Chronic Hepatitis C Progression Research Articles

Prevalence of Toxoplasma gondii 36-KDa antigen and chronic Hepatitis C: another evidence of an Association.

In chronic hepatitis C (CHC), Toxoplasma gondii infection can lead to more severe diseases and is capable of changing the disease course. Former studies were concerning anti-T. gondii IgG/IgM seroprevalence in CHC patients regardless the antigenic proteins that are associated with active infection. Therefore, this study aimed to evaluate association between prevalence of 36-KDa T. gondii antigen (TAg) and both CHC progression and liver and viral biochemical parameters. One hundred-twenty five CHC patients (65 with fibrosis and 60 with cirrhosis) and forty healthy controls constituted this study. Demographics and clinical data were collected. Both TAg and HCV-NS4 were identified using ELISA. In contrast to healthy controls (0%), both seropositivity (P = 0.043) and mean serum level (P = 0.025) of TAg were higher in cirrhotic patients (43.3 %; 1.2 ± 0.2ng/mL) compared to fibrotic patients (26.2 %; 0.7 ± 0.1ng/mL). T. gondii infection was significantly (P < 0.05) associated with liver and viral biochemical parameters including increased ALT and AST activities, total bilirubin and AFP levels and decreased albumin and platelets count levels. Interestingly, TAg positivity were associated with elevated HCV-NS4 level compared to negative TAg patients (212.5 ± 25.3 vs. 133.9 ± 17.4µg/mL (P = 0.026); r = 0.559 (P < 0.0001)). In conclusion, this study highlighted association between T. gondii parasitemia and CHC progression since TAg was more prevalent among cirrhotic than fibrotic patients and healthy controls. The presence of TAg was associated with impaired liver functions and increased HCV-NS4 levels. Further studies are needed to define the mechanism of this association.

High blood glucose levels are associated with fibrosis/cirrhosis progression in chronic hepatitis C

ABSTRACT Chronic hepatitis C (CHC) leads eventually to liver fibrosis, advanced hepatic disease and related deaths. Therefore, it is very important to assess clinical risk factors associated with rapid CHC and hepatic fibrosis progression. Former studies reported diabetes mellitus synergistic interactions with other host factors to fibrosis progression. Here, we aimed to evaluate the association between elevated blood glucose levels and CHC progression according to METAVIR system in patients chronically infected with HCV-genotype 4 and to evaluate the correlation between elevated glucose levels and liver- and viral-related biochemical parameters. A total of 160 patients with CHC (80 with liver fibrosis and 80 with cirrhosis) and 40 healthy volunteers, negative for HCV, were included. Our results revealed that cirrhotic patients had high (P = .0001) fasting (169.1 ± 50.2 mg/dL), postprandial (208 (123–320) mg/dL), and random (176.8 ± 51 mg/dL) glucose levels compared to patients with liver fibrosis (105.0 ± 32, 120 (105-135), and 113.5 ± 35 mg/dL, respectively). Mean serum fasting, postprandial and random glucose levels were significantly (P = .0001) increased with an increase in fibrosis stages, F1< F2< F3< F4. Blood glucose levels were also significantly (P < .05) correlated with liver disease related biological parameters and HCV-Ab titer. In conclusion, our results highlighted the fibrogenic impact of elevated glucose levels on CHC patients.

Impact of direct-acting antiviral regimens on mortality and morbidity outcomes in patients with chronic hepatitis c: Systematic review and meta-analysis.

The long-term effects of direct-acting antiviral therapies (DAAs) for chronic hepatitis C (CHC) remain uncertain. The objective of this systematic review and meta-analysis was to assess the impact of DAAs on CHC progression and mortality. We searched Ovid MEDLINE, Ovid EMBASE and PubMed databases (January 2011 to March 2020) for studies that compared the efficacy of DAAs to a non-DAA control in patients with CHC. Main outcomes were the adjusted hazard ratios (HRs) for mortality, liver decompensation, HCC occurrence and recurrence. Pooled estimates of HRs were determined using random-effects meta-analyses with inverse variance weighting, with sensitivity analyses and meta-regression to explore the effects of clinical factors. We identified 39 articles for the primary analysis. Compared with unexposed individuals, patients treated with DAA had a reduced risk of death (HR; CI=0.44; 0.38-0.52), decompensation (HR; CI=0.54; 0.38- 0.76) and HCC occurrence (HR; CI=0.72; 0.61- 0.86). The protective effect of DAA on HCC recurrence was less clear (HR; CI=0.72; 0.44-1.16). Sustained virologic response (SVR) attainment was a significant predictor of reduced mortality (HR; CI=0.33; 0.23-0.46), decompensation (HR; CI=0.11; 0.05-0.24), HCC occurrence (HR; CI=0.31; 0.27-0.37) and HCC recurrence (HR; CI=0.32; 0.20-0.51). Meta-regression showed no evidence of effect modification by patient age, sex, presence of cirrhosis or length of follow-up. In conclusion, our findings show protective effects of DAA treatment and DAA-related SVR on CHC progression and mortality.

Association of human platelet antigens polymorphisms with the levels of serum fibrosis marks in chronic hepatitis C patients

BackgroundHost genetic polymorphisms influence the fibrosis progression of chronic hepatitis C (CHC) patients. Previous studies have shown the association of human platelet antigens (HPAs) polymorphisms with CHC. However, little is known regarding the association of HPAs polymorphisms with the fibrosis progression of CHC. The aim of this study was to determine the association of HPA -2, -3, -5 and -15 polymorphisms with the levels of serum fibrosis marks in CHC patients. MethodsThe HPA -2, -3, -5 and -15 were genotyped by 5ˊ-nuclease assay in 211 CHC patients, while the serum concentration of hyaluronic acid (HA), collagen IV (CIV), amino-terminal pro-peptide of type III procollagen (PIIINP), and laminin (LN) from the same samples were measured by time resolved fluorescence immunoassay. ResultsThe level of serum LN was significantly lower in CHC patients with HPA-15aa genotype compared to those with HPA-15ab/bb (P = 0.032) but did not differ among HPA-2, -3 and -5 genotypes. There were no difference in HA, CIV and PIIINP levels among HPA-2, -3,-5 and -15 genotypes. ConclusionsThis study demonstrates that HPA-15 aa polymorphism is associated lower serum LN in CHC, which suggests that HPA -15 aa may be involved in the fibrosis progression of CHC.

Autophagy, Mitophagy and MicroRNA Expression in Chronic Hepatitis C and Autoimmune Hepatitis

Although the role of autophagy has been implicated in several forms of chronic hepatitis, it is still not fully understood. Active autophagy eliminates damaged molecules and organelles (such as mitochondria) by lysosomal degradation. In the present study, we aimed to examine and compare autophagy activity in chronic hepatitis C (CHC) and autoimmune hepatitis (AIH) by detecting the expression of autophagy (LC3 and p62) and mitochondrium-related (TOMM20) proteins, as well as the levels of selected microRNAs (miR-101, -155, -204 and − 224) known to be involved in the regulation of autophagy. In addition, the expression levels were related to pathohistological parameters. Liver biopsy samples, including 45 CHC and 18 AIH cases, were immunohistochemically stained for LC3, p62 and TOMM20 and the expression of miRNAs was determined using real-time PCR. We found elevated LC3 and p62 in AIH samples as compared with CHC ones, indicating an activated autophagy that is impaired in AIH as no degradation of p62 seemed to occur. Moreover, p62 showed strong correlation with necroinflammatory grades in the AIH group. The observed elevated levels of TOMM20 and p62 suggest a less efficient elimination of damaged mitochondria in AIH as opposed to CHC, in which autophagy seems to have a more active function. The level of miR-101 was increased in case of CHC as compared with AIH, however, miR-155, -204 and 224 resulted in no expressional. Furthermore, miR-224 level correlated with steatosis and miR-155 expression with fibrosis stage in CHC. In conclusion, dissimilar autophagic activity was observed in CHC and AIH, suggesting a close association between impaired autophagy and severity of necroinflammation. This impairment may not be regulated by the analyzed miRNAs. Nevertheless, miR-224 and − 155 seem to be associated with CHC progression.

Changes and significance of serum soluble programmed death-1 in patients with chronic hepatitis C

Objective To analyze the changes and significance of serum soluble programmed death-1 (sPD-1) in patients with chronic hepatitis C (CHC) and study its role in the progression of CHC. Methods Serum levels of sPD-1 in CHC patients and healthy controls (HC) were measured using ELISA and compared. Correlations of serum sPD-1 with peripheral hepatitis C virus (HCV) RNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver fibrosis (indicated by APRI) were analyzed. Results The serum sPD-1 level in the CHC group was significantly higher than that in the HC group (P<0.05), and positively correlated with peripheral HCV RNA, ALT and AST (P<0.05). In addition, the serum sPD-1 levels in patients with APRI greater than 1.2 (indicating severe liver fibrosis) were higher than those in patients without or with mild liver fibrosis (P<0.05). Conclusions sPD-1 might be involve in the progression of CHC. Measuring serum sPD-1 in CHC patients would assist the prediction of disease progression and help to make the correct diagnosis and appropriate clinical therapy decision. Key words: Soluble programmed death-1; Chronic hepatitis C; Liver fibrosis

Effectiveness and Cost-Effectiveness of Triple Therapy With Telaprevir and Boceprevir for Chronic Hepatitis C: A Decision Analysis From the Brazilian Public Health System Perspective

ObjectivesBecause of the lack of evidence regarding long-term effectiveness and cost-effectiveness of first-generation direct-acting antivirals for chronic hepatitis C (CHC) treatment in Brazil, we performed a cost-utility analysis comparing standard dual therapy (peginterferon plus ribavirin [pegIFN/RBV]), boceprevir, and telaprevir for CHC patients. MethodsWe developed a state-transition Markov model simulating the progression of CHC. Long-term outcomes included remaining life expectancy in life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Short-term outcomes included sustained virological response rates (SVR). Direct medical costs were obtained from Brazilian databases. A lifelong time horizon was considered and a 5% annual discount rate was applied for costs and clinical outcomes. A willingness-to-pay threshold of approximately $20 000 per QALY was used. We performed multiple sensitivity analyses. ResultsFor short- and long-term scenarios, therapy with boceprevir was dominated by telaprevir, which was more effective than standard dual therapy (75.0% vs 40.4% SVR rate, 13.47 vs 12.59 LYs, and 9.74 vs 8.49 QALYs, respectively) and was also more expensive ($15 742 vs $5413). The corresponding ICERs were $29 854/SVR, $11 803/LY, and $8277/QALY. Based on our model, triple therapy with telaprevir was the most cost-effective treatment for the Brazilian health system. Despite a lack of data regarding the Brazilian population, we incorporated as many applicable parameters as possible. ConclusionsTelaprevir is more effective and cost-effective than boceprevir. Our model may be applied for other settings with a few adjustments in the input parameters.

Quality of life in patients with chronic hepatitis C infection: Severe comorbidities and disease perception matter more than liver-disease stage.

Background and aimsThis study evaluated the clinical and non-clinical determinants of health-related quality of life (HRQoL) associated with untreated chronic hepatitis C (CHC) in France.MethodsFrom 01/2014 to 01/2015, untreated CHC patients were invited to complete a questionnaire including EQ-5D utility instrument and two visual analogue scales (VAS) measuring overall health and fatigue in three French centers (Paris, Lille and Montpellier). Answers were analyzed in mixed models (taking into account the clustering effects of centers and physicians).ResultsFive hundreds and five patients were enrolled: 52% males; the mean age was 54; 41% had BMI>25; 64% had genotype 1; 36% were at the stage of severe fibrosis (F3-F4); 38% had severe comorbidities other than liver-related. In the univariate analysis, EQ-5D utility was associated with socio-demographic variables as age, place of birth, education, and employment; CHC-related variables as conditions of HCV screening and severity of fibrosis; CHC-unrelated variables as comorbidities other than CHC, being overweight, and psychiatric disorders; feelings about CHC disease as perception of progression, lack of information on CHC and its treatments, and entourage’s feeling. In multivariate analysis, EQ-5D utility was affected by not being in employment (0.72 vs. 0.80), having severe comorbidities other than CHC (0.72 vs. 0.79), being overweight (0.73 vs. 0.78), and feeling worried about CHC progression (0.66 vs. 0.72–0.84). Similar results were found for the VAS.ConclusionsThe presence of severe comorbidities and worrying about CHC progression, but not stage of fibrosis, seem to alter significantly EQ-5D health utility in CHC French patients.

Impact of DARC rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study.

The Duffy antigen receptor for chemokines (DARC) rs12075 polymorphism regulates leukocyte trafficking and proinflammatory chemokine homeostasis. Hepatitis C virus (HCV)-mediated liver fibrosis is associated with an uncontrolled inflammatory response. In this study, we evaluate the association between the DARC rs12075 polymorphism and liver stiffness progression in HCV-infected patients. We carried out a retrospective cohort study (repeated measures design) in 208 noncirrhotic patients with chronic hepatitis C (CHC) who had at least two liver stiffness measurements (LSM) with a separation of at least 12 months. We used generalized linear models to analyze the association between DARC rs12075 polymorphism and outcome variables. During a follow-up of 46.6 months, the percentage of patients with stages of fibrosis F0/F1 decreased (p < 0.001), while LSM values and the percentage of patients with cirrhosis increased (p < 0.001). This pattern of changes was maintained in each of the groups of patients analyzed according to their rs12075 genotypes (AA or AG/GG). However, the variations in liver stiffness characteristics were lower in patients with the rs12075 AG/GG genotype (AG/GG versus AA). Thereby, in the adjusted analysis, patients with the rs12075 AG/GG genotype had a lower risk of an increased value of LSM2/LSM1 arithmetic mean ratio (AMR = 0.83; p = 0.001) and of an increase in LSM ≥ 5 kPa (odds ratio (OR) = 0.28; p = 0.009). Besides, patients with rs12075 AG/GG had a lower risk of cirrhosis progression (OR = 0.24; p = 0.009). No significant associations were found for an increase in LSM ≥ 10 kPa. We found an association between the DARC rs12075 single nucleotide polymorphism (SNP) and CHC progression. Specifically, patients with the DARC rs12075 AG/GG genotype had a lower risk of liver fibrosis progression and development of cirrhosis.

Evaluation of liver steatosis, measured by controlled attenuation parameter, in patients with hepatitis C-induced advanced liver fibrosis and hepatocellular carcinoma.

Steatosis is a documented feature of chronic hepatitis C (CHC). There is an association between steatosis decrease and fibrosis progression. The association between steatosis and advanced fibrosis versus hepatocellular carcinoma (HCC) development has not been precisely evaluated. The controlled attenuation parameter (CAP) was applied as an immediate and efficient process to detect and quantify hepatic steatosis with adequate accuracy. The aim of this study was to assess the difference in liver steatosis between patients with hepatitis C virus-related advanced hepatic fibrosis versus HCC. This cross-sectional study included 130 patients with HCC, attending the multidisciplinary HCC clinic, Cairo University, and 54 patients with CHC between October 2015 and June 2016. Clinical and laboratory characteristics were recorded. Liver stiffness and CAP were obtained by using the FibroScan 502, touch. All included patients had genotype 4. The mean CAP value was significantly lower in HCC (209.5±57.1 dB/m) versus CHC (259.9±54.9 dB/m). Receiver operating characteristic curve revealed an area under the curve of 0.75 for the differentiation between groups. At a cutoff value of 237 dB/m, sensitivity was 72.3%, specificity was 70.7%, positive likelihood ratio was 2.5, and negative likelihood ratio was 0.4 in the differentiation between CHC versus HCC. Logistic regression analysis revealed an odds ratio of 6.4 for the diagnosis of HCC with CAP of less than 237 dB/m. Multivariate analysis, controlling for age, sex, BMI, triglycerides, and cholesterol levels, revealed a significantly increased odds for HCC diagnosis (odds ratio: 4.3, P=0.006). The progression of CHC is associated with a decrease in steatosis, particularly toward advanced fibrosis and HCC. Steatosis reduction less than 237 dB/m is likely to be associated with HCC.

CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C.

Natural killer cells (NK cells) play an essential role in the immunological mechanism underlying chronic hepatitis C (CHC). Impairment of NK cell function facilitates persistent infection with hepatitis C virus (HCV) and hepatocellular carcinogenesis. However, the mechanism by which NK cell activity is suppressed in CHC is not completely understood. In this study, we focused on carcinoembryonic antigen–related cell‐adhesion molecule 1 (CEACAM1). CEACAM1 is thought to suppress NK cell function. We examined the effect of CEACAM1 on NK cell function in CHC. We investigated the function of CEACAM1 in vitro using Huh7.5.1 cells and the HCV‐Japanese fulminant hepatitis (JFH)‐1 strain. We analyzed serum CEACAM1 level, NK cell function, and CEACAM1 messenger RNA (mRNA) level in human liver samples. Levels of CEACAM1 on the cell surface, CEACAM1 mRNA levels, and soluble CEACAM1 levels in supernatants were significantly higher in Huh7.5.1 cells infected with JFH‐1 (Huh7.5.1/JFH‐1 cells) than in Huh7.5.1 cells. Significantly higher NK cell cytotoxicity was observed toward K562 cells after coculture with CEACAM1 knockout Huh7.5.1/JFH‐1 cells than after coculture with Huh7.5.1/JFH‐1 cells. CEACAM1 expression was induced by the HCV E2 glycoprotein in HCV infection. Significantly higher serum CEACAM1 levels were detected in patients with CHC compared with healthy subjects and patients who achieved sustained virological responses. The expression of CD107a on NK cells from patients with CHC was negatively correlated with serum CEACAM1 levels. Significantly higher levels of CEACAM1 mRNA were detected in HCV‐infected livers compared with uninfected livers. Conclusion: CEACAM1 expression was induced in hepatocytes following HCV infection and decreased NK cell cytotoxicity. These results demonstrate a possible role for CEACAM1 in the pathogenesis of CHC and hepatocellular carcinoma progression.

Gut Dysbiosis Associated With Hepatitis C Virus Infection.

Little is known about the effect of hepatitis C virus (HCV) infection on gut microbiota and the relationship between alteration of gut microbiota and chronic hepatitis C (CHC) progression. We performed a comparative study of gut microbiota composition between CHC patients and healthy individuals. Fecal samples from 166 CHC patients were compared with those from 23 healthy individuals; the gut microbiota community was analyzed using 16S ribosomal RNA gene sequencing. CHC patients were diagnosed with persistently normal serum alanine aminotransferase without evidence of liver cirrhosis (LC) (PNALT, n = 18), chronic hepatitis (CH, n = 84), LC (n = 40), and hepatocellular carcinoma in LC (n = 24). Compared with healthy individuals, bacterial diversity was lower in persons with HCV infection, with a decrease in the order Clostridiales and an increase in Streptococcus and Lactobacillus. Microbiota dysbiosis already appeared in the PNALT stage with the transient increase in Bacteroides and Enterobacteriaceae. Predicted metagenomics of microbial communities showed an increase in the urease gene mainly encoded by viridans streptococci during CHC progression, consistent with a significantly higher fecal pH in CH and LC patients than in healthy individuals or those in the PNALT stage. HCV infection is associated with gut dysbiosis, even in patients with mild liver disease. Additionally, overgrowth of viridans streptococci can account for hyperammonemia in CH and LC. Further studies would help to propose a novel treatment strategy because the gut microbiome can be therapeutically altered, potentially reducing the complications of chronic liver disease.

Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.

IntroductionChronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.MethodsNIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0–2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.ResultsSeven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74).ConclusionThe identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.

Erythrocyte antioxidative enzymes activities in patients with chronic hepatitis C treated with pegylated interferon alpha-2a and ribavirin

Background/Aim. In hepatitis C virus infection, oxidative stress and antioxidant imbalance are major triggers for the disease occurrence and its progression. The aim of the research was to determine the erythrocyte antioxidative enzymes activities, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), before and after therapy with pegylated interferon alpha-2a and ribavirin and to evaluate their clinical significance as potential diagnostic markers of sustained virological response (SVR). Methods. The study included 53 patients with chronic hepatitis C (CHC) and 56 healthy controls. SOD, GPx, CAT, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured in patients both before and after the treatment. Results. SOD, GPx and CAT activities prior to the treatment were significantly lower in CHC patients compared to the controls (p &lt; 0.001), and they were significantly higher after the treatment (p &lt; 0.001). A significant positive correlation existed between SOD, GPx, and CAT activites, before and after the treatment (p &lt; 0.001) and with those of aminotransferases prior to the treatment (p &lt; 0.001). After the treatment, only GPx activity showed significant negative correlation with that of aminotransferases (p &lt; 0.001). Receiver operating characteristic curve analysis for SOD, GPx and CAT showed following values: area under the curve of 0.975, 0.988, and 0.817 respectively; sensitivity of 93.5%, 71.7%, 100% respectively and specificity of 100% for all, respectively. Forty six SVR achievers had significant increase of SOD, GPx and CAT activities (p &lt; 0.001 for all), unlike 7 SVR non-achievers (p = 0.31, p = 0.717, p = 0.85, respectively). Conclusion. Oxidative stress is the initiator of onset and progression of CHC. The combined antiviral therapy leads to the restoration of antioxidant balance. GPx, SOD and CAT may be diagnostic markers of CHC treatment outcome.

Increase of Soluble Programmed Cell Death Ligand 1 in Patients with Chronic Hepatitis C.

Objectives: To determine whether the soluble programmed cell death ligand 1 (sPD-L1) levels in patients with chronic hepatitis C (CHC) are associated with the clinical features of the disease and the efficacy of treatment, including interferon (IFN)-α.Methods: We investigated the sPD-L1 levels in the sera of 80 genotype 1b Japanese patients with CHC who underwent 12 weeks of telaprevir (TVR)- or simeprevir (SMV)-based triple therapy followed by 12 weeks of dual therapy with pegylated IFN-α plus ribavirin. Serum was also obtained from 22 patients with chronic hepatitis B (CHB) and from 10 healthy donors (HC). The sPD-L1 levels were measured using an ELISA kit. In addition, we examined the PD-L1 expression on the cell surface of immortalized hepatocytes (HPT1) after incubation with cytokines, including IFN-γ.Results: The pretreatment serum sPD-L1 levels were significantly increased in patients with CHC (median 109.3 pg/ml, range 23.1-402.3) compared with patients with CHB (69.2 pg/ml, 15.5-144.8; P <0.001) and HC (100.3 pg/ml, 40.1-166.6; P = 0.039). No significant differences in the sustained virological response (SVR) rates were found between the TVR- (85.0%, n=40) and SMV-treated (80.0%, n=40) groups, and the pretreatment levels of serum sPD-L1 were not significantly different between patients who achieved SVR (105.0 pg/ml, 23.1-402.3) and non-SVR patients (133.5 pg/ml, 39.9-187.2; P = 0.391). The pretreatment level of sPD-L1 was positively correlated with the alanine aminotransferase and alpha-fetoprotein levels (R2 = 0.082, P = 0.016, and R2 = 0.149, P = 0.002, respectively). Although immortalized hepatocytes do not express PD-L1, we confirmed that PD-L1 expression was induced after stimulation with IFN-γ.Conclusions: In this study, we first found that sPD-L1 was increased in patients with CHC. Our results indicate that the level of serum sPD-L1 might be associated with the progression of CHC and the generation of hepatocellular carcinoma.

Role of polymorphic markers for the genes of hemostasis and platelet receptors in liver fibrosis progression in patients with chronic hepatitis C

to estimate the clinical and prognostic value of the carriage of different allele variants of the gene polymorphisms of the coagulation system and platelet receptors in the progression of liver fibrosis (LF) in patient with chronic hepatitis C (CHC). The investigation enrolled 177 patients with CHC and liver cirrhosis at its outcome who were divided into 2 groups according to the rate of LF progression: 1) 89 patients with rapid (rapid fibrosis) and 2) 88 patients with slow (slow fibrosis) progression. The polymorphism of the study genes was studied using a real-time polymerase chain reaction and a melting curve analysis. In CHC patients, the FV 1691G/A genotype was more often in the rapid progressors than that in the slow progressors (10.11% vs 1.14%; p=0.011). The A allele of the 1691 G/A FV gene was more common in the rapid fibrosis group than that in the slow fibrosis group (1.7% vs 5.56%, odd ratio 9.787; p=0.139). In our investigation, the polymorphic marker GA in the FII 20210 G/A gene, as well as the 4G allele (5G4G + 4G4G genotypes) and the 4G allele of PAI-I -675 5G/4G were more often seen in the rapid fibrosis group than that in the slow fibrosis group; the detection rate was only at the trend level (p=0.118, p=0.112, and p=0.117 respectively). There were no significant differences between the groups in the spread of variant genotypes and alleles of other study genes. Integral model construction by coding «profibrogenic» genotypes (FV 1691 G/A, FII 20210 G/A, PAI-I -675 5G/4G) showed that the fibrosis progression rate expressed as fibrosis units annually also increased with higher total scores (p=0.039), indicating the combined effect of these genes. The carriage of mutant genotypes of FV 1691 G/A, FII 20210 G/A, and PAI-I -675 5G/4G genes is a prognostic factor for rapid CHC progression.

Cost-effectiveness analysis of sofosbuvir-based regimens for chronic hepatitis C

BackgroundA new scenario of therapy for chronic hepatitis C (CHC) is being established with the approval of sofosbuvir (SOF).ObjectiveTo estimate the cost-effectiveness of SOF-based regimens approved in the Summary of...

Management of treatment-naïve chronic hepatitis C genotype 1 patients: a cost-effectiveness analysis of treatment options.

New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost-effectiveness analysis of boceprevir (BOC)- and telaprevir (TVR)-based triple therapy according to different patients' selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1-F4 fibrosis, (ii) only F2-F4 and (iii) only F3-F4. For each strategy, TVR interleukin-28B-guided (IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio (ICER) for F1-F4 strategy relative to F3-F4 was €5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and €7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1-F4 strategy relative to F3-F4 was €1818679 (TVR IL28B-guided) and €1866437 (BOC RVR-guided) per end-stage liver disease or death (ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization.

Imbalance between CD56+bright and CD56+dim natural killer cell subsets in the liver of patients with recurrent hepatitis C after liver transplantation

Progressive liver fibrosis remains a major problem for patients with recurrent chronic hepatitis C(CHC) after liver transplantation (LT). However, the involvement of natural killer (NK) and natural killer T (NKT) cells, which predominate in the liver, in recurrent CHC after LT remains unclear.In the present study, we investigated the status of NK and NKT cells in the liver and peripheral blood obtained from 10 patients with recurrent CHC after LT (LT-C), 15 patients with CHC, and 7 normal donors for living donor LT. CD56+ NK cells were separated into two subsets: CD56+bright subset, which is identified as major NK cytokine producer, and CD56+dim subset, which has greater spontaneous cytotoxicity. We found a significant decrease in the CD56+bright subset in the liver of patients with LT-C compared to patients with CHC (P<0.01) and normal donors (P=0.03). The expression of inhibitory NK cell receptor NKG2A was significantly increased on intrahepatic CD56+bright subset in LT-C patients, and activated CD69+CD56+dim NK cell subset was significantly increased in the liver of LT-C patients. Our results suggest that a significant imbalance between CD56+bright and CD56+dim NK cell subsets in the liver may contribute to the progression of recurrent CHC after LT.

Angiopoietin-2 Serum Levels Improve Noninvasive Fibrosis Staging in Chronic Hepatitis C: A Fibrogenic-Angiogenic Link

AimsAccurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis.MethodsSerum levels of angiopoietin-1 and -2 were measured by ELISA in 108 CHC patients who underwent pretreatment liver biopsy. The correlation between angiopoietins and clinical and demographic variables with liver fibrosis was analyzed by univariate regression. Significant factors were then subjected to multivariate analysis, from which we constructed a novel noninvasive liver fibrosis index (AngioScore), whose performance was validated in an independent series of 71 CHC patients. The accuracy of this model was compared with other documented fibrosis algorithms by De Long test.ResultsAngiopoietins correlated significantly with hepatic fibrosis; however, only angiopoietin-2 was retained in the final model, which also included age, platelets, AST, INR, and GGT. The model was validated and behaved considerably better than other fibrosis indices in discriminating all, significant, moderate and severe liver fibrosis (0.886, 0.920, 0.923). Using clinically relevant cutoffs, we classified CHC patients by discarding significant fibrosis and diagnosing moderate and severe fibrosis with greater accuracy, sensitivity, and specificity.ConclusionsOur novel noninvasive liver fibrosis model, based on serum angiopoietin-2 levels, outperforms other indices and should help substantially in managing CHC and monitoring long-term follow-up prognosis.