Basal Core Promoter Research Articles

Hepatitis B Virus Core Promoter Mutations in Patients With Chronic Hepatitis B and Hepatocellular Carcinoma in Bucharest, Romania

Background:Accurate and personalized molecular virological diagnosis of hepatitis B virus (HBV) infection is crucial for individualized selection of patients for antiviral therapy in Romania.Objectives:We aimed to investigate HBV mutations in Romanian patients with chronic HBV infection, also to match HBV genotypes with HBV mutations identified and clinical outcomes.Patients and Methods:This was a cross-sectional study. A total of 484 Romanian patients with chronic HBV infection and hepatocellular carcinoma (HCC) were investigated. This was performed in Fundeni Clinical Institute, Bucharest, Romania during January 2005 to August 2010. HBsAg positive patients with chronic HBV infection admitted to Fundeni Clinical Institute were randomly enrolled in the study. Analysis was performed in the Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania. Indirect diagnosis was performed with enhanced chemiluminescence method using Architect i2000SR and HBV-DNA was quantified with COBAS TaqMan HBV PCR. Direct sequencing of the PCR-products was performed with the PCR-product sequencing kit. HBV genotyping was performed with INNO-LiPA DR Amplification and INNO-LiPA HBV precore-core.Results:We detected two HBV genotypes; A (8.1%) and D (60.5%), and a mixture of genotypes A and D (31.4%) (P < 0.001). Basal core promoter (BCP) A1762T/G1764A and precore (PC) G1896A mutations were detected in these Romanian patients with chronic HBV infection. HBV chronic carriers had mainly genotype D (54.4%) and HBV WT (64.0%). BCP A1762T, G1764A and PC G1896A were significantly associated with HCC-tissue HBV sequencing (75.3%) (P < 0.001). PC G1896A alone was detected in HCC-serum HBV sequencing group (66.7%).Conclusions:Genotype D was the main genotype detected in Romanian patients with chronic HBV infection. Genotype D presented both BCP and PC mutations more frequently.

Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: characterization and impact on liver disease progression to hepatocellular carcinoma.

BackgroundThe contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naïve Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC.MethodsThe mutation profile was determined from the sequence analysis of the full-length HBV genome and compared with the reference HBV sequences. SPSS 16.0 and R software were used to delineate their statistical significance in predicting HCC occurrence.ResultsAge was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p≤0.01). Beyond the classical mutations in basal core promoter (BCP) (A1762T/G1764A) and precore (G1862T), persistence of progressively accumulated mutations in enhancer-I, surface, HBx and core were showed significant association to liver disease progression. BCP_T1753C, core_T147C, surface_L213I had contributed significantly in the disease progression to HCC (p<0.05) in HBeAg positive patients whereas precore_T1858C, core_I116L, core_P130Q and preS1_S98T in HBeAg negative patients. Furthermore, the effect of individual mutation was magnified by the combination with A1762T/G1764A in HCC pathogenesis. Multivariate risk analysis had confirmed that core_P130Q [OR 20.71, 95% CI (1.64–261.77), p = 0.019] in B cell epitope and core_T147C [OR 14.58, 95% CI (1.17–181.76), p = 0.037] in CTL epitope were two independent predictors of HCC in HBeAg positive and negative patients respectively.ConclusionsThus distinct pattern of mutations distributed across the entire HBV genome may be useful in predicting HCC in high-risk CHB patients and pattern of mutational combinations may exert greater impact on HCC risk prediction more accurately than point mutations and hence these predictors may support the existing surveillance strategies in proper management of the patients.

Occult hepatitis B virus infection with positive hepatitis B e antigen

BackgroundHepatitis B e antigen (HBeAg) is a marker to indicate active replication of hepatitis B virus (HBV). Occult HBV infection (OBI), referred to persistence of HBV DNA in serum and/or liver without detectable serum hepatitis B surface (HBsAg), usually has low HBV DNA levels. The presence of HBeAg in OBI is unusual. MethodsWe report 2 patients who presented negative for HBsAg but positive for HBeAg and HBV DNA. HBV markers were quantified in the longitudinal sera in a period of 1–2years. The HBV DNA sequences were analyzed in 2 patients' sera and 1 patient's liver. ResultsBoth patients were also positive for total anti-HBs and anti-HBc but negative for anti-HBe and anti-HBc IgM. HBV DNA levels were 234–567IU/ml in case 1 and 42–1130IU/ml in case 2. The alignment analysis of the S gene showed that HBV in both patients was genotype C, serotype adr. Cloning analysis of the a determinant of HBsAg showed that the immune escape mutants were predominant in both patients over the follow-up period. The HBV had double mutations (A1762T and G1764A) in the basal core promoter but had no mutation in the pre C/C gene in both patients. ConclusionsThe patients with negative HBsAg but positive HBeAg may represent a unique type of OBI. Test for HBeAg would be critical to identifying such type of OBI.

Correlation between the promoter basal core and precore mutations and HBsAg quantification in French blood donors infected with hepatitis B virus.

Hepatitis B virus (HBV) basal core promoter (BCP) and precore (PC) mutations, HBV viral load and HBV surface antigen (HBsAg) quantitation were screened to assess correlations between these HBV markers in asymptomatic chronic hepatitis B carriers in France. From January 2006 to July 2007, 200 sera were collected from patients who were discovered to be HBsAg-positive when they volunteered to give blood. Direct sequencing of precore/core gene was used to detect A1762T/G1764A mutations in the BCP and G1896A in the PC region. HBV viral load and HBsAg were quantified with two commercials assays. The prevalence of the BCP and PC mixed/mutants were 37% and 60% respectively (P = 0.0001). HBV DNA level and HBsAg titer were significantly lower in subjects harboring the mixed/mutant PC virus compared to those infected by the wild phenotype. No significant difference was observed in HBV viral loads of blood donors infected by wild or mixed/mutant BCP viruses. Mutant or mixed PC virus was associated with male gender, HBeAb-positive status and HBV/D and HBV/E genotypes. BCP mutations were associated with age, and both HBV/A-HBV/E genotypes.The genetic properties of HBV in this cohort showed that most of the blood donors had a negative HBeAg serological status and harbored the PC mutant phenotype in combination with low levels of both HBV DNA and HBsAg. As the study was conducted in healthy subjects who could be considered as asmptomatic carriers, these results suggest a possible protective effect of the G1896A mutation against severe liver lesions.

Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure: a multicenter cross-sectional study in China.

In China, acute-on-chronic liver failure (ACLF) is mostly caused by hepatitis B virus (HBV). However, the mechanism remains unclear. This study aims to investigate the association between both HBV genotype and mutations in basal core promoter (BCP) and pre-core/core (pre-C/C) regions with the development of HB-ACLF. A multicenter cross-sectional study was performed in China. Serum samples from 522 patients were analyzed, including 231 patients with mild-chronic hepatitis B (CHB-M), 84 with severe-chronic hepatitis B (CHB-S) and 207 with HB-ACLF. HBV genotype and related mutations in the BCP and pre-C/C regions were determined by direct sequencing. A significantly higher ratio of HBV genotype B to C was detected in HB-ACLF patients than in CHB-M or CHB-S patients. The A1762T/G1764A, A1846T and G1896A mutations were significantly more common in HB-ACLF patients infected with either genotype B or C as compared with CHB-M, whereas the C1913A/G and A2159G mutations were more associated with HB-ACLF in genotype C patients. Comparing with CHB-S, the A1762T/G1764A mutation in genotype B and the A2159G mutation in genotype C were significantly more common in HB-ACLF patients. A multivariate analysis showed that factors such as HBV genotype B, age ≥40years and A1762T/G1764A, A1846T and G1896A mutations were independently associated with the development of HB-ACLF. Chronic HBV infection with genotype B, A1762T/G1764A, A1846T and G1896A mutations has a higher possibility to develop HB-ACLF. These virological factors could serve as possible molecular markers for prediction of the clinical outcomes of chronic HBV infection.

Genetic characterization and genotyping of hepatitis B virus (HBV) isolates from donors with an occult HBV infection.

Screening of Thai blood donors has resulted in the detection of donors with an occult HBV infection (OBI), where HBsAg is undetectable, but hepatitis B virus (HBV) DNA is present in serum in low concentrations. This study was designed to determine whether the occurrence of OBI in donors was linked to the HBV genotype and possibly to mutations in the surface (S) and core (C) gene regions. Mutations in the S and C gene regions in 48 Thai donors with OBI were mapped by sequencing. Genotyping was determined with the INNO-LiPA test and by phylogenetic analysis of sequences from the S and C genes. The majority of OBI samples were genotype C (81·3%) with 6·3% of samples being genotype B. In addition, two genotype I isolates were identified. Mutations in the S region (100%) were found especially in loop 1 of the major hydrophilic loop (MHL) at positions I110L, T114S, T126I and S113T, whereas mutations in the C region (65%) were within the basal core promoter region (position A1762T/G1764A) and precore region (position G1896A). The majority of OBI samples were HBV genotype C, although genotype I, which is newly emerging in Thailand, was also detected. The study demonstrated that OBI was probably not associated with a particular HBV genotype or with certain mutations in the S and C gene regions. However, mutations in the C gene region which could potentially impair viral replication and HBsAg production and potentially lead to OBI were identified.

Correlation of Primary Hepatocellular Carcinoma with HBV Genotypes, Subgenotypes and Gene Mutations in Gansu Province

Abstract Objective To investigate the occurrence of basal core promoter (BCP) and pre-C mutations in patients with hepatitis B virus (HBV) infection in Gansu Province, China, and to analyze the correlation of HBV mutation and HBV genotype with primary hepatocellular carcinoma (HCC). Methods PCR-RFLP was applied to detect HBV subgenotypes, and the presence of the pre-C and BCP mutations in 62 patients with HCC, 70 patients with hepatitis B induced liver cirrhosis (LC) and 90 patients with chronic hepatitis B (CHB). Results In HCC patients, genotype C was the major genotype (70.97%). The pre-C mutation was found in 59.68%, 31.43% and 16.67% patients with HCC, LC and CHB, respectively. The frequency of BCP mutations was significantly different between patients with HCC, LC and CHB (74.19%, 51.43% and 37.78%, respectively; X2=30.727, 19.540, respectively, P &lt; 0.01). Patients in HCC group had a higher incidence of pre-C as well as BCP mutations compared to the other groups. The prevalence of pre-C and BCP mutations was significantly higher in patients with genotype C1 (44.32% and 69.32%, respectively) compared to patients with other subgenotypes (P &lt; 0.05). Conclusions The incidence of pre-C and BCP mutations increases with disease progression. Pre-C and BCP mutations frequently occur in patients with genotype C1. HBV genotype C, pre-C mutations and BCP mutations are closely related to the occurrence of HCC.

Molecular epidemiological study of hepatitis B virus genotypes in Southwest, China.

Hepatitis B virus (HBV) is highly endemic in Southwest China; an area with many ethnic minorities. Information about the genetic distribution of HBV is still limited. In 2010, a multistage cluster sampling method was carried out in the Southwest China. Five hundred forty serum samples of participants were collected. Polymerase chain reaction followed by nucleotide sequencing of parts of the HBV S and C genes was performed. HBV genotype and subgenotype were determined. Recombination analysis was carried out. HBV infectious markers, HBV DNA and mutations in the basic core promoter (BCP) A1762T/G1764A and G1896A were analyzed. The results show us that HBV genotypes C/D recombinant (38.6%), B (31.6%), and C (23.3%), were predominant in Southwest China. C/D4 (96.8%) was endemic in the Tibetan and B2 (43.5%) in Han, and C1 (66.7%) was predominant in the Yi minority. 67.5% (56/83) of genotype C/D was Hepatitis B surface antigen (HBsAg) positive/Hepatitis B e antigen (HBeAg) positive/HBV DNA≥20,000 IU/ml, BCP A1762T/G1764A double mutation was frequent in genotype C and C/D, and G1896A was frequent in B and B/C. Thus, HBV genotypes distribution differed significantly in area and minority in Southwest China. C/D recombinant is endemic in the Tibetan, while B, C genotypes are predominant in Han minority. C/D recombinant exhibits higher frequency with HBeAg positive, high level of HBV DNA and BCP A1762T/G1764A double mutation.

Mutations in pre-core and basal-core promoter regions of hepatitis B virus in chronic HBV patients from Golestan, Iran.

It has been reported that the mutation of the pre-core (PC) and basal-core promoter (BCP) may play an important role in the development of HBV-related hepatocellular carcinoma (HCC). In this study the PC and BCP mutations were investigated in chronic HBV patients. In this study, 120 chronic HBV patients from Golestan, Northeast of Iran who were not vaccinated against HBV, were recruited from the year 2008 to 2012. HBV-DNA extraction from plasma and PCR were performed and positive PCR products were subjected to automated sequencing. One hundred out of 120 (83.3%) patients were HBeAg negative. Comparison of our nucleotide sequences with reference sequence showed high rate mutation in BCP and PC region (96.66%). Frame shift mutation was found in 78 (65%) of patients in BCP region, among them 8 (6.6%) patients showed mutation in PC region. Our results demonstrated high rate of mutations in BCP and PC regions among HBV chronic patients in Northeast of Iran.

Su1004 Drug Resistance, Basal Core Promoter and Pre-Core Stop Mutations in a Large Cohort of North American Children With Hepatitis B: Results for the Pediatric Cohort Study of the NIDDK-Sponsored Hepatitis B Research Network (HBRN)

Su1004 Drug Resistance, Basal Core Promoter and Pre-Core Stop Mutations in a Large Cohort of North American Children With Hepatitis B: Results for the Pediatric Cohort Study of the NIDDK-Sponsored Hepatitis B Research Network (HBRN)

Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers

Background and objectivePrecore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about...

The Role of the Basal Core Promoter (BCP) and Precore Codon 28 Mutations in the Treatment Response to the Pegylated Interferon

Ad dress for Cor res pon den ce: Gulsun Cavdar MD, Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey Gsm: +90 506 503 56 19 E-mail: gakincioglu@hotmail.com Re cei ved: 05.12.2013 Ac cep ted: 20.12.2013 Viral Hepatitis Journal, pub lis hed by Ga le nos Pub lis hing. Sukran Kose, suheyla serin senGer, Gulsun cAVDAr, Pelin ADAr Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey Research Article

Hepatitis B Virus Precore and Basal Core Promoter Mutations in Different Groups of Hepatitis B

Background: Hepatitis B virus (HBV) is one of the most common DNA viruses that can cause aggressive hepatitis, cirrhosis and hepatocellular carcinoma. Since the basal core promoter (BCP) and the precore (PC) regions are important for viral replication, these regions were examined for naturally occurring mutations and were correlated with the genotype, e antigen status, and severity of liver disease. The appearance of PC/ core gene and BCP variants heralds the initiation of the seroconversion phase from hepatitis B e antigen (HBeAg) to anti-HBe, leading to a vigorous immune response.

Genetic Variability of the Basal Core Promoter/Precore Region of the HBV Strains Circulating among the Treatment-Naive HIV/HBV Co-Infected Patients of Eastern India

Background & Objective: Co-infection with hepatitis B virus (HBV) is frequent among the human immunodeficiency virus (HIV) infected individuals due to their similar transmission routes with the risk of developing end-stage liver disease being higher among this cohort. Since HBV replicates via error prone reverse transcriptase phenomenon, different mutations occur in the HBV genome. Of which, mutations within the basal core promoter [BCP] (A1762T/G1764A) and the precore region (G1896A) had been previously reported to be associated with advanced liver diseases in HBV mono-infection.

The Effect of HBV Genotype C on the Development of HCC Differs Between Wild-Type Viruses and Those With BCP Double Mutations (T1762A1764)

Background:Association of hepatitis B virus (HBV) genotype C with hepatocellular carcinoma (HCC) development remains controversial. HBV basal core promoter (BCP) double mutations (T1762A1764) are very strong confounding factors of genotypes B and C in HCC development.Objectives:To investigate the association of HBV genotype C with HCC development after controlling for BCP double mutations.Materials and methods:Four hundred and two serum samples from patients with HCC, liver cirrhosis (LC) and chronic hepatitis (CH) and also from asymptomatic HBsAg carriers were analyzed.Results:Genotypes B (31.1%), C (62.8%), and I (6.1%) were detected. With the severity of liver disease the prevalence of genotype B decreased, but genotype C increased. No trend was found for genotype I. The prevalence of BCP double mutations in genotypes C and I viruses was significantly higher than genotype B. BCP double mutations are risk factors for CH, LC and HCC. Genotype C was not identified as a particular risk factor for HCC prior to the stratification analysis but after that genotype C viruses with BCP double mutations were found to be a particular risk factor for HCC (P = 0.008, OR = 17.19 [95% CI: 2.10 - 140.41]), but those with the wild-type BCP were not. In the interaction analysis, genotype C and BCP double mutations were found to have a synergistic effect on HCC development (P < 0.0001, OR = 52.56 [95% CI: 11.49-240.52]).Conclusions:The effect of HBV genotype C on the development of HCC differs between wild-type viruses and those with BCP double mutations, suggesting that not all individuals infected with genotype C HBV are at increased risk of HCC.

Clinical Presentation and Disease Phases of Chronic Hepatitis B Using Conventional Versus Modified ALT Criteria in Asian Americans

The modified normal alanine aminotransferase (ALT) value (i.e., males <30 and females <19 IU/L) is a better criteria associated with histological activity in chronic hepatitis B (CHB). This study was aimed to assess if the modified ALT criteria could be better associated with disease phases in a cohort of Asian Americans (AsAm) with CHB. This two-center retrospective study evaluated 198 non-treated AsAm with CHB and a mean follow-up of 21 months. Both conventional and modified ALT criteria were used to determine the differences and clinical value using modified ALT criteria in classifying CHB phases. Among HBeAg (+) patients (29.3 %), HBV pre-core (PC) and basal core promoter (BCP) mutations were detected in 24.4 % and 31.3 %, respectively. Using baseline conventional ALT criteria, 97/153 (63.4 %) patients could be categorized into CHB phases 1 to 4, whereas 56/153 (36.6 %) were indeterminate. Using the modified ALT criteria, 43 (28.1 %) patients had phase changes of which 31/43 (72.1 %) were moved from phase 1 and indeterminate to phases 2 and 4, more active CHB phases. In 13/31 of these patients with liver biopsy, 6 (19.4 %) reported stage 2-4 fibrosis and 10 (32.3 %) reported grade 1-2 inflammation. Using modified ALT criteria to evaluate 48/153 patients with full data at baseline and the end of 1-year follow-up, we observed that 19/48 (39.6 %) changed their CHB phases; 5/48 (10.4 %) moved from phases 1 and 3 to phases 2 and 4; 2/48 (4.2 %) remained in the active phases; 10/48 (20.8 %) became indeterminate. HBV PC and BCP mutations were detectable in 24.4 % and 31.3 % of HBeAg (+) AsAm patients, respectively. Compared with conventional ALT criteria, modified ALT criteria is more sensitive in identifying CHB patients in active phases.

Effect of combined mutations in the enhancer II and basal core promoter of hepatitis B virus on development of hepatocellular carcinoma in Qidong, China

To investigate the roles of mutations in enhancer II (Enh II), basal core promoter (BCP) and precore (PC) regions of hepatitis B virus (HBV) in the progression of hepatocellular carcinoma (HCC) in Qidong, China. We conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited between August and September 1996. The HBV DNA sequence was determined in 152 HCC and 131 chronic hepatitis patients. Mutation exchanges during follow up in 115 cases were compared with 108 controls with serum samples taken during a similar length of follow up. In addition, a longitudinal study was conducted in 22 cases in which serial serum samples were available before HCC. After adjustment for age, history of cigarette smoking and alcohol consumption, hepatitis B e-antigen positivity, T1653, V1753 and T1762/A1764 double mutations were associated with risk of HCC. Multivariate analysis showed that T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. Moreover, a significant biological gradient of HCC risk by number of mutations in Enh II/BCP regions was observed. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of mutations in Enh II/BCP regions accumulated during the development of HCC. T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. The effect of combined mutations in Enh II/BCP regions increased the risk and persistence of at-risk sequence mutations and was critical for HCC development.

Prevalence of Mutations in Basal Core Promoter and Precore Region of Hepatitis B Virus in Vaccinated and Nonvaccinated Individuals of the Aboriginal Nicobarese Tribe of Car Nicobar Island, India

The aim of this study was to explore the prevalence of basal core promoter (BCP) and precore gene (PC) mutations in hepatitis B virus (HBV) isolates among the Nicobarese tribe and their relationship with genotypes and HBeAg status. A total of 726 blood samples were collected from two villages of the Car Nicobar Island where mass vaccination was performed in the year 2000. HBV DNA was isolated and the BCP and PC regions were amplified and sequenced directly. The samples positive for HBV DNA were tested for HBsAg, HBeAg and anti-HBe. Among the 211 and 515 samples collected from vaccinated and nonvaccinated persons, 16 and 82 were positive for HBV DNA, respectively. Among the vaccinated individuals, only 1 had a mutation in both the BCP and PC gene. Among the nonvaccinated subjects, 3 (4.5%) had an A1762T mutation, 8 (12.1%) had a G1764A mutation, 11 (16.7%) had a G1896A mutation and 4 (6.1%) had a G1899A mutation. The HBeAg-negative subjects had a significantly higher frequency of BCP and PC mutations than the HBeAg-positive subjects. The prevalence of a PC mutation was higher than that of a BCP mutation. The present study stresses the need for the continuous surveillance of subjects with BCP and PC mutations, as the mutations may contribute to the progression of liver disease.

Core promoter: A critical region where the hepatitis B virus makes decisions

The core promoter (CP) of the viral genome plays an important role for hepatitis B virus (HBV) replication as it directs initiation of transcription for the synthesis of both the precore and pregenomic (pg) RNAs. The CP consists of the upper regulatory region and the basal core promoter (BCP). The CP overlaps with the 3'-end of the X open reading frames and the 5'-end of the precore region, and contains cis-acting elements that can independently direct transcription of the precore mRNA and pgRNA. Its transcription regulation is under strict control of viral and cellular factors. Even though this regulatory region exhibits high sequence conservation, when variations appear, they may contribute to the persistence of HBV within the host, leading to chronic infection and cirrhosis, and eventually, hepatocellular carcinoma. Among CP sequence variations, those occurring at BCP may dysregulate viral gene expression with emphasis in the hepatitis B e antigen, and contribute to disease progression. In this review these molecular aspects and pathologic topics of core promoter are deeply evaluated.

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 anti-HBe 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.