amino acids to tyrosine, and tyrosine. Furthermore, there were significant correlations among OCT concentrations and IP10 and IL18 levels. There were weak correlations between serum OCT concentrations and liver histology. The cumulative incidence of HCC in the high-OCT concentration group (≥75.3 ng/ml) was higher than that in the low-OCT concentration group. Conclusion: The measurement of serum OCT concentration may provide a useful marker of disease severity, and thus could be a useful marker for a high risk of HCC occurrence.

The potential of signal peptide peptidase as a therapeutic target for hepatitis C.

INTRODUCTION: Chronic infection with hepatitis C virus (HCV) causes liver steatosis, cirrhosis, metabolic syndrome with inflammation, and eventually leads to hepatocellular carcinoma. HCV core protein is a well-known capsid protein and pathogenic factor related to lipid accumulation, type 2 diabetes mellitus, and carcinogenesis. Cleavage of the C-terminal transmembrane region by signal peptide peptidase (SPP) is required for maturation of the core protein. Areas covered: Herein, this review details the general aspects of the structure, lifecycle, pathogenesis, and maturation of the HCV core protein, the function of SPP, and clinically available direct-acting antivirals (DAAs). SPP is classified into a group of GXGD-type intramembrane proteases including presenilin-1, which is a component of γ-secretase complex. Several SPP inhibitors were previously identified from γ-secretase inhibitors, but have not yet been improved based on specificity to SPP. Finally, the author discusses the potential of SPP inhibitors for hepatitis C therapy. Expert opinion: Currently available DAAs therapies are limited because of different viral genotypes and underlying conditions in each patient. DAA-resistant viruses have also been reported. Development of SPP-selective inhibitors may improve current HCV therapies by decreasing in the emergence of DAA-resistant viruses irrespective of viral genotype.

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons.

Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For grazoprevir, the 50% effective concentration (EC50) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC50 for grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n = 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced grazoprevir antiviral activity by 137- and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n = 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir. The activity profiles of grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.

Hepatitis C virus-induced NK cell activation causes metzincin-mediated CD16 cleavage and impaired antibody-dependent cytotoxicity.

BACKGROUND & AIMS: The Fc receptor family for immunoglobulin (Ig)G type III (FcγRIII, CD16) is an activating receptor on natural killer (NK) cells and an essential mediator of antibody-dependent cellular cytotoxicity (ADCC). There is only limited information on its role during chronic hepatitis C virus (HCV) infection. We studied CD16 expression in relation to NK cell functional activity in HCV-infected patients and sought mechanistic insights into virus-induced modulation. METHODS: NK cell CD16 expression and activation status were evaluated ex vivo by flow cytometry in HCV-infected patients and healthy controls (HC) as well as in vitro after co-culture with HCV-infected HuH7.5 cells. Rituximab-mediated ADCC was assessed in HC and HCV-infected patients using Daudi cells as a target. The role of metzincins in CD16 down-modulation was assessed using specific inhibitory molecules and by evaluating intracellular mRNA levels. RESULTS: HCV-infected patients exhibited increased frequencies of ex vivo activated NK cells and a concomitantly decreased NK CD16 expression, which resulted in impaired ADCC activity. Moreover, exposure of NK cells to culture-derived HCV recapitulated the ex vivo findings of decreased CD16 expression and increased NK cell activation. Importantly, blockade of metzincin-mediated shedding activity, including selective a disintegrin and metalloproteinase 17 (ADAM-17) inhibition, restored NK CD16 expression. Successful treatment with direct-acting antivirals partially improved NK ADCC function despite delayed CD16 reconstitution. CONCLUSION: Chronic HCV infection induces NK cell activation resulting in ADAM-17-dependent CD16 shedding and consequent impaired ADCC function. Altered ADCC may contribute to failure to eradicate HCV-infected hepatocytes. LAY SUMMARY: We show here that hepatitis C virus (HCV) activates natural killer (NK) lymphocytes which, as a consequence, loose their Fc receptor for IgG (CD16), an essential molecule for antibody binding. We show that this occurs through the action of enzymes named metzincins, resulting in altered NK-mediated antibody-dependent killing (ADCC) of target cells. This mechanism may contribute to HCV persistence and may represent a general phenomenon whereby some viruses can escape host's immune responses.

PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.

 Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases. MATERIAL AND METHODS: A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223. RESULTS: Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020). CONCLUSION: SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.

Effect of Antiviral Therapy on Serum Activity of Angiotensin Converting Enzyme in Patients with Chronic Hepatitis C.

INTRODUCTION: Renin-angiotenzin system (RAS) is frequently activated in patients with chronic liver disease. Angiotenzin - II (AT-II), produced by angiotenzin converting enzyme (ACE), has many physiological effects, including an important role in liver fibrogenesis. Combined antiviral therapy with PEG-IFN and ribavirin besides its antiviral effect also leads to a reduction in liver parenchyma fibrosis. AIM OF THE STUDY: Determining the value of ACE in serum of patients with chronic hepatitis C before and after combined antiviral therapy, as well as the value of ACE activities in sera of the control group. MATERIALS AND METHODS: We studied 50 patients treated at Gastroenterohepatology Department, in the time-period of four years. Value of ACE in serum was determined by Olympus AU 400 device, with application of kit "Infinity TN ACE Liquid Stable Reagent". HCV RNA levels in sera were measured by real time PCR. HCV RNA test was performed with modular analysis of AMPLICOR and COBAS AMPLICOR HCV MONITOR test v2.0, which has proved infection and was used for quantification of the viruses and monitoring of the patients' response to therapy. Liver histology was evaluated in accordance with the level of necroinflammation activity and stage of fibrosis. RESULTS: Serum activities of ACE in chronic hepatitis C patients is statistically higher than the values in the control group (p=0.02). Antiviral therapy in chronic hepatitis C patients statistically decreases serum activities of ACE (p= 0.02) and indirectly affects fibrogenesis of the liver parenchyma. Correlation between ACE and ALT activity after the therapy was proved (0.3934). CONCLUSION: Our findings suggest that the activity of ACE in serum is a good indirect parameter of the liver damage, and could be used as an indirect prognostic factor of the level of liver parenchyma damage. Serum activity of ACE can be used as a parameter for non-invasive assessment of intensity of liver damage.

Prediction of the Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Patients after Sustained Virological Response by Aspartate Aminotransferase to Platelet Ratio Index.

BACKGROUND/AIMS: Following sustained virological response (SVR) for chronic hepatitis C (CHC) infection, patients with advanced fibrosis require regular monitoring for hepatocellular carcinoma (HCC). The aspartate aminotransferase to platelet ratio index (APRI) is a simple noninvasive surrogate marker known to reflect fibrosis. METHODS: We retrospectively analyzed 598 patients who achieved SVR with interferonbased therapy for CHC. RESULTS: Over a median of 5.1 years of follow-up, there were eight patients diagnosed with HCC and a 5-year cumulative incidence rate of 1.3%. The median pretreatment APRI was 0.83, which decreased to 0.29 after achieving SVR (p<0.001). Both the pre- and posttreatment indices were associated with HCC development. The 5-year cumulative HCC incidence rates were 0% and 2.8% for patients with pretreatment APRI <1.0 and ≥1.0, respectively (p=0.001) and 0.8% and 12.8% for patients with posttreatment APRI <1.0 and ≥1.0, respectively (p<0.001). Pretreatment APRI at a cutoff of 1.0 had a 100% negative predictive value until 10 years after SVR. CONCLUSIONS: HCC development was observed among CHC patients who achieved SVR. The pre- and post-treatment APRI could stratify HCC risk, indicating that the APRI could be a useful marker to classify HCC risk in CHC patients who achieved SVR. However, given the small number of HCC patients, this finding warrants further validation.

Comparison of Therapeutic Response and Clinical Outcome between HCV Patients with Normal and Abnormal Alanine Transaminase Levels.

BACKGROUND AND AIMS: Patients with chronic hepatitic C (HCV) infection and normal serum alanine transaminase (ALT) levels were considered to have mild disease. In Taiwan, these patients were not suggested for interferon (IFN) based therapies. The aim of study is to compare therapeutic outcomes between HCV patients with normal and elevated ALT levels. METHODS: We conducted a retrospective study on 3241 HCV patients treated by IFN based therapies. Patients with normal ALT levels were classified as group A (n = 186) while those with elevated ALT levels were group B (n = 3055). RESULTS: At baseline, incidence of diabetes mellitus, low platelet counts and cirrhosis were significantly higher in group B patients. The sustained virologic response (SVR) rate was comparable between the 2 groups (65.3% vs. 65.3%, P = .993). But significantly higher incidence of HCC development after HCV treatment was observed in group B (7.4% vs. 3.2%, P = .032). No significant differences with respect to the outcome of liver decompensation, spontaneous bacterial peritonitis, and mortality were noted between 2 groups. Multivariate analysis showed younger age, female gender, non-HCV genotype 1, lower viral load, higher platelet counts and non-cirrhosis were favorable factors for achieving SVR, rather than ALT levels. Further analysis revealed older age, cirrhosis, lower platelet levels and non- peg-interferon treatment are risk factors of HCC development. CONCLUSIONS: HCV patients with normal ALT levels had similar response to antiviral therapy and low rate of HCC development after therapy. Antiviral therapies begun at early course of HCV infection may be beneficial to prevent disease progression.

Impact of aldo-keto reductase family 1 member B10 on the risk of hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND AIM: Aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was recently reported to be upregulated in some chronic liver diseases. However, its relevance in hepatocellular carcinoma (HCC) development is not fully assessed, especially in patients with chronic hepatitis C virus (HCV) infection. METHODS: Aldo-keto reductase family 1 member B10 expression in the liver of 550 patients with chronic HCV infection was immunohistochemically assessed and quantified. A multivariate Cox model was used to estimate the hazard ratios (HRs) of AKR1B10 expression for HCC development, and the cumulative incidence of HCC was evaluated using the Kaplan-Meier method. RESULTS: Aldo-keto reductase family 1 member B10 expression in the patients ranged from 0% to 80%. During the median follow-up of 3.2 years, 43 of 550 patients developed HCC. Multivariate analysis demonstrated that high AKR1B10 expression (≥6%) was an independent risk factor for HCC (HR, 6.43; 95% confidence interval, 2.90-14.25; P < 0.001). The 5-year cumulative incidences of HCC were 22.8% and 2.2% in patients with high and low AKR1B10 expression, respectively (P < 0.001). In subgroup analyses, the effects of high AKR1B10 expression on HCC development risk were significant over strata. In particular, HRs attributed to high AKR1B10 expression were significant in the subgroups that had been considered at a lower risk of HCC, such as in patients with younger age and mild hepatic fibrosis or those who achieved sustained virological response after interferon therapy. CONCLUSION: Various degrees of AKR1B10 upregulation in the liver were observed in patients with chronic HCV infection, and high AKR1B10 expression could be a novel predictor of HCC.

Nucleoside Inhibitors of Hepatitis C Virus NS5B Polymerase: A Systematic Review.

Nowadays, a large number of people in the world are suffering from chronic Hepatitis C. HCV NS5B polymerase conserved across the identified 7 HCV genotypes is considered to be the most promising target in combating HCV. During the past decade, significant progress has been made in the discovery of novel nucleoside HCV NS5B polymerase inhibitors. A potent anti-HCV drug, sofosbuvir with high cure rates has been approved. Besides, quite a few nucleoside anti-HCV agents are being evaluated in clinical trials. The purpose of this review is to present recent progress in the development of nucleoside HCV NS5B polymerase inhibitors, focusing on lead compounds that hold great promise for medicinal use and their structure-activity relationships (SARs) in order to provide guidance for future drug design and discovery.

Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity.

OBJECTIVE: Inflammation and oxidative stress drive disease progression in chronic hepatitis C (CHC) towards hepatocellular carcinoma. HCV is known to increase intracellular levels of reactive oxygen species (ROS), but how it eliminates ROS is less well known. The role of the ROS scavenger glutathione peroxidase 4 (GPx4), induced by HCV, in the viral life cycle was analysed. DESIGN: The study was performed using a replicative in vitro HCV infection model and liver biopsies derived from two different CHC patient cohorts. RESULTS: A screen for HCV-induced peroxide scavengers identified GPx4 as a host factor required for HCV infection. The physiological role of GPx4 is the elimination of lipid peroxides from membranes or lipoproteins. GPx4-silencing reduced the specific infectivity of HCV by up to 10-fold. Loss of infectivity correlated with 70% reduced fusogenic activity of virions in liposome fusion assays. NS5A was identified as the protein that mediates GPx4 induction in a phosphatidylinositol-3-kinase-dependent manner. Levels of GPx4 mRNA were found increased in vitro and in CHC compared with control liver biopsies. Upon successful viral eradication, GPx4 transcript levels returned to baseline in vitro and also in the liver of patients. CONCLUSIONS: HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens.

Non-Invasive Evaluation of Hepatic Fibrosis: The Diagnostic Performance of Magnetic Resonance Elastography in Patients with Viral Hepatitis B or C.

PURPOSE: To compare the accuracy of magnetic resonance elastography (MRE) with that of aspartate aminotransferase-to-platelet ratio index (APRI) for estimating the stage of hepatic fibrosis in patients with chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection. MATERIALS AND METHODS: We retrospectively enrolled 160 patients with chronic hepatitis and 25 healthy living liver donors. Fibrosis stage (METAVIR, F0 to F4) was determined histopathologically for all patients. APRI was recorded at the time of histopathologic examination and liver stiffness values were measured on MRE quantitative stiffness maps. The cutoff values, sensitivity, and specificity of MRE and APRI for each fibrosis stage were determined using receiver operating characteristic (ROC) analysis. RESULTS: MRE had a significantly greater area under the ROC curve than APRI score for discriminating among METAVIR stages F2-F4. Using a cutoff value of 2.80 kPa, MRE had a sensitivity of 94.4% and a specificity of 97.8% for detecting significant fibrosis (≥F2). There were no significant differences in fibrosis stage between patients with HBV and those with HCV infection. For ≥F2, the cutoffs were 2.47 kPa (100% sensitivity), 2.80 kP (maximum sum of sensitivity and specificity), and 3.70 kPa (100% specificity). CONCLUSIONS: MRE is a more accurate modality than APRI for detecting significant fibrosis in patients with chronic HBV or HCV infection. Antiviral treatment should be considered in patients with liver stiffness values ≥ 2.8 kPa.