Significance of hepatitis B genotype in acute exacerbation,HBeAg seroconversion,cirrhosis-related complications,and hepatocellular carcinoma

The pathologic role of hepatitis B virus (HBV) genotype in Chinese patients with HBV infection is largely unknown. We examined the relationship between HBV genotypes, and hepatitis B e antigen (HBeAg) seroconversion, acute exacerbation, cirrhosis-related complications, and precore/core promoter mutations. Three hundred forty-three HBV patients (288 were asymptomatic, 55 presented with cirrhosis-related complications) were recruited. HBV genotypes and precore/core promoter mutations were determined by line probe assays. Genotypes B and C were the 2 most common genotypes, contributing 28% and 60%, respectively. The median age of HBeAg seroconversion for patients with genotype B was 9 years earlier than patients with genotype C (P =.011). There were no differences in the liver biochemistry, HBV DNA level, and cumulative risk of acute exacerbation (defined as increased alanine aminotransferase level > or =1.5 x upper limit of normal) between patients with genotypes B and C. There was a trend for patients with genotype B to have a higher cumulative rate of HBeAg seroconversion compared with patients with genotype C at the initial follow-up of 6 years (P =.053), but this difference became insignificant during subsequent follow-up. The prevalence of both genotypes was the same in patients with and without cirrhosis-related complications and/or hepatocellular carcinoma. Genotype B was associated with precore mutations (P <.0001), whereas genotype C was associated with core promoter mutations (P <.0001). In conclusion, although patients with genotype B had earlier HBeAg seroconversion, there was no significant reduction in the risk of development of complications. Genotypes B and C are associated with high prevalence of precore and core promoter mutations, respectively.     

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.     

Clinical significance and evolution of core promoter and precore mutations in HBeAg-positive patients with HBV genotype B and C: a longitudinal study.

BACKGROUND/AIMS: The aims of this longitudinal study were to investigate whether the clinical outcome and evolution of core promoter and precore mutations were different during hepatitis B e antigen (HBeAg) seroconversion between hepatitis B virus (HBV) genotypes B and C in HBeAg-positive patients with chronic hepatitis B. PATIENTS AND METHODS: The core promoter and precore sequences were determined from serial sera of 156 HBeAg-positive patients with chronic HBV infection. RESULTS: In HBV genotype C, the T1762/A1764 mutant was detected earlier than the A1896 mutant, and the frequency was significantly higher than in HBV genotype Ba over the entire follow-up period. In HBV genotype Ba, A1896 was found earlier than the T1762/A1764 mutant, and the frequency was significantly higher than in genotype C only before HBeAg seroconversion, and the A1896 mutant played an important role in HBeAg seroconversion in HBV genotype Ba. In addition, the T1846 variant was an independent factor associated with HBeAg seroconversion. Furthermore, HBV genotype C was associated with the development of G or C1753 and T1766/A1768 mutations, and the reactivation of hepatitis after HBeAg seroconversion. Based on Cox's regression analysis, the significant risk factors of liver cirrhosis were older age at entry [hazard ratio (HR)=1.085, 95% confidence interval (CI)=1.036-1.136, P=0.001], alanine transaminase (ALT) >80 U/l (HR=3.48, 95% CI=1.37-8.86, P=0.009), and the T1762/A1764 mutant (HR=5.54, 95% CI=2.18-14.08, P<0.001). CONCLUSIONS: Our study showed that different HBV genotypes were associated with various mutations in the core promoter and precore regions during HBeAg seroconversion. T1762/A1764 mutation could be useful in predicting clinical outcomes in HBeAg-positive patients with HBV infection.     

Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion

Mutations in the core promoter and precore regions are frequently found in hepatitis B e antigen (HBeAg)-negative patients, but precore stop codon mutation is restricted to hepatitis B virus (HBV) genotypes that have T at nucleotide 1858. The aims of this study were to determine the role of core promoter and/or precore mutations in HBeAg seroconversion and their impact on the subsequent course of liver disease, and to determine if core promoter mutations are more frequently selected in patients with HBV genotypes that preclude the development of precore stop codon mutation. Serial sera from 45 patients with chronic HBV infection were polymerase chain reaction (PCR)-amplified, and the HBV core promoter and precore regions were sequenced. Ninety-two percent of patients had core promoter or precore mutations after HBeAg seroconversion: 42% had core promoter changes only, 38% had precore stop codon mutations only, and 12% had changes in both regions. Seventy-three percent of the patients had persistently normal aminotransferases, and only 8% had multiple flares in aminotransferases after HBeAg seroconversion. Core promoter changes were significantly more common in patients infected with HBV who have C at nucleotide 1858 (91% vs. 27%; P <.01), while precore stop codon changes were exclusively found in patients infected with HBV who have T at nucleotide 1858 (87% vs. 0; P <.01). The vast majority of our patients had core promoter and/or precore mutations after HBeAg seroconversion. Nevertheless, most patients had sustained remission of liver disease. Our data suggest that core promoter changes are preferentially selected in patients infected with HBV genotypes that preclude the development of precore stop codon mutation.     

Association of core promoter/precore mutations and viral load in e antigen-negative chronic hepatitis B patients

Apart from core promoter A1762T/G1764A and precore G1896A mutations, other hepatitis B virus (HBV) mutants are detected in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to determine the effects of those mutants on clinical manifestation and viral loads of genotypes B and C HBV. Seventy-nine HBeAg-negative CHB patients with hepatitis flare were enrolled in this study and their HBV precore/core region were sequenced. Serial biochemical profiles and viral loads were assessed and compared. Fifty-three patients (67%) were infected by genotype B HBV and 26 (33%) were infected by genotype C HBV. The clinical manifestation and HBV viral loads were comparable between the two groups. However, genotype B was significantly associated with precore G1896A mutation (92.5%), and more mutations within nucleotide 1809-1817 were detected in patients infected by genotype B as compared with those infected by genotype C (18.9%vs 3.8%). Most of the cases had mutations at the -2, -3 or -5 position from the precore AUG initiation codon. Triple core promoter mutations T1753C/A1762T/G1764A [corrected] appeared to be linked to genotype C rather than genotype B HBV (19.2%vs 1.9%; P = 0.013). In multivariate analysis, the presence of either triple core promoter 1753/1762/1764 mutation or nucleotide 1809-1817 mutation was the only factor associated with lower HBV viral load (<70 Meq/mL) (odds ratio = 9.01; 95% CI 1.11-71.43; P = 0.04). In conclusion, minor HBV variants with mutations in the core promoter and precore region were detectable in genotypes B and C. Such HBV variants are genotype specific and related to viraemia levels.     

乙型肝炎病毒前C区和BCP区突变及基因型对HBeAg表达的影响

研究乙型肝炎病毒前C区和BCP区突变及基因型对HBeAg表达的影响。分别用基因芯片和基因测序的方法检验HBV DNA阳性的乙型肝炎病毒前C区和BCP区突变及基因型,应用时间分辨免疫荧光法检测HBeAg含量,按照有无HBV前C区1896、BCP区1762、1764双突变、基因型等指标进行分组分析。无前C区1896和BCP区1762/1764双突变组、单纯1762、1764双突变和1896突变组以及1896、1762、1764联合突变组之间相互比较,HBeAg含量相差显著,F=6.47,P〈0.01;B、C基因型间HBeAg含量相比,相差无显著性,t=0.1394,P〉0.05。乙型肝炎病毒前C区和BCP区突变能显著影响HBeAg量的表达,从而导致乙型肝炎病毒致病能力的变化。     

HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C

Hepatitis B virus (HBV) genotype and precore/core promoter mutations have been implicated in spontaneous and interferon alfa (IFN-alpha)-related hepatitis B e antigen (HBeAg) seroconversion. We performed a retrospective analysis of a previously reported randomized controlled trial to determine the effects of HBV genotype and precore/core promoter mutations on IFN-alpha response in patients with HBeAg-positive chronic hepatitis. Clinical data and stored sera from 109 (95%) patients in the original trial were analyzed. Seventy-three patients received IFN-alpha and 34 received no treatment (controls). Almost all patients had HBV genotypes B (38%) and C (60%). Antiviral response was achieved in 39% and 17% of IFN-alpha-treated patients (P =.03) and in 10% and 8% of untreated controls (P =.88) with HBV genotype B and C, respectively. Multivariate analysis identified HBV genotype B, elevated pretreatment alanine aminotransferase (ALT) levels, and low pretreatment HBV-DNA levels but not IFN-alpha treatment as independent factors associated with antiviral response. Among the 66 patients with elevated pretreatment ALT level, antiviral response was achieved in 57% and 21% of IFN-alpha-treated patients (P =.019), and in 25% and 8% of untreated controls (P =.45) with HBV genotype B and C, respectively. Multivariate analysis showed that genotype B and low pretreatment HBV-DNA levels were independent predictors of antiviral response. In conclusion, our data showed that HBV genotype B was associated with a higher rate of IFN-induced HBeAg clearance compared with genotype C. Stratification for HBV genotypes should be considered in future clinical trials of antiviral therapy of chronic hepatitis B.     

Hepatitis B virus precore mutations and HBeAg negative reactivation of chronic hepatitis B after interferon therapy

The objective of this study was to look for HBV precore mutations in three patients with chronic active hepatitis B who developed HBV-DNA-positive/HBeAg-negative reactivation after HBe seroconversion induced by interferon therapy. Direct sequencing of polymerase chain reaction products was performed on serum collected before and after HBe seroconversion. In two patients precore sequence showed only wild-type HBV before and after interferon therapy. In one patient, precore sequence showed only wild-type HBV before interferon therapy and a mixed infection by wild-type HBV and precore mutant viruses (1858 and 1896 nucleotide mutations) after treatment. The presence of HBeAg/anti-HBe immune complexes was found after HBe seroconversion in all cases. Our results suggest that: 1) precore mutations are not always found in patients with chronic hepatitis B who develop HBV DNA-positive/HBeAg-negative reactivation; and 2) HBeAg negativity, despite the presence of wild-type HBV, might be due to HBeAg/anti-HBe immune complexes. We speculate that the production of these immune complexes may be favored by interferon therapy.     

Cellular immune responses in hepatitis B virus e antigen negative chronic hepatitis B

The immunopathogenesis of hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) virus (HBV) infection has not been adequately investigated. We studied the cellular immune responses of peripheral lymphocytes using proliferating assays, intracellular cytokine staining (ICS) and ELISPOT interferon-gamma (IFN-gamma) assays after non-specific and specific stimulation with whole HBV proteins and synthetic peptides. Thirty patients with HBeAg negative CHB, eleven HBsAg inactive carriers, nine patients with acute hepatitis B and 22 healthy controls were included in the study. Patients with HBeAg negative CHB demonstrated an increased number of peripheral CD8+ T cells while their peripheral blood mononuclear cells showed increased proliferation after in vitro stimulation with overlapping hepatitis B core derived peptides and an envelope derived epitope (HBs 182-191 aa), similar to those observed in acute hepatitis B. Using ICS, we found an expanded population of IFN-gamma producing T lymphocytes, CD4+ and CD8+, after non-specific stimulation, in HBeAg negative CHB compared to all other groups. HBeAg negative CHB and acute hepatitis B patients had a similarly increased number of core specific T cells measured by the IFN-gamma assays. Inactive HBsAg carriers showed minimal proliferative responses overall while they exhibited an increased number of envelope specific effector T cells (measured by ICS). In conclusion, we showed that overall CD4+ T cell responses from patients with HBeAg negative CHB were comparable to those of acute hepatitis B, while inactive HBsAg carriers despite their limited proliferative capacity the effector activity of their peripheral T cells was maintained.     

Epidemiological study of hepatitis B virus genotypes, core promoter and precore mutations of chronic hepatitis B infection in Hong Kong

BACKGROUND/AIMS: We conducted a population study to document the prevalence of hepatitis B virus (HBV) genotypes in Hong Kong. METHODS: HBV genotypes, core promoter (CP) and precore mutations were determined in 776 asymptomatic patients. RESULTS: 92.6% patients had single genotype [B (32.5%), C (62.5%)]. 99.1% of genotype B was subtype Ba. Patients with age <50 years had a lower prevalence of genotype B than patients with age >51 years (32.5% vs. 41%, respectively, P=0.028). Compared to patients with genotype C, patients with genotype B had a higher cumulative rate (P=0.018) and younger age (40.1 vs. 34.2 years, respectively, P=0.018) of HBeAg seroconversion. There were no differences in the HBV DNA levels between patients with genotypes B and C, and with wild-type and mutants of CP and precore regions. By multivariate analysis, patients with genotype C and with CP mutations had higher alanine aminotransferase (ALT) levels. CONCLUSIONS: B and C were the two most common HBV genotypes in Hong Kong. The former had a higher chance of earlier HBeAg seroconversion and lower ALT levels. The prevalence of genotype B was lower in patients with age <50, probably related to influx of immigrants from China since 1949.     

Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B

Background. Mutations in the precore stop codon (G1896A) and the basal core promoter (A1762T and G1764A) are frequently found in hepatitis B envelope antigen (HBeAg)-negative chronic hepatitis B. However, the clinical significance of these mutations remains controversial. We therefore investigated the influence of hepatitis B virus (HBV) genotypes, as well as precore/basal core promoter mutants, on the clinical and virological features of patients with HBeAg-negative chronic hepatitis B. Methods. Serum samples from 37 patients with HBeAg-negative chronic hepatitis B were collected for serological and molecular assays. The precore and basal core promoter regions were amplified by polymerase chain reaction and the amplicons were directly sequenced and analyzed. HBV geno-type was determined by polymerase chain reaction-restriction fragment length polymorphism. Results. Most of the patients had detectable serum HBV DNA, and genotypes B and C were the predominant strains. The overall prevalence of the precore stop codon mutant and basal core promoter mutant was 67% and 60%, respectively. The baseline clinical and virological features of patients with genotype B and genotype C infection were comparable. However, in the patients with precore/basal core promoter dual mutations there was a significantly lower proportion of individuals with a high detectable serum HBV DNA level (>100 pg/ml) than in the patients with either the precore stop codon mutation alone or the basal core promoter mutation alone (P = 0.04 by the logistic regression test for the trend). Conclusions. Our data suggest a high prevalence of precore stop codon and basal core promoter mutation in Taiwanese patients with HBeAg-negative chronic hepatitis B, and the influence of the basal core promoter mutation on HBV replication is modulated by the emergence of the precore stop codon mutation. Received: May 14, 2001 / Accepted: September 14, 2001     

HBeAg negative variants and their role in the natural history of chronic hepatitis B virus infection

Molecular virology methods including polymerase chain reaction,cloning and sequencing have revolutionised our understanding of viral genome variation.In the case of hepatitis B virus(HBV),sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection.The appearance of the precore stop codon(with G-for-A substitution at position 1896)and basal core promoter(BCP)(with A-for-T and G-for-A,at positions 1762 and 1764,respectively)variants which reduce or abrogate hepatitis B e antigen(HBeAg)production,heralds the initiation of the seroconversion phase from HBeAg to antiHBe positivity.The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response(immune clearance phase).Most patients after HBeAg seroconversion become"inactive HBsAg carriers".However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B(CHB)with high viremia levels(reactivation phase).The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world.This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections.Frequent acute exacerbations accompanied by high viral replication,elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.     

JGH Foundation emerging leadership lecture. Significance of hepatitis B virus genotypes and mutations in the development of hepatocellular carcinoma in Asia

Advances in molecular biology technology in the last two decades have allowed detailed study of the viral mutations and genomic heterogeneity of hepatitis B virus (HBV). The first mutant discovered was precore stop codon mutation. It was reported in HBeAg-negative patients and initially thought to associate with fulminant hepatitis. Subsequent studies have suggested that it is merely one of the mechanisms of losing HBeAg by the virus. Another mutation that can downregulate the production of HBeAg is the basal core promoter mutation, which is located in the X gene upstream of the precore region. Based on the configuration of codon 15 and the stability of the epsilon of the precore region, these two mutants will be differentially selected during the course of HBeAg seroconversion. The most common HBV genotypes in South-East Asia are genotype B and C HBV. The higher hepatocellular carcinoma (HCC) risk of genotype C HBV has been confirmed by longitudinal studies in Hong Kong and Taiwan. One possible carcinogenic mechanism is its association with basal core promoter mutation, which has also been found to be a risk factor of HCC. Within genotype C HBV, subgenotype Cs is predominant in South-East Asia and subgenotype Ce is predominant in East Asia. Subgenotype Ce HBV has been found to have the highest risk of HCC as compared with subgenotype Cs or genotype B HBV. The understanding of the carcinogenic mechanisms of these HBV strains may shed light into future therapeutics in the prevention and treatment of HBV-related HCC.     

A 13-year longitudinal study of the impact of double mutations in the core promoter region of hepatitis B virus on HBeAg seroconversion and disease progression in patients with genotype C chronic active hepatitis

The pathogenic role of core promoter (CP) mutations (T1762/A1764) of hepatitis B virus (HBV) in hepatitis B e antigen (HBeAg) seroconversion or disease progression remains unclear. We investigated the clinical relevance of these mutants over a long-term follow-up period of up to 15 years. In this longitudinal cohort study, 29 HBeAg-positive patients with biopsy-proved chronic active hepatitis without cirrhosis were regularly monitored for >10 years. The viral isolates were characterized, using the frozen liver tissue obtained on the day of biopsy. Long-term outcomes were compared between patients with and without CP mutations of HBV at baseline. HBV genotyping showed that 100% of study subjects were infected with genotype C HBV. During a median follow-up period of 12.5 years, patients without double CP mutations of HBV at baseline showed a tendency towards achieving an earlier HBeAg seroconversion than those with (6.9 vs 9.4 years, P = 0.062) double CP mutations. Double CP mutations at baseline were also significantly associated with the eventual development of cirrhosis or hepatocellular carcinoma (P = 0.013), whereas the absence of double CP mutations predicted inactive carrier status at the last follow-up (P = 0.027). At 10 years, liver-related tests were also significantly better in patients without double CP mutations of HBV than in those with these mutations, as reflected by higher platelet counts and albumin levels (P = 0.036 and P = 0.044, respectively). Double T1762/A1764 mutations are significantly related to liver deterioration in HBeAg-positive genotype C active hepatitis patients. A longer period of immune clearance coupled with delayed HBeAg seroconversion appears to contribute to disease progression in patients harbouring these mutations in the CP region of HBV.     

乙型肝炎病毒基因型对乙型肝炎病毒变异的影响

目的探讨乙型肝炎病毒(HBV)基因型对病毒前核心区(前C区,nt1896)及基本核心启动子(BCP,nt1762/1764)变异的影响.方法416例血清HBsAg阳性、HBV DNA定量大于1.0×104拷贝/ml的患者,采用微流基因芯片检测HBV基因型、前C区及BCP变异.结果416例HBV感染者中406例有基因分型结果:B型20.9%、C型65.9%、BC混合型10.8%,10例患者未分出基因型.302例为HBeAg(-)且HBV DNA( )患者,其中248例(82.12%)有前C区或BCP变异,41.06%为前C区变异,31.12?P变异,2种同时变异为9.94%.B型患者前C区变异率为22.9%(20/87),与C型患者前C区变异率39.4%(108/274)及B、C混合型变异率40.0%相比均有显著差异(P＜0.01).在BCP变异及双变异,C型患者变异率均大于B型患者,但差异无统计学意义(P＞0.05).B、C混合型患者前C区及BCP变异率与C型相似.结论HBV基因型可影响病毒前C区及BCP变异,以C型为著.     

Geographic distribution, virologic and clinical characteristics of hepatitis B virus genotypes in China

The significance of hepatitis B virus (HBV) genotypes for the heterogeneity of chronic HBV infection and severity of liver disease is not well understood. The aim of this study was to determine the distribution and virologic characteristics of HBV genotypes in China and possible association with the diversity of liver disease. The study includes 1096 chronic HBV carriers from nine provinces in China. We collected clinical and laboratory data and analysed the HBV strains in sera by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and nucleotide sequencing techniques. The most common HBV genotypes were B (41%) and C (53%), while genotypes A and D were also found. A North-South divide was identified in genotype B and C distribution - genotype C was predominant in northern China, while genotype B was more prevalent in southern provinces. Patients with genotype B were younger than those with genotype C, and had a lower prevalence of HBeAg - 65%vs 72%, respectively (P = 0.03). However, the severity of liver disease did not differ significantly between patients infected with genotype B or C - neither when comparing liver function tests (1024 patients), nor hepatic inflammation and fibrosis (264 patients). Amongst 47 patients with genotype D (by PCR-RFLP), 37 (79%) were infected with a new subtype (designated Dc), having a recombination fragment from genotype C precore/core region. This is the first large-scale HBV genotype study from China and convincing documentation of the North-to-South gradient of genotypes C vs B in this country. HBV DNA recombination over the surface and precore/core genes increases the diversity of HBV strains and may have diagnostic and clinical implications.     

Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion

In high endemic areas of hepatitis B virus (HBV) infection, the vast majority of infection is acquired perinatally or during early childhood. The age of the patient is, therefore, almost equivalent to the duration of HBV infection. The natural history of chronic HBV infection consists of three chronological phases: immune tolerance, immune clearance and low replicative phases. The prevalence of hepatitis B e antigen (HBeAg) in asymptomatic HBV carriers is around 90% before 15 years of age, and decreases remarkably to less than 10% after 40 years of age. The immune clearance phase is characterized by a series of hepatitis flares and remissions. These will be followed eventually by HBeAg seroconversion, which is usually accompanied by remission of liver disease and confers favourable outcome. However, patients with persistent HBeAg seropositivity over 40 years of age are associated with a significantly higher risk for progression to cirrhosis than those with HBeAg seroconversion before 40 years of age, and thus should be considered as patients with 'delayed' HBeAg seroconversion. Antiviral or immunomodulatory therapy should be considered seriously for these patients.     

Relationship of clinical and virological factors with hepatitis activity in hepatitis B e antigen-negative chronic hepatitis B virus-infected patients

To investigate the factors associated with active disease among hepatitis B surface antigen (HBsAg) positive/hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection we studied chronic HBV infected patients who had undetectable HBeAg at the first visit. HBV DNA was determined by the cross-linking assay (NAXCOR) and polymerase chain reaction (PCR). Mutations in the core promoter and precore regions and viral genotypes were studied. Clinical outcome of these patients were followed and categorized as: (i) relapse (ALT > 200 IU/L or three times the previous levels); (ii) active hepatitis (elevated ALT < 200 IU/L with concomitant detectable HBV DNA); or (iii) remission. A total of eighty-five patients were followed up for 5.5 ± 1.0 years. At first visit, 31 (36.5%) patients had elevated ALT levels, 12 (14.1%) had measurable HBV DNA by the cross-linking assay and 26 (30.6%) by PCR. Sixteen (18.8%) patients had hepatitis relapse, 13 (15.3%) had active hepatitis, and 56 (65.9%) remained in remission. Core promoter and precore stop codon mutants were found in 27 and 12 patients, respectively. Eleven and 20 had genotype B and C HBV, respectively. Initial elevated ALT and detectable HBV DNA were associated with active liver disease. Patient demographics, viral mutants or genotypes failed to predict disease activity. Hence, serum ALT and HBV DNA levels offer the best prediction of natural course of HBeAg-negative chronic HBV infection.     

Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance

The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB.     

Hepatitis B virus core and core-related antigen quantitation in Chinese patients with chronic genotype B and C hepatitis B virus infection

BACKGROUND AND AIMS: Hepatitis B virus (HBV) core-related antigen (HBcrAg) and HBV core antigen (HBcAg) assays were developed for the measurement of serum HBV load. The aim of this study was to assess the clinical utility of these assays in Chinese patients with chronic genotype B and C HBV infection. METHODS: One hundred and ninety-three chronic hepatitis B patients were enrolled. Serum HBcrAg and HBcAg were measured by chemiluminescence enzyme immunoassay, and HBV-DNA was measured by using a sensitive polymerase chain reaction assay. The data were analyzed in patients with HBV genotype B (HBV/B) and genotype C (HBV/C). The HBcrAg/HBcAg ratio was calculated and compared between patients with and without hepatitis B e antigen (HBeAg). RESULTS: The concentrations of HBcrAg and HBcAg showed significant positive correlation with the HBV-DNA concentration in both HBV/B (r = 0.79, P < 0.001, and r = 0.77, P < 0.001, respectively) and HBV/C (r = 0.87, P < 0.001, and r = 0.90, P < 0.001, respectively). The cut-off for a positive HBcAg corresponded to approximately 4.5 log copies/mL, and that for a positive HBcrAg result corresponded to 3-4 log copies/mL. The HBcrAg/HBcAg ratio was higher in patients with HBeAg than in those without HBeAg. CONCLUSIONS: The HBcrAg assay and HBcAg assay are clinically useful in viral quantitation of HBV/B and HBV/C. A combination of these assays would be a valuable tool for analyzing the clinical status of HBV infection.