Disease Progression In Hepatitis Research Articles

Different treatment strategies in patients with HBeAg-positive and negative chronic hepatitis B

Patients with HBeAg-positive and negative chronic hepatitis B (CHB) have different immunological states and disease progression. Hence, the previously recommended antiviral therapy strategies for the two are different. In recent years, the antiviral indications have gradually eased, and the treatment goal has began to pursue clinical cure, as experts and scholars have gradually attached importance to the potential risk of disease progression in hepatitis B patients. Antiviral treatment strategies are gradually becoming uniform for patients with HBeAg-positive and negative. However, among them, HBeAg-negative patients can be combined with HBsAg quantification and other indicators to further screen the clinically cured dominant population in order to formulate the next treatment strategy.

4210\xa0Da and 1866\xa0Da polypeptides as potential biomarkers of liver disease progression in hepatitis B virus patients

HBV infection is recognized as a serious global health problem, and hepatitis B virus infection is a complicated chronic disease leading to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). New biochemical serum markers could be used to advance the diagnosis and prognosis of HBV-associated liver diseases during the progression of chronic hepatitis B into cirrhosis and HCC. We determined whether the 4210 Da and 1866 Da polypeptides are serum metabolite biomarkers of hepatopathy with hepatitis B virus. A total of 570 subjects were divided into five groups: healthy controls, those with natural clearance, and patients with CHB, LC, and HCC. The 1866 Da and 4210 Da polypeptides were measured by Clin-ToF II MALDI-TOF–MS. There were significant differences in 4210 Da and 1866 Da levels among the five groups (P < 0.001). For the differential diagnosis of CHB from normal liver, the areas under the receiver operating characteristic (ROC) curve of 4210 Da and 1866 Da and their combination via logistic regression were 0.961, 0.849 and 0.967. For the differential diagnosis of LC from CHB, the areas under the ROC curve were 0.695, 0.841 and 0.826. For the differential diagnosis of HCC from CHB, the areas under the ROC curve were 0.744, 0.710 and 0.761, respectively. For the differential diagnosis of HCC from LC, the areas under the ROC curve of 4210 Da and 1866 Da were 0.580 and 0.654. The positive rate of 1866 Da was 45.5% and 69.0% in AFP-negative HCC patients and that of 4210 Da was 60.6% 58.6% in AFP-negative HCC patients of the study HCC vs. CHB and HCC vs. LC. The 4210 Da and 1866 Da polypeptide levels were positively correlated with HBV DNA levels (P < 0.001, r = 0.269; P < 0.001, r = 0.285). The 4210 Da and 1866 Da polypeptides had good diagnostic value for the occurrence and progression of HBV-related chronic hepatitis, liver cirrhosis and hepatocellular carcinoma and could serve to accurately guide treatment management and predict clinical outcomes.

Impact of sustained virologic response on chronic kidney disease progression in hepatitis C.

AIMTo determine how sustained virological response at 12 wk (SVR12) with direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection affects chronic kidney disease (CKD) progression.METHODSA retrospective analysis was performed in patients aged ≥ 18 years treated for HCV with DAAs at the VA Greater Los Angeles Healthcare System from 2014-2016. The treatment group was compared to patients with HCV from 2011-2013 who did not undergo HCV treatment, prior to the introduction of DAAs; the control group was matched to the study group in terms of age, gender, and ethnicity. Analysis of variance and co-variance was performed to compare means between SVR12 subgroups adjusting for co-variates.RESULTSFive hundred and twenty-three patients were evaluated. When comparing the rate of change in estimated glomerular filtration rate (eGFR) one-year after HCV treatment to one-year before treatment, patients who achieved SVR12 had a decline in GFR of 3.1 mL/min ± 0.75 mL/min per 1.73 m2 compared to a decline in eGFR of 11.0 mL/min ± 2.81 mL/min per 1.73 m2 in patients who did not achieve SVR12 (P = 0.002). There were no significant clinical differences between patients who achieved SVR12 compared to those who did not in terms of cirrhosis, treatment course, treatment experience, CKD stage prior to treatment, diuretic use or other co-morbidities. The decline in eGFR in those with untreated HCV over 2 years was 2.8 mL/min ± 1.0 mL/min per 1.73 m2, which was not significantly different from the eGFR decline noted in HCV-treated patients who achieved SVR12 (P = 0.43).CONCLUSIONPatients who achieve SVR12 have a lesser decline in renal function, but viral eradication in itself may not be associated improvement in renal disease progression.

Role of Novel Micro-RNA Identified by Small RNA Sequencing in the Disease Progression of Hepatitis C Infection

Role of Novel Micro-RNA Identified by Small RNA Sequencing in the Disease Progression of Hepatitis C Infection

Infection With Hepatitis C Virus Genotype 3 Is an Independent Risk Factor for End-Stage Liver Disease, Hepatocellular Carcinoma, and Liver-Related Death.

Few studies have examined factors associated with disease progression in hepatitis C virus (HCV) infection. We examined the association of 11 risk factors with adverse outcomes in a population-based prospective cohort observational study of Alaska Native/American Indian persons with chronic HCV infection. We collected data from a population-based cohort study of liver-related adverse outcomes of infection in American Indian/Alaska Native persons with chronic HCV living in Alaska, recruited from 1995 through 2012. We calculated adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for end-stage liver disease (ESLD; presence of ascites, esophageal varices, hepatic encephalopathy, or coagulopathy), hepatocellular carcinoma (HCC), and liver-related death using a Cox proportional hazards model. We enrolled 1080 participants followed up for 11,171 person-years (mean, 10.3 person-years); 66%, 19%, and 14% were infected with HCV genotypes 1, 2, and 3, respectively. On multivariate analysis, persons infected with HCV genotype 3 had a significantly increased risk of developing all 3 adverse outcomes. Their aHR for ESLD was 2.1 (95% CI, 1.5-3.0), their aHR for HCC was 3.1 (95% CI, 1.4-6.6), and their aHR for liver-related death was 2.4 (95% CI, 1.5-4.0) compared with genotype 1. Heavy alcohol use was an age-adjusted risk factor for ESLD (aHR, 2.2; 95% CI, 1.6-3.2), and liver-related death (aHR, 2.9; 95% CI, 1.8-4.6). Obesity was a risk factor for ESLD (aHR, 1.4; 95% CI, 1.0-1.9), and diabetes was a risk factor for ESLD (aHR, 1.5; 95% CI, 1.1-2.2). Male sex was a risk factor for HCC (aHR, 3.6; 95% CI, 1.6-8.2). In a population-based cohort study of American Indian/Alaska Native persons with chronic HCV infection, we found those infected with HCV genotype 3 to be at high risk for ESLD, HCC, and liver-related death.

The Role of Circulating MicroRNAs as Markers of Disease Progression in Hepatitis C Virus Infected Egyptian Patients

Background: The discovery of miRNAs circulating in the peripheral blood has opened new directions of research to identify new non-invasive markers for diagnosis of diseases. Aim: The aim of the study was to evaluate the expression levels of circulating plasma miRNAs (miRNA-21 & miRNA-122) in Egyptian patients with chronic uncomplicated and complicated HCV. Patients & Methods: This study was conducted on 60 Chronic HCV infected patients. Patients were divided into three groups (20 patients each): uncomplicated HCV, cirrhosis, and hepatocellular carcinoma (HCC). All patients were subjected to laboratory investigations including complete blood picture, liver function tests. Expression levels of miRNA-21 and -122 in plasma using RT-PCR were determined. Results: MiRNA-21 showed significant fold increase in chronic uncomplicated HCV while significant fold decrease in cirrhotic and HCC groups (P = 0.036). On the other hand, miRNA-122 showed significant fold elevation in both chronic uncomplicated and cirrhotic groups and significant fold decrease in HCC group (P = 0.005). ROC curve analysis for miRNA-122 yielded 68.4% sensitivity and 100% specificity for the differentiation of HCC patients from non-HCC at a cutoff 0.184. Neither miRNA-21 nor miRNA-122 was a successful predictor for HCC diagnosis. Conclusion: MiRNA-122 can be used as novel non-invasive biomarker for monitoring HCV related disease progression.

Correlation between Th17 and nTreg cell frequencies and the stages of progression in chronic hepatitis B.

Several studies have suggested that the balance of T helper 17 (Th17) and natural regulatory T (nTreg) cells in the Th17‑mediated immune response are critical in the pathogenesis of viral hepatitis. The aim of the present study was to examine the role of circulating Th17 and nTreg cells in the disease progression of hepatitis B virus (HBV) infection. A total of 40 patients with chronic HBV (CHB), 27 patients with HBV‑associated cirrhosis, 20 patients with HBV‑associated liver failure and 20 healthy controls were enrolled in the present study. The frequencies of Th17 and nTreg cells in the peripheral blood were examined using flow cytometry. Th17‑associated serum cytokine levels were measured using an enzyme‑linked immunosorbent assay. The results revealed a significantly higher frequency of circulating Th17 cells in the patients with CHB, cirrhosis and liver failure compared, with the normal controls, particularly in the patients with liver failure. The same trend was observed in the serum levels of interleukin (IL)‑17. The frequency of Th17 cells and the serum levels of IL‑17 were positively correlated with the levels of alanine aminotransferase and the prothrombin times. There was a significantly higher frequency of circulating nTreg cells in the patients with CHB, compared with the normal controls. The nTreg cell frequencies were significantly and positively correlated with plasma HBV DNA load, and were negatively correlated with Th17 frequencies in the cohort of patients with HBV. Taken together, the results suggested that Th17 cell‑mediated inflammation is associated with progression from CHB to cirrhosis, and to liver failure. Peripheral Th17 cell frequency and serum levels of IL‑17 may assisting in predicting the severity of liver damage and fibrosis.

Effects of HIV infection on the disease progression of hepatitis C in patients with HIV/HCV coinfection

Objective To analyze the differentiation status of CTL and to evaluate its clinical value in patients with HIV/HCV coinfection. Methods Twenty-eight patients with HIV/HCV coinfection and twelve patients with single HCV infection were enrolled in this study. The technique of Fibro-Scan was used to evaluate liver fibrosis. The viral load of HCV was detected by real-time quantitative PCR. Flow cytometry analysis was performed to measure the differentiation status of CTL. Results Both of the levels of alanine transaminase (ALT) and alkaline phosphatase (ALP) in patients with HIV/HCV coinfection were significantly higher than those in patients with single HCV infection [(53.7464±48.1180) U/L vs (27.4750±13.9850) U/L, P=0.012; (24.5071±8.1940) g/L vs (16.9667±7.1890) g/L, P=0.009]. The liver stiffness of patients with HIV/HCV coinfection was higher than that of patients with single HIV infection [(5.9500, 5.8250) Kpa vs (5.1500, 1.0500) Kpa, P=0.117]. Compared with the patients with single HCV infection, the patients with HIV/HCV coinfection showed higher viral loads of HCV [(6.4768, 5.3434) lg copy/ml vs (2.6815, 1.6990) lg copy/ml, P=0.012], but lower clearance rate of HCV [32.14% vs 75%, P=0.032]. Compared with the patients with single HCV infection, the patients with HIV/HCV coinfection showed lower percentages of CD27+ CD28+ CTL [(28.265±15.095)% vs (18.068±10.263)%, P=0.017), but higher percentages of CD27+ /-CD28+ CTL [(62.449±14.561)% vs (71.111±12.681)%, P=0.066]. A trend toward negative correlation was observed between the percentage of CD27+ CD28+ CTL and the degree of liver stiffness (r=-0.310, P=0.058). Conclusion HIV infection could accelerate the progression of liver disease in patients with HIV/HCV coinfection by affecting the differentiation of CTL. Key words: HIV; HCV; Coinfection; CTL differentiation

Liver disease progression in hepatitis C virus carriers with normal alanine aminotransferase levels

We read with great enthusiasm the article of Wiese et al.1 that, in our opinion, has a paramount relevance to understanding the natural history of hepatitis C virus (HCV) infection. In particular, this article does greatly in helping us to evaluate the progression to more severe liver damage of the so-called healthy HCV carriers (i.e., viremic persons with normal alanine aminotransferase [ALT] levels and liver histology). It is known that up to 30%-40% of patients with chronic HCV infection have persistently normal ALT levels,2 with many of them showing normal liver histology or minimal fibrosis. The natural course of HCV infection in these patients is not well known. Whereas some studies showed that HCV carriers with normal ALT have mild and stable disease, others reported a significant progression of fibrosis in approximately 20%-30% of such patients.3 In their first study4 describing the 20-year follow-up of over 1,000 women infected in East Germany in January 1979 by contaminated anti-D immune globulin, the researchers reported that 26 patients should be considered as true healthy carriers (i.e., normal liver, normal ALT, and persistent HCV viremia). At 25-year follow-up,5 only 11 women had remained in a healthy state, whereas the others had progressed to chronic hepatitis C (CHC). However, in this third evaluation after 35-year follow-up,1 no mention has been made about the histological and clinical status of these otherwise healthy, HCV-infected women. Thus, we wonder how many of these carriers had remained in a true healthy state 35 years after contamination and how many further carriers had progressed to CHC. Furthermore, the degree of liver damage was more or less severe in the carriers progressing to CHC with respect to other patients; were differences observed in virological response between the two groups of patients? Indeed, whether healthy HCV carriers should be offered antiviral treatment in clinical practice has been the subject of an ongoing debate.6 Introduction of the combination therapy of pegylated interferon plus ribavirin results in higher response rates,7 with a favorable risk/benefit ratio also in patients with mild or no fibrosis.8, 9 The important data of the East Germany HCV Study Group might give an answer to this unmet issue: What should we treat, the infection or the disease?10 Claudio Puoti, M.D.1 Lia Bellis, M.D.1 Olga Mitidieri Costanza, M.D.2 Maria Giuseppa Elmo, M.D.3 1Department of Internal Medicine and Liver Unit Marino General Hospital Rome, Italy 2Molecular Biology Unit Marino General Hospital Rome, Italy 3Department of Mental Health, Local Health Center Rome, Italy

HLA-DPB1 Variant Effect on Hepatitis B Virus Clearance and Liver Cirrhosis Development Among Southwest Chinese Population.

Background:Previous studies have shown that genetic variants in HLA-DP genes affect disease progression in hepatitis B virus (HBV) infection.Objectives:We aimed to evaluate possible association between HLA-DPB1 rs9277534 polymorphism and different clinical complications of hepatitis B virus (HBV) infection.Materials and Methods:Snapshot assay was used to investigate the association of rs9277534 polymorphism in 342 patients with persistent HBV infection and 342 age and gender-matched HBV spontaneous clearance controls. Patients were categorized into asymptomatic HBV carriers (AsC, n = 104), chronic hepatitis B (CHB, n = 116), and liver cirrhosis (LC, n = 122) subgroups.Results:There was a significantly higher proportion of the rs9277534 minor allele A in HBV spontaneous clearance control than that in HBV persistent infection group (OR = 0.58, 95%CI = 0.46-0.73, P < 0.0001). Genotypic analysis showed that GA and AA genotypes were associated with HBV spontaneous clearance (GA: OR = 0.56, 95%CI = 0.40-0.79, P = 0.019; AA: OR = 0.24, 95%CI = 0.14-0.44, P < 0.0001). A significant difference was found between AsC and LC groups in the distribution of AA genotype (OR = 9.32, 95%CI = 1.293-67.14, P = 0.027).Conclusions:Variant at rs9277534 could affect both the spontaneous clearance of HBV infection and progression from asymptomatic HBV carriers to HBV-related liver cirrhosis in Southwest Han Chinese population.

Hepatitis B surface antigen level complements viral load in predicting viral reactivation in spontaneous HBeAg seroconverters

The level of hepatitis B surface antigen (HBsAg) has been shown to complement hepatitis B virus (HBV)-DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg seroconverters remains unclear. A retrospective cohort of 390 Taiwanese spontaneous HBeAg seroconverters with a mean follow-up period of 7.4 years was enrolled. The relationships between HBV-DNA/HBsAg levels and HBeAg-negative hepatitis/active viral replication (HBV-DNA level ≥ 2000 IU/mL) were investigated. In the overall cohort, serum HBV-DNA level served as a better predictor for HBeAg-negative hepatitis compared with HBsAg level. However, in those with HBV-DNA level < 2000 IU/mL, a higher HBsAg level was associated with a higher risk of HBeAg-negative hepatitis (P = 0.015). Multivariate analysis showed the hazard ratio of HBsAg level ≥ 1000 IU/mL versus < 1000 IU/mL was 4.1 (95% confidence interval: 1.3-13.6). When using the end-point of active viral replication, HBsAg ≥ 1000 IU/mL remained as an independent risk factor, with a hazard ratio of 2.5 (95% confidence interval: 1.1-5.9). In spontaneous HBeAg seroconverters with HBV-DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL is associated with increased risks of HBeAg-negative hepatitis and active viral replication. Combining HBV-DNA < 2000 IU/mL and HBsAg level < 1000 IU/mL may be used to define minimal viral activity.

Insulin resistance and steatosis in HBV-HCV co-infected patients: Role of PNPLA3 polymorphisms and impact on liver fibrosis progression.

To evaluate steatosis, insulin resistance (IR) and patatin-like phospholipase domain-containing 3 (PNPLA3) and their relation to disease progression in hepatitis B and C viruses (HCV-HBV) co-infected patients. Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled: 66 had HBV-HCV, 66 HBV and 198 HCV infection. Prevalence of steatosis, IR and PNPLA3 polymorphisms and their relation to anthropometric, biochemical, virological and histological parameters were evaluated. Prevalence of steatosis in group HBV-HCV was similar to that in HCV (47.0% vs 49.5%, respectively); group HBV showed the lowest steatosis (33.3%). Group HBV-HCV had a lesser degree of steatosis than HCV (P = 0.016), lower HCV RNA levels (P = 0.025) and lower prevalence and degree of IR (P = 0.01). PNPLA3 polymorphisms were associated with steatosis. Group HBV-HCV showed higher levels of liver fibrosis than group HCV (P = 0.001), but similar to that observed in HBV group. In HBV-HCV group, liver fibrosis was not associated with steatosis, IR or PNPLA3. HBV infection was the independent predictor of advanced liver fibrosis. HBV-HCV co-infected patients have lower degree of hepatic steatosis, IR and HCV RNA than HCV mono-infected; co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance.

A cohort study in the assessment of liver fibrosis and markers of disease progression in hepatitis B and D coinfection

Results We assessed data from 64 patients (of which 27 were males 42%) with a median age of 54±14 (range: 23 to 64 years). The median fibrosis was 0.44±0.23 and the median necroinflammatory activity was 0.54±0.24. The median FIB-4 score was 1.89±3.23 at the second visit versus 1.26±2.07 at the third visit. The median APRI score was 1.18±1.67 at the second visit compared to 1.79 ±2.53 at the third visit (p=0.05, 95%CI: 0.0389, 0.43681). Regression analysis showed a correlation between FibroTest (considered the gold standard in this study, in the absence of histology data from liver biopsy), FIB-4 (p=0.43) and APRI (p=0.011).

Association of Interferon-gamma Induced Protein 10 Promoter Polymorphisms with the Disease Progression of Hepatitis B Virus Infection in Chinese Han Population

Background and AimsInterferon-gamma induced protein 10 (IP-10) was suggested to be involved in liver injury in viral hepatitis. This study aimed to investigate the impact of the single nucleotide polymorphisms (SNP) G-201A (rs1439490) in IP-10 gene on disease progression of hepatitis B virus (HBV) infection.MethodsThe -201 SNP in IP-10 promoter was genotyped from 577 patients with different illness categories and 275 health controls; In vitro IP-10 promoter activity was compared between haplotype GG and AA homozygotes using luciferase reporter system in HepG2 cells. In vivo expression of IP-10 was compared between patients with -201 AA genotype and GG genotype.ResultsThe detected frequency of G-201A SNP was 17.8%, 25.3%, 26.6%, and 13.8% for patients with acute hepatitis B (AHB), patients with mild chronic hepatitis B (CHB-M), patients with severe chronic hepatitis B (CHB-S), and health controls, respectively. In vitro IP-10 promoter-driven luciferase activity in pGL3-Enhancer-201A transfected HepG2 cells was 1.43-fold higher than that in pGL3-Enhancer-201G transfected HepG2 cells (P<0.01). In vivo IP-10 transcriptional expression of peripheral blood mononuclear cells was 1.38-fold higher in patients with -201 AA genotype than in patients with -201 GG genotype (P<0.01).ConclusionG-201A in promoter region of IP-10 gene was associated with liver disease progression in patients with HBV infection through up-regulating IP-10 expression.

Entecavir treatment prevents disease progression in hepatitis B virus-related acute-on-chronic liver failure: establishment of a novel logistical regression model.

Hepatitis B-related acute-on-chronic liver failure (ACLF) has a poor prognosis with very high mortality. Unfortunately, most prognostic predictive models of liver failure are complicated and offer suboptimal sensitivity. Experience in entecavir (ETV)-treated patients with hepatitis B virus (HBV)-ACLF is limited. This study was designed to evaluate the efficacy and safety of ETV in patients with HBV-ACLF and to develop a novel model (Tongji prognostic predictor model, TPPM) for prognostic prediction of HBV-ACLF patients. In this retrospective study, 248 patients with HBV-ACLF were enrolled. There were no significant differences in baseline clinical and virologic characteristics between patients treated with and without ETV. The 1- and 3-month survival rates of patients in the ETV-treated group (n=124) were 72.58 and 61.29%, respectively, significantly higher than that in NA-free group (n=124), which were 53.23 and 45.97%, respectively. By Hosmor and Lemeshow test, TPPM for HBV-ACLF had a very good degree of fit with disease prognosis. Based on this unique group of patients, the TPPM scoring offered a better prediction value in both specificity and sensitivity for 3-month mortality of patients with HBV-ACLF compared with MELD scoring system with statistically significant difference. In the patients with HBV-ACLF, using a cutoff of 0.22 for 3-month predicted mortality by TPPM, the positive predictive value was 93.6% and negative predictive value 91.3%. ETV treatment prevented disease progression and increased the survival of patients with HBV-ACLF. The established TPPM scoring system offers superior predictor value in both specificity and sensitivity for HBV-ACLF patients when compared with MELD.

Adding pegylated interferon to a current nucleos(t)ide therapy leads to HBsAg seroconversion in a subgroup of patients with chronic hepatitis B

BackgroundNucleos(t)ides effectively halt disease progression in hepatitis B but require long-term medication. ObjectivesTo determine whether add-on of peg-IFN to an ongoing nucleos(t)ide therapy accelerates decline of HBsAg and induces seroconversion. Study designWe observed HBsAg kinetics in 12 patients on a stable oral therapy with undetectable HBV-DNA who additionally received peg-IFN-alfa 2a as an individualized therapy. 3 patients were HBeAg positive. Mean baseline HBsAg was 4695 (range 16–15,120)IU/ml. ResultsA continuous decline of HBsAg was observed in 2 patients. The slope, respectively, became detectable at week 8 or 16. HBsAg had dropped by 2.90log10 or 4.25log10 fold at week 48, and anti-HBs appeared at week 40 or 32. Patient A – HBe-positive, genotype A, F3 fibrosis – had been HBV-DNA negative for 10 months receiving entecavir plus tenofovir. Previous therapy with peg-IFN had been unsuccessful, but now the patient experienced HBeAg seroconversion at week 24. Patient B – HBeAg negative, genotype D, cirrhosis – had a low initial HBsAg level of 16U/l. Receiving entecavir, his HBV-DNA had previously been non-detectable for 27 months. In the remaining 10 patients HBsAg declined only by a mean of 0.09log10 (range 0.01–0.25log10) after 8–24 (mean 16.4) weeks, and therefore, peg-IFN was stopped. No unexpected side effects were observed. DiscussionWe observed that the add-on of peg-IFN induced HBsAg seroconversion in 2 out of 12 patients. Response rates may have been higher with prolongation of therapy. The add-on concept merits to be evaluated in a clinical trial.

Aboriginal Taiwanese hepatitis B carriers have more favorable viral factors than Han Chinese carriers

Several viral factors are associated with disease progression in hepatitis B virus (HBV) carriers. Compared with Taiwanese Han Chinese, Taiwanese aborigines have a higher prevalence of chronic HBV infection and a higher standardized mortality rate of chronic liver diseases but a lower standardized mortality rate of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether aboriginal Taiwanese HBV carriers have more favorable viral factors which reduce the risk for HCC than Han Chinese carriers. Blood samples from 3,488 HBV carriers (1,527 aborigines and 1,961 Han Chinese) were assayed for aminotransferases, hepatitis B e antigen (HBeAg), HBV DNA, and HBV genotype. Aboriginal HBV carriers had a lower HBeAg-positive rate (5.3% vs. 10.2%, P < 0.0001) and a lower viral load of HBV DNA > 2,000 IU/ml (27.4% vs. 36.7%, P < 0.0001) but a higher rate of alcohol consumption (40.0% vs. 19.3%, P < 0.0001) than Han Chinese carriers. The prevalence of HBV genotype B in aboriginal carriers (92.7%) was significantly higher than that in Han Chinese carriers (72.7%) in all age groups (P < 0.05). In addition, patients with rare genotype D infections were clustered in a township in southern Taiwan. In conclusion, aboriginal Taiwanese HBV carriers have more favorable viral factors than Han Chinese carriers, which may be partly responsible for the lower standardized mortality rate of HCC in Taiwanese aborigines.

Single nucleotide polymorphism at exon 7 splice acceptor site of OAS1 gene determines response of hepatitis C virus patients to interferon therapy

Background and Aim: Response to interferon therapy and disease progression in hepatitis C virus (HCV) infected patients differs among individuals, suggesting a possibility of a contribution of host genetic factors. 2′‐5′‐oligoadenylate synthetase 1 (OAS1), an important component of the innate immune system with a proven antiviral function, may therefore have a relationship with the response to interferon therapy and clinical course of HCV disease. Our aim was to determine the frequency of single nucleotide polymorphism (SNP) at exon 7 splice acceptor site (SAS) of the OAS1 gene in relation to the interferon response and status of HCV infection. Methods: A 203 bp fragment containing exon 7 SAS was amplified in 70 HCV chronic patients and 50 healthy controls. SNP was examined using restriction fragment length polymorphism (RFLP) genotyping method. Correlations of SNP genotypes with response to interferon and clinical status of patients were statistically analyzed. Results: There was an increasing trend of response from AA to AG to GG genotypes (P = 0.007). Genotype AA was associated with non‐response to interferon and higher degree of liver fibrosis (P = 0.05). Multivariate analysis showed this SNP as independent and a significant determinant of the outcome of interferon therapy (odds ratio 4.913 [95% confidence interval 1.365–8.2], P = 0.006). Conclusions: This is the first study to show a significant association between the functional SNP at exon 7 SAS of OAS1 gene and the viral response to interferon in chronic HCV patients. Patients with AA genotype were associated with progressive HCV disease and viral resistance to interferon therapy. This OAS SNP is a potential bio‐marker to predict IFN response in chronic hepatitis C patients.

Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection

Background and objectiveT-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) represents a novel mechanism of T-cell dysfunction in chronic viral diseases. However, the role of Tim-3 in the pathogenesis of chronic hepatitis B (CHB) is not well understood. We investigated Tim-3 expression on peripheral T cell subsets and analyzed the relationship between Tim-3 expression and disease progression in HBV infection.Methodsperipheral blood samples were obtained from CHB patients (n = 40), including 23 patients with moderate CHB [MCHB] and 17 with severe CHB [SCHB]. Control samples were obtained from nine acute hepatitis B patients (AHB) and 26 age-matched healthy subjects. The expression of Tim-3 on T cells was determined by flow cytometry.ResultsTim-3 expression was elevated on peripheral CD4+ and CD8+ T cells from AHB and CHB patients compared to those from healthy controls. The percentage of Tim-3+ T cells was further increased in SCHB patients relative to MCHB patients and showed a positive correlation with conventional markers for liver injury (alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB) and international normalized ratio (INR) level). The frequency of Tim-3-expressing T cells was negatively correlated with T-bet mRNA expression and plasma interferon-gamma (INF-gamma) levels. Further, Tim-3 expression on CD4+ or CD8+ T cells was reduced in CHB patients with disease remission after antiviral treatment and in AHB patients during the convalescence phase.ConclusionsOur results suggest that over-expression of Tim-3 is involved in disease progression of CHB and that Tim-3 may participate in skewing of Th1/Tc1 response, which contributes to persistency of HBV infection.

Association of TBX21 T‐1993C polymorphism with viral persistence but not disease progression in hepatitis B virus carriers

Transcription factor T-bet is responsible for the differentiation of naive T lymphocytes, and its expression level is linked with different responses to some viral infections, including hepatitis B virus (HBV) infection. In this report we examine whether promoter polymorphisms of the TBX21 gene (encoding T-bet) are associated with susceptibility to HBV persistence or disease progression in chronic HBV carriers. Three previously reported promoter polymorphisms, T-1993C, T-1514C and G-1499A, were analyzed by polymerase chain reaction restriction fragment length polymorphism analysis. Two common polymorphisms, T-1993C and T-1514C, were selected for genotyping in 1074 chronic HBV carriers, 310 spontaneously recovered controls and 374 HBV naive controls. Of 1074 HBV carriers, 234 were considered to be asymptomatic carriers and 840 were found to have chronic progressive liver disease including cirrhosis and hepatocellular carcinoma. Haplotypes were constructed for each subject and associations with the susceptibility to persistent HBV infection were estimated by logistic regression. The -1993C allele in the TBX21 promoter was significantly more common among chronic HBV carriers compared with recovered controls (chi(2) = 6.65, P = 0.01). In contrast, the frequency of TT haplotype at positions -1993/-1514, was significantly higher in recovered controls than chronic HBV carriers (P = 0.0027, odds ratio = 1.57; 95% confidence interval, 1.16-2.12). In HBV carriers, the TBX21 promoter polymorphisms were not linked to disease progression. The TBX21 promoter polymorphisms do not appear to be determinant of disease progression in Chinese HBV carriers. The T-1993C polymorphism in the TBX21 promoter influences susceptibility to persistent HBV infection.