Chinese Experience on theLamivudine in Treatment of Chronic Hepatitis B Infection

Lamivudine, the β-L-enatimer of 2^ , 3^ -thiacytidine, is a potent inhibitor of HBV polymerase, which block HBV DNA synthesis in hepatocytes. Thousands of chronic hepatitis B patients throughout the world have been treated with lamivudine with favorable result. This reportsummerized the efficacy of lamivudine in treatment of chronic hepatitis B virus infection in mainland China. This multicenter, double-blind, randomized,     

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

INTRODUCTION Hepatitis B (HBV) is a hepatotropic DNA virus capable of causing both acute and chronic hepatitis in humans. It is estimated that over 350 million people are chronically infected with HBV worldwide. Currently approved thera- peutic strategies for treatment of HBV include interferon- alpha (IFN-a), the nucleoside analogue lamivudine and the nucleotide analogue adefovir[1,2]. However, only a minority of patients treated with IFN-a has a long-term sustained response with …     

Molecular analysis of hepatitis B virus isolates in Mexico： Predominant circulation of hepatitis B virus genotype H

INTRODUCTIONHepatitis B virus(HBV)is an important cause of morbidity and mortality worldwide.It is estimated that2billion people are infected with HBV and350million individuals suffer from chronic HBV infection in the world[1,2].Chronic HBV infection may …     

Chronic hepatitis B and metabolic risk factors:A call for rigorous longitudinal studies

Long-term nucleos(t)ide analogue therapy in chronic hepatitis B virus(HBV)infection is effective in suppressing viral replication and reducing liver-related complications. However, HBV-related liver events can still occur in different patient sub-groups. There is emerging evidence that, similar to chronic hepatitis C virus infection, metabolic risk factors may play a role in the disease process of chronic HBV. While the mechanistic nature of metabolic-HBV interactions remains uncertain, studies in different HBV-infected populations have demonstrated that hepatic steatosis, increased body-mass index, diabetes, or a combination of different metabolic risk factors are associated with an increased risk of hepatocellular carcinoma and cirrhosis. The impact of metabolic risk factors is especially prominent in patients with quiescent virological activity,including on-treatment patients with effective viral suppression. As the proportion of on-treatment chronic HBV patients increases worldwide,longitudinal studies determining the relative risks of different metabolic parameters with respect to clinical outcomes are needed. Future studies should also determine if metabolic-directed interventions can improve disease outcomes in chronic HBV.     

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.     

Current and future antiviral drug therapies of hepatitis B chronic infection

Despite significant improvement in the management of chronic hepatitis B virus(HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon(IFN)-α and monotherapy with five nucleos(t)ide analogues(NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection.     

Clinical features of hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death,and chronic hepatitis B is a serious worldwide problem.The epidemiology of HCC is distinctive.Hepatitis B virus (HBV) plays a major role in hepatocarcinogenesis.Prevention of HBV-related HCC is a key issue in current hepatology.This paper describes the prevention and clinical features of HBVrelated HCC,along with a short review of the disease.     

HLA class Ⅱ associated with outcomes of hepatitis B and C infections

Several factors influence the clinical course of hepatitis B virus(HBV)and hepatitis C virus(HCV)infection.The human leukocyte antigen(HLA)system,the major histocompatibility complex(MHC)in humans,has been considered one of the most important host factors with respect to outcomes.To date,conventional genotyping studies have shown that HLA classⅡloci are mainly associated with spontaneous clearance of HBV and HCV.However,the specific HLA locus associated with the outcomes of hepatitis virus infection remains unclear.A recent genome-wide association study(GWAS)using a comprehensive approach for human genotyping demonstrated single nucleotide polymorphisms(SNPs)associated with the outcomes of hepatitis virus infection.Examination of large numbers of cohorts revealed that several SNPs in both HLA-DPA1 and HLADPB1 loci are associated with persistent HBV infection in Asian populations.To date,however,few studies have focused on HLA-DP because polymorphisms of HLA-DP haplotype do not vary greatly as compared with other loci of HLA.There are not enough studies to reveal the function of HLA-DP.GWAS additionally detected candidate SNPs within HLA loci associated with chronic HBV or HCV hepatitis,hepatic fibrosis,and the development of hepatocellular carcinoma.The results of one cohort were not always consistent with those of other cohorts.To solve several controversial issues,it is necessary to validate reported SNPs on HLA loci in global populations and to elucidate the HLA-allele-regulated molecular response to hepatitis virus infection.     

Individualized management of pregnant women with high hepatitis B virus DNA levels

Hepatitis B is a major health concern in the Asia-Pacific region,and is endemic in China,Southeast Asia,and Africa.Chronic hepatitis B virus(HBV)infection may cause hepatic cirrhosis and liver cancer.It is estimated that there are more than 350 million chronic HBV carriers worldwide,of whom approximately one quarter will die of chronic hepatitis B-related liver diseases.HBV is transmitted horizontally through blood and blood products or by sexual transmission,and vertically from mother to infant.Perinatal infection is the predominant mode of transmission in countries with a high prevalence of hepatitis B surface antigen(HBsAg)carriage,and perinatal transmission leads to high rates of chronic infection.Therefore,it is important to prevent the mother-to-child transmission(MTCT)of HBV.Research has shown that pregnant women with high HBV DNA levels have an increased risk of MTCT.However,most of the obstetrics guidelines do not make a distinction between pregnant women with high HBV DNA levels and those who are HBsAg positive only.This review addresses the management of pregnant women with high levels of HBV viremia,in terms of antiviral therapy,use of hepatitis B immunoglobulin(HBIG),the combined application of hepatitis B vaccine and HBIG,choice of delivery mode and feeding practices.     

Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C

BACKGROUND & AIMS: Recent studies suggest that hepatitis B virus (HBV) genotype B is associated with less active liver disease than HBV genotype C. The aim of our study was to determine if HBV genotype B is associated with higher rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion compared with genotype C. METHODS: A retrospective study using stored sera from 332 Chinese patients with chronic HBV infection followed for a mean of 48 months (range, 12-98) were tested for HBV genotype using a line-probe assay. RESULTS: HBV DNA was detected in 273 patients, 122 had HBV genotype B and 147 genotype C. Patients with genotype B had a significantly lower prevalence of HBeAg at presentation and significantly higher rates of spontaneous HBeAg seroconversion during follow-up. HBV genotype B patients who were HBeAg positive were significantly younger, and spontaneous HBeAg seroconversion occurred approximately 1 decade earlier compared with HBV genotype C patients. Multivariate analyses identified high alanine aminotransferase (baseline and follow-up), age >30 years, and genotype B as independent factors associated with spontaneous HBeAg seroconversion. CONCLUSIONS: HBV genotype B is associated with earlier HBeAg seroconversion than genotype C. This finding may explain the less active/progressive liver disease in patients with genotype B.     

新疆维吾尔族慢性乙型肝炎患者HBV基因型分布及其特点

目的探讨新疆维吾尔族慢性乙型肝炎患者HBV基因型分布及其特点。方法采用型特异性引物巢式PCR法对127例维吾尔族慢性乙型肝炎患者进行基因分型,并测序验证。结果基因D型占39．4%（50/127）,基因B型占22．0%（28/127）,基因C型占16．5%（21/127）,基因BD混合型占9．4%（12/127）,基因CD混合型占8．7%（11/127）,基因BCD混合型占3．9%（5/127）; HBeAg阳性与HBeAg阴性的维吾尔族慢性乙型肝炎患者基因型分布,差异无统计学意义（x^2= 6．033,P＞0．05）;不同年龄维吾尔族慢性乙型肝炎患者HBV基因型分布差异无统计学意义（x^2= 3．137,P＞0．05）;不同性别维吾尔族慢性乙型肝炎患者HBV基因型分布差异亦无统计学意义（x^2= 8．058,P＞0．05）。结论新疆维吾尔族慢性乙型肝炎患者HBV基因型以D型占优势,其次可见B、C型及BD、CD、BCD混合型。同一疾病谱的慢性HBV感染者基因型分布可能与宿主HBeAg状态、年龄、性别无明显关系。     

Hepatitis B virus genotype A is more often associated with severe liver disease in northern India than is genotype D.

BACKGROUND: The clinical outcome of chronic hepatitis B may depend on hepatitis B virus (HBV) genotype. Data from India on this aspect are limited and contradictory. We studied the frequency of HBV genotypes and their clinical significance. METHODS: Stored sera from patients with chronic HBV infection were tested for HBV genotype using PCR-RFLP. Clinical data, and biochemical and serological parameters were retrieved from medical records; patients were classified as having chronic hepatitis or cirrhosis. RESULTS: Of 70 patients studied (mean age [SD] 38.4 [17.0] years; 63 men; ALT 140 [177] U/L), 32 had chronic hepatitis and 38 had cirrhosis. HBeAg was positive in 50/67 (75%), and anti-HBe in 12/66 (18%). Genotype A was the commonest (37; 53%), followed by D (32; 46%) and C (1; 1%). Patients with genotype A more often had ALT elevation exceeding 1.5 times normal (30/37 [81%] than those with genotype D (18/31 [58%]; p< 0.05). They also more often had positive HBeAg (32/37; 86%) and negative anti-HBe (33/36; 92%) than those with genotype D (18/29 [62%] and 21/29 [72%], respectively; p< 0.05 each). Of 37 patients with genotype A, 23 (62%) had cirrhosis and 14 (38%) had chronic hepatitis; of 32 patients with genotype D, 15 (47%) had cirrhosis and 17 (53%) had chronic hepatitis (p=ns). In the subgroup aged> 25 years, genotype A patients more often had cirrhosis than those with genotype D (23/28 [82%] vs 13/23 [57%]; p < 0.05). CONCLUSION: HBV genotypes A and D were the commonest in our population. Genotype A was more often associated with ALT elevation, HBeAg positivity, absence of anti-HBe and, among those aged 25 years and above, cirrhosis of liver, than was genotype D.     

Comparative study of genotype B and C hepatitis B virus-induced chronic hepatitis in relation to the basic core promoter and precore mutations

BACKGROUND: The clinicopathological profiles and outcome of chronic hepatitis B can differ by hepatitis B virus (HBV) genotypes. In Japan, genotype B and C are two major HBV genotypes. The basic core promoter and precore mutations are other known viral factors for disease activity, although the relationship between HBV genotypes and these mutations is not fully understood. METHODS: The HBV genotypes in 90 patients with chronic hepatitis B were determined using an ELISA. Obtained data were correlated with clinicopathological parameters, basic core promoter, precore and the nucleotide 1858 mutations of the HBV genome. RESULTS: Among 90 cases, 20 (22.2%) had genotype B and 70 (77.8%) had genotype C HBV. Genotype B patients were older than genotype C patients (44.0 +/- 13.9 vs 34.7 +/- 11.0 P = 0.0022). The HBeAg was more prevalent in genotype C than B patients (P = 0.0008) while anti-HBe was more common in genotype B than C patients (P = 0.0002). Serum aspartate aspartate aminotransferase/alanine aminotransferase levels (B: 220.7 +/- 612.8/257.0 +/- 498.0 IU/L vs C: 111.3 +/- 122.8/201.6 +/- 229.4 IU/L, P = 0.16/0.48) and HBV viral loads in blood (B: 6.1 +/- 3.1 log genome equivalent [LGE]/mL vs C: 6.7 +/- 2.3 LGE/mL, P = 0.42) were equivalent. The seroconversion from HBeAg to anti-HBe occurred significantly earlier in genotype B than C patients (62 +/- 53 months vs 136 +/- 54 months, P = 0.0028) during the mean observation period of 149 +/- 82 months even under various therapeutic modalities. The categories III and IV of the histological activity index in genotype C were higher (III: P < 0.005, IV: P < 0.05, n = 68) than that in B patients whereas category II was higher in genotype B than C patients (P < 0.05). The double mutation (1762T/1764A) in the basic core promoter was more frequently found in genotype C than in B HBV (P = 0.0068), whereas the precore mutation (1896A) was more common in genotype B than C HBV (P = 0.0233). The incidence of 1858C that was complementary to the precore mutation site in the stem-loop structure in, was equally rare in both genotype B and C HBV. CONCLUSIONS: Genotype B patients were older, had earlier HBeAg seroconversion and exhibited more severe lobular necroinflammation, less portal inflammation and fibrosis than genotype C patients. This genotypic difference is related to the basic core promoter and precore mutations irrespective of 1858C. (c) 2004 Blackwell Publishing Asia Pty Ltd.     

Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D

BACKGROUND AN AIMS: Current interferon alfa (IFN) treatment of chronic hepatitis B has limited efficacy. The role of hepatitis B virus (HBV) genotypes for response to IFN was investigated. PATIENTS AND METHODS: HBV genotype was determined by direct sequencing of the HBV X gene in 165 consecutive patients with chronic replicative hepatitis B treated with standard IFN. HBV genotype A or D was found in 144 cases. RESULTS: Sustained response (six months after treatment) to standard IFN therapy was higher in HBV genotype A compared with HBV genotype D infected patients (49% v 26%; p<0.005). Sustained response to IFN was 46% versus 24% (p<0.03) in hepatitis B e antigen (HBeAg) positive hepatitis (n = 99) and 59% versus 29% (p<0.05) in HBeAg negative hepatitis (n = 45) for HBV genotype A compared with HBV genotype D. HBeAg status had no negative impact on IFN response. Multivariate logistic regression identified HBV genotype A and high pretreatment alanine aminotransferase levels (>2 x upper limit of normal) as independent positive predictive parameters of IFN response. CONCLUSIONS: The present study indicates that HBV genotypes A and D are important and independent predictors of IFN responsiveness in chronic hepatitis B. HBV genotype adapted treatment regimens may further improve treatment efficacy in chronic hepatitis B.     

Hepatitis B virus genotypes in chronic liver disease patients from New Delhi, India

INTRODUCTION Approximately, two billion people in the world have been infected by Hepatitis B virus (HBV), 350 million of whom are chronic carriers of the virus[1,2]. Worldwide HBV isolates have been classified into eight genotypes: A, B, C, D, E, F, G an…     

Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion

The underlying mechanisms for earlier hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) genotype B when compared with genotype C are unknown. We aimed to determine whether there were any differences in the T helper (Th) responses during hepatitis flares in HBeAg-positive patients with genotypes B and C. Proliferative response measured by (3)H-thymidine uptake and Th responses measured by Enzyme-Linked Immunosorbent Spot assays for interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-4, IL-5 and IL-10 were performed in 10 patients with genotype B and 10 with genotype C with hepatitis flares. HBV genotypes, core promoter, precore mutations, sequence of HBV core region and HBV DNA levels were determined. There was no difference in the HBV DNA levels during hepatitis flares between patients with genotypes B and C. Patients with genotype B had a significantly higher number of IFN-gamma producing cells [with hepatitis B core antigen (HBcAg) stimulation] and lower number of IL-10 producing cells (with HBcAg and HBeAg stimulation) compared with patients with genotype C (P = 0.011, =0.043, <0.001 respectively). There was a trend (P = 0.058) that patients with genotype B had a higher cumulative rate of HBeAg seroconversion. Patients with precore mutants also had a significantly higher number of IFN-gamma producing cells (with HBcAg stimulation) and lower number of IL-10 producing cells (with HBeAg stimulation) compared to patients without precore mutant (P = 0.038, =0.016 respectively). HBV genotype B induces a greater Th1 and lesser Th2 response than genotype C. This provides immunologic evidence for the higher chance of HBeAg seroconversion in patients with genotype B.     

Multicentre study of hepatitis B virus genotypes in France: correlation with liver fibrosis and hepatitis B e antigen status

The clinical significance of hepatitis B virus (HBV) genotypes is still under debate. The aims of this study were to assess the distribution of HBV genotypes in France and to identify the associations between HBV genotypes and patient demographics, severity of liver disease and HBeAg status in patients referred to tertiary care centres. This was a French, multicentre, retrospective study on 262 patients with chronic HBV infection. HBV genotypes were determined using INNO-LiPA. Liver fibrosis damage was evaluated by histological analysis of biopsy samples. Patients were mainly male (74%), of Caucasian (65%), Asian (17%) or African (18%) ethnicity and 36% were HBeAg positive. All A-G genotypes were found, the most frequent being genotypes D (27%) and A (24%), followed by E (13%) and C (12%), and B (7%). Mixed genotypes were detected in 16% of the cases. Genotype A was associated with sexual contact (P < 0.001) and genotype D with transfusion (P < 0.001) and HBe antibody positivity (P = 0.03).The distribution of HBV genotypes differed with regard to the ethnicity, and may reflect migration patterns. Genotypes A and D were the most frequent in France. Genotype A was associated with HBeAg positivity and genotype D with HBe antibody positivity. In our European patients, we find no clear association between a given HBV genotype and liver disease severity.     

定量检测慢性乙型肝炎患者肝组织乙型肝炎病毒DNA的临床价值

目的探讨慢性乙型肝炎(CHB)患者肝内乙型肝炎病毒(HBV)DNA载量与血清HBV DNA、乙型肝炎病毒e抗原(HBeAg)水平的相关性及其在抗病毒治疗中的意义.方法41例HBeAg阳性CHB患者,在干扰素α和拉米夫定联合治疗前进行肝穿刺,取肝组织分别进行HBV DNA检测及组织学检查,据肝组织HBVDNA载量小于等于或大于104fg/cm3将其分为两组,治疗前及治疗期间监测其肝功能、血清HBeAg及HBV DNA情况.结果(1)肝组织HBV DNA载量高于血清HBV DNA载量(对数值4.081±1.127与3.163±1.010,t=2.218,P＜0.05),二者高度相关(r=0.840,t=4.322,P＜0.001);肝组织HBV DNA载量与血清HBeAg亦呈正相关(r=0.459,t=3.056,P＜0.005).(2)肝组织HBV DNA载量与肝组织炎症活动度呈反向关系(x2=3.874,P＜0.05).(3)治疗期间两组患者血清HBV DNA水平均明显下降,治疗前肝组织HBV DNA水平低者效果较好;治疗1年时HBeAg、抗-HBe血清转化率以肝组织HBV DNA水平低者为高(HBeAg转阴率68.4%与36.4%,x2=4.194,P＜0.05;抗-HBe阳转率73.7%与40.9%,x2=4.447,P＜0.05).结论肝组织HBV DNA水平较血清HBV DNA、HBeAg水平更能准确反映肝组织HBV DNA复制情况,且能间接反映机体的免疫状态,可作为抗病毒治疗适应证选择及疗效预测因子.