Cuiling Yang

Statin therapy improves response to interferon alfa and ribavirin in chronic hepatitis C: A systematic review and meta-analysis

The treatment of interferon alfa (IFN-α) and ribavirin for chronic hepatitis C virus (HCV) infection achieves limited sustained virological response (SVR). We conducted a systematic review and meta-analysis to explore the efficacy of adding statins to IFN-α and ribavirin therapy for chronic hepatitis C. Studies with data pertinent to the effect of statins on chronic hepatitis C were reviewed, and randomized controlled trials (RCTs) evaluating the efficacy of the addition of statins to IFN-α and ribavirin were included in meta-analysis. The primary outcome measure was SVR. Secondary outcome measures were rapid virological response (RVR) and early virological response (EVR). The literature was systematically searched through October 2012. After screening of the 1724 non-duplicated entries, 54 potentially relevant studies were fully reviewed. Of those, 18 studies were relevant and 5 RCTs met the inclusion criteria for meta-analysis. In comparison with IFN-α and ribavirin therapy, the addition of statins significantly increased SVR (OR=2.02, 95% CI: 1.38-2.94), RVR (OR=3.51, 95% CI: 1.08-11.42) and EVR (OR=1.89, 95% CI: 1.20-2.98). The SVR increase remained significant for HCV genotype 1 (OR=2.11, 95% CI: 1.40-3.18). There were no significant increases in adverse events and withdrawals with the addition of statins. In conclusion, the addition of statins to IFN-α and ribavirin improves SVR, RVR, and EVR without additional adverse events and thus may be considered as adjuvant to IFN-α and ribavirin for chronic hepatitis C. Statins might also be used for HCV genotypes other than genotype 1, or in patients in whom the use of protease inhibitors is contraindicated or not indicated.

Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri

Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti-viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor β1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation.

Genetic variations of PD1 and TIM3 are differentially and interactively associated with the development of cirrhosis and HCC in patients with chronic HBV infection.

Cooperation or interaction of programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) molecules is more relevant than either molecule alone to immune dysfunction in chronic viral infection and cancers. This study simultaneously investigated polymorphisms at PD1 +8669 and TIM3 -1516 loci in 845 hepatitis B virus (HBV) chronically infected patients [151 asymptomatic carriers, 202 chronic hepatitis, 221 cirrhosis and 271 hepatocellular carcinoma (HCC)], 141 HBV infection resolvers and 318 healthy controls. Multivariate analysis showed that, in addition to gender, age, ALT, albumin and HBV DNA, PD1 +8669 genotype AA was associated with cirrhosis compared with patients without cirrhosis (OR, 2.410; P=0.001). TIM3 -1516 genotypes GT+TT, together with gender, age, ALT, AST, direct bilirubin, albumin and HBeAg status, were associated with HCC compared with cirrhosis patients without HCC (OR, 2.142; P=0.011). The combined carriage of PD1 +8669 AA/TIM3 -1516 GT or TT was higher in cirrhosis and HCC pooled patients than in patients without cirrhosis (OR, 2.326; P=0.020) and in HCC patients than in cirrhosis patients (OR, 2.232; P=0.013). These data suggest that PD1 and TIM3 polymorphisms may differentially and interactively predispose cirrhosis and HCC in chronic HBV infection.

Association of Genetic Variation of Sodium Taurocholate Cotransporting Polypeptide with Chronic Hepatitis B Virus Infection

BACKGROUND Sodium taurocholate cotransporting polypeptide (NTCP) plays an important role in the enterohepatic circulation of bile acids and hepatocyte function and was recently proposed to be a functional receptor for hepatitis B virus (HBV). OBJECTIVE This study investigated the association of the functional polymorphism c.800C>T (p.S267F) (rs2296651) of the NTCP gene with HBV infection. METHODS The study included 244 patients with chronic HBV infection, 76 HBV infection resolvers, and 113 healthy controls. The polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS The distribution of the genotype and allele frequency of rs2296651 polymorphism was significantly different among the HBV patients, HBV infection resolvers, and healthy controls (p=0.034 and p=0.039, respectively). The frequency of genotype CT in HBV patients was significantly higher than that in healthy controls (11.9% vs. 4.4%, p=0.026, odds ratios [OR]=2.913, 95% confidence intervals [95% CI]=1.097-7.738). The frequency of allele T in HBV patients was also significantly higher than that in healthy controls (5.9% vs. 2.2%, p=0.029, OR=2.793, 95% CI=1.067-7.312). The frequency of genotype CT and allele T in HBV patients was higher than that in HBV infection resolvers although the difference was not significant. The genotype and allele frequency between infection resolvers and healthy controls and between HBV patients with different clinical diseases had no significant difference. CONCLUSION These findings suggest that the rs2296651 polymorphism may predispose the susceptibility to and chronicity of HBV infection.

Serum Levels of B-Cell Activating Factor in Chronic Hepatitis B Virus Infection: Association with Clinical Diseases

B-lymphocyte activation is a common characteristic of chronic hepatitis B virus (HBV) infection. B cell-activating factor (BAFF) plays a crucial role in the development and activation of B lymphocytes. This study investigated serum BAFF levels in 232 patients with different clinical diseases of chronic HBV infection [33 chronic asymptomatic HBV carrier (ASC), 53 chronic hepatitis (CH), 72 liver cirrhosis (LC), and 74 hepatocellular carcinoma (HCC)] and 61 gender- and age-matched healthy controls. Serum BAFF levels in HBV patients were significantly elevated compared with healthy controls (P<0.001). HCC patients had significantly higher levels of serum BAFF than ASC, CH, and LC (all P<0.001). Serum levels of BAFF in LC were significantly higher than in ASC (P<0.001) and CH (P=0.002). Serum level of BAFF was an independent variable associated with the presence of HCC in comparison with other disease groups in multivariate analysis. The area under receiver-operating characteristic curve (AUC) value of BAFF levels was 0.914 for HCC versus ASC, 0.825 for HCC versus CH, and 0.607 for HCC versus LC, respectively. The AUC value of BAFF levels was 0.854 for LC versus ASC and 0.748 for LC versus CH, respectively. The AUC value of BAFF (0.888) for HCC was higher than that of alpha-fetoprotein (0.776). We first demonstrate that serum BAFF levels in chronic HBV infection are elevated, correlated with clinical diseases, and could be used as a biomarker for indicating disease mechanisms, activity, and diagnosis.

IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection.

Interleukin (IL)-21 may affect both T-cell and B-cell responses and was suggested to be involved in response to HBV infection. This study explored IL21rs907715 and rs2221903 and IL21R T-83C and rs3093301 polymorphisms and serum IL-21 and IgE levels in 395 patients with chronic HBV infection, 75 HBV infection resolvers and 174 healthy controls. IL21R T-83C was not polymorphic in the study populations. IL21 rs2221903 AG was less frequent in HBV patients than in resolvers (p<0.001, OR=0.364, 95% CI=0.211-0.629) or in controls (p=0.017, OR=0.589, 95% CI=0.381-0.911). IL21R rs3093301 TT was more frequent in HBV patients than in controls [p value after Bonferroni correction (pc)=0.022, OR=1.908, 95% CI=1.158-3.142] and more frequent in resolvers than in controls (pc=0.010, OR=2.965, 95% CI 1.375-6.392). The carriage of IL21 rs2221903 AG/IL21R rs3093301 CT+IL21 rs2221903 AG/IL21R rs3093301 TT was less frequent in patients than in resolvers (pc=0.007, OR=0.236, 95% CI=0.096-0.579) and more frequent in resolvers than in controls (pc=0.014, OR=4.354, 95% CI=1.660-11.420). IL21 rs2221903 was, by interaction with IL21R rs3093301, associated with serum IL-21 and IgE levels in HBV patients. It is suggested that IL21 rs2221903 and IL21R rs3093301 polymorphisms may, independently or interactively, affect the susceptibility to and/or persistence of HBV infection potentially through altering IL-21 and IgE production.

Inhibition of Hepatitis C Virus Replication In Vitro by Xanthohumol, A Natural Product Present in Hops

Hepatitis C virus is a major cause of chronic liver disease worldwide. Xanthohumol, a prenylated flavonoid from hops, has various biological activities including an antiviral effect. It was previously characterized as a compound that inhibits bovine viral diarrhea virus, a surrogate model of hepatitis C virus. In the present work, xanthohumol was examined for its ability to inhibit hepatitis C virus replication in a cell culture system carrying replicating hepatitis C virus RNA replicon. 0.2 % DMSO and 500 units/mL interferon-alpha treatments were set as a negative and positive control, respectively. The inhibitory effect by xanthohumol was determined by the luciferase activity of the infected Huh7.5 cell lysates and the hepatitis C virus RNA levels in the culture. Xanthohumol at 3.53 µM significantly decreased the luciferase activity compared to the negative control (p < 0.01). Xanthohumol at 7.05 µM further decreased the luciferase activity compared to xanthohumol at 3.53 µM (p = 0.015). Xanthohumol at 7.05 µM or 14.11 µM achieved an inhibitory effect similar to that of interferon-alpha 2b (p > 0.05). Xanthohumol at 3.53 µM significantly reduced the hepatitis C virus RNA level compared to the negative control (p = 0.001). Although the results of xanthohumol at 7.05 µM had a higher variation, xanthohumol at the 7.05 µM and 14.11 µM decreased the hepatitis C virus RNA level to that achieved by interferon-alpha (p > 0.05). In conclusion, xanthohumol displays anti-hepatitis C virus activity in a cell culture system and may be potentially used as an alternative or complementary treatment against the hepatitis C virus.

Association between TNFAIP3 nonsynonymous single-nucleotide polymorphism rs2230926 and chronic hepatitis B virus infection in a Chinese Han population

BackgroundSingle-nucleotide polymorphisms (SNPs) in tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) gene have been linked to inflammatory, immunological and malignant diseases. Hepatitis B virus (HBV) infection is characterized by immunopathogenesis. This study investigated the association of rs2230926, a nonsynonymous SNP in TNFAIP3 gene, with chronic HBV infection.MethodsFour hundred and fifty-five patients with chronic HBV infection with clinical diseases of chronic hepatitis (n = 183), liver cirrhosis (n = 167) and hepatocellular carcinoma (n = 105), 92 HBV infection resolvers and 171 healthy controls were included. All subjects were of Chinese Han ethnicity. Genotyping of rs2230926 was carried out by polymerase chain reaction-restriction fragment length polymorphism method.ResultsThe gender and age between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotypes of rs2230926 in HBV patients, HBV infection resolvers and healthy controls are in Hardy-Weinberg equilibrium. The genotype and allele frequencies of TNFAIP3 rs2230926 polymorphism between HBV patients, HBV infection resolvers and healthy controls had no significant difference. The genotype and allele frequencies of TNFAIP3 rs2230926 polymorphism between HBV patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma also showed no significant difference.ConclusionsThe TNFAIP3 rs2230926 polymorphism is not suggested to be associated with the susceptibility of chronic HBV infection or the progression of HBV-related diseases in this study. Replicative studies and studies in large control and HBV patient populations of different ethnicity by genotyping more polymorphisms in TNFAIP3 gene are needed.

Genetic variations of SOCS1 are associated with chronic hepatitis B virus infection.

Suppressor of cytokine signaling (SOCS)-1 is involved in viral infection through regulation of both innate and adaptive immunity. The SOCS1 gene polymorphisms may affect the outcome of viral infection. The relationship between SOCS1 polymorphisms and hepatitis B virus (HBV) infection has not yet been explored. This study genotyped SOCS1 rs243327 and rs33932899 polymorphisms in 477 patients with chronic HBV infection, 93 HBV infection resolvers and 215 healthy controls. In statistical analysis, p-values less than 0.05 in multiple comparisons were corrected by Bonferroni method and presented as pc. The results showed that the allele T-containing genotypes (CT+TT) of rs243327 were higher in HBV patients than resolvers and lower in resolvers than healthy controls although the difference was not significant. The allele T of rs243327 was significantly lower in resolvers than controls (p = 0.033). The genotype GC and allele C of rs33932899 were significantly less frequent in HBV patients than controls (pc < 0.001 and p < 0.001, respectively). The haplotype T/G of rs243327/rs33932899 was significantly more frequent in HBV patients than resolvers (pc < 0.001) or controls (pc = 0.009). These data indicate that SOCS1 polymorphisms might affect the susceptibility and outcome of HBV infection.

Association of genetic variation in B-cell activating factor with chronic hepatitis B virus infection

The outcome of hepatitis B virus (HBV) infection is considered to be related to the host immunogenetic susceptibility. B cell activating factor (BAFF) is involved in both B cell and T cell mediated immunity and its circulating levels were shown to be significantly elevated in HBV-related liver diseases. This study examined BAFF rs9514828 and rs12583006 polymorphisms in 386 patients with various liver diseases related to chronic HBV infection, 69 HBV infection resolvers, and 191 healthy controls. Both rs9514828 and rs12583006 polymorphisms and serum BAFF levels were determined in 232 patients with chronic HBV infection, and 61 healthy controls. The results showed that patients with chronic hepatitis had higher frequencies of rs9514828 genotype TT (19.75% vs. 11.86%, OR=2.397, 95% CI=1.121-5.125, P=0.023), genotypes CT+TT (74.69% vs. 63.55%, OR=1.478, 95% CI=1.050-2.080, P=0.045), and allele T (47.22% vs. 37.72%, OR=1.478, 95% CI=1.050-2.080, P=0.025) compared with patients with cirrhosis. Patients with chronic HBV infection and HBV infection resolvers had higher frequency of rs9514828 and rs12583006 haplotype TA compared with healthy controls (21.6% vs. 15.0%, OR=1.672, 95% CI=1.138-2.456, P=0.009 and 27.3% vs. 15.0%, OR=2.258, 95%CI=1.272-4.007, P=0.005, respectively). The rs9514828 and rs12583006 genotypes had no significant association with serum BAFF levels. These results suggest that the rs9514828 allele T may predispose to the liver inflammation in chronic HBV infection, and the rs9514828 and rs12583006 polymorphisms may combinatorially confer susceptibility to chronic HBV infection and resolution of the infection, possibly not through direct effect on serum BAFF levels.