• Hepatitis B virus/genetics
• Hepatitis B virus/physiology
• Humans
• Virus Replication/genetics
• Viral Regulatory and Accessory Proteins/genetics
• Viral Regulatory and Accessory Proteins/metabolism
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Animals
• Genotype
• Mice
• Polymorphism, Genetic
• Phenotype
• Hepatitis B/virology
• Hepatitis B/genetics
• Hepatocytes/virology
• Hepatocytes/metabolism

• National Institutes of Health (US)
• Japan Agency for Medical Research and Development

• (sub)genotypes
• hepatitis B virus
• hepatocellular carcinoma
• oncogenic pathways
• viral oncogenesis

• Humans
• Hepatitis B virus/genetics
• Proteomics
• Genotype
• Cell Line, Tumor
• Signal Transduction
• Africa South of the Sahara
• Proteome
• rhoC GTP-Binding Protein/metabolism
• rhoC GTP-Binding Protein/genetics
• Carcinoma, Hepatocellular/virology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/genetics
• Transfection
• Liver Neoplasms/virology
• Liver Neoplasms/metabolism
• Liver Neoplasms/genetics
• Hepatitis B/virology
• Hepatitis B/metabolism
• Hepatitis B/genetics

• https://cansa.org.za/, accessed on 1 January 2023 Cancer Association of South Africa

Despite being vaccine-preventable, hepatitis B virus (HBV) infection remains the seventh leading cause of mortality in the world. In South Africa (SA), over 1.9 million people are chronically infected with HBV, and 70% of all Black chronic carriers are infected with HBV subgenotype A1. The virus remains a significant burden on public health in SA despite the introduction of an infant immunization program implemented in 1995 and the availability of effective treatment for chronic HBV infection. In addition, the high prevalence of HIV infection amplifies HBV replication, predisposes patients to chronicity, and complicates management of the infection. HBV research has made significant progress leading to better understanding of HBV epidemiology and management challenges in the SA context. This has led to recent revision of the national HBV infection management guidelines. Research on developing new vaccines and therapies is underway and progress has been made with designing potentially curative gene therapies against HBV. This review summarizes research carried out in SA on HBV molecular biology, epidemiology, treatment, and vaccination strategies.

• HIV Infections/complications
• HIV Infections/epidemiology
• Hepatitis B/complications
• Hepatitis B/epidemiology
• Hepatitis B/prevention & control
• Hepatitis B Vaccines/therapeutic use
• Hepatitis B virus/genetics
• Humans
• Infant
• South Africa/epidemiology

HBeAg, a non-particulate protein of hepatitis B virus (HBV), is translated from the precore/core region as a precursor, which is post-translationally modified. Subgenotype A1 of HBV, which is a risk factor for hepatocellular carcinoma (HCC), has unique molecular characteristics in the basic core promoter/precore regions. Carriers of A1 exhibit early HBeAg loss. We sought to further characterize the precore proteins of A1 in vitro. HuH-7 cells were transfected with subgenomic constructs expressing individual precore proteins. Western blot analysis using DAKO anti-core antibody showed the expected sizes and a 1 kDa larger band for P22, P20 and P17. Using confocal microscopy, a cytoplasmic accumulation of HBeAg and precursors was observed with P25-expressing plasmid, whereas P22 localized both in the cytoplasm and nucleus. P20 and P17, which lack the carboxy end of P22 showed strong nuclear accumulation, implicating a nuclear localization signal in the N-terminal 10 amino acids. G1862T, unique to subgenotype A1, is frequently found in HBV from HCC patients. P25 with G1862T showed delayed and reduced HBeAg expression/secretion. Knock-out of core in the replication competent clones led to precore protein accumulation in the cytoplasm/perinuclear region, and decreased HBeAg secretion. Knock-out of precore proteins increased HBsAg secretion but intracellular HBsAg expression was unaffected. Over-expression of precore proteins in trans led to decreased HBsAg expression and secretion. Intracellular trafficking of HBV A1 precore proteins was followed. This was unaffected by the CMV promoter and different cell types. In the viral context, precore protein expression was affected by absence of core, and affected HBsAg expression, suggesting an interrelationship between precore proteins, HBcAg and HBsAg. This modulatory role of HBeAg and its precursors may be important in viral persistence and ultimate development of HCC.

Many mutation analyses of the HBV genome have been performed in the search for new prognostic markers. However, the Kozak sequence preceding precore was covered only infrequently in these analyses. In this study, the HBV core promoter/precore region was sequenced in serum samples from European inactive HBV carriers. Quadruple mutation GCAC1809-1812TTCT was found with a high prevalence of 42% in the Kozak sequence preceding precore among all HBV genotypes. GCAC1809-1812TTCT was strongly associated with coexistence of basal core promoter (BCP) double mutation A1762T/G1764A and lower HBV DNA levels. In vitro GCAC1809-1812TTCT lead to drastically diminished synthesis of pregenomic RNA (pgRNA), precore mRNA, core, HBsAg, and HBeAg. Calculation of the pgRNA secondary structure suggests a destabilization of the pgRNA structure by A1762T/G1764A that was compensated by GCAC1809-1812TTCT. In 125 patients with HBV-related cirrhosis, GCAC1809-1812TTCT was not detected. While a strong association of GCAC1809-1812TTCT with inactive carrier status was observed, BCP double mutation was strongly correlated with cirrhosis, but this was only observed in absence of GCAC1809-1812TTCT. In conclusion, our data reveal that GCAC1809-1812TTCT is highly prevalent in inactive carriers and acts as a compensatory mutation for BCP double mutation. GCAC1809-1812TTCT seems to be a biomarker of good prognosis in HBV infection.

HBV core promoter/precore region was sequenced in serum samples of European inactive HBV carriers, revealing that GCAC1809-1812TTCT mutation is highly prevalent in inactive carriers.

• Clinical practice
• Hepatology
• Molecular biology
• Virology

• B-NHL
• HBV
• viral infection

• HBV
• Sub-Saharan Africa
• basal core promoter
• subgenotype A1

• Case-Control Studies
• Codon, Initiator
• Hepatitis B Antibodies/metabolism
• Hepatitis B virus/classification
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/virology
• Humans
• Mutation
• Phylogeny
• Promoter Regions, Genetic
• Rwanda
• Viral Proteins/genetics

Hepatitis B virus (HBV) infection, a global public health problem can be asymptomatic, acute or chronic and can lead to serious consequences of infection, including cirrhosis, and hepatocellular carcinoma. HBV, a partially double stranded DNA virus, belongs to the family Hepadnaviridae, and replicates via reverse transcription of an RNA intermediate. This reverse transcription is catalyzed by a virus-encoded polymerase that lacks proof reading ability, which leads to sequence heterogeneity. HBV is classified into nine genotypes and at least 35 subgenotypes, which may be characterized by distinct geographical distributions. This HBV diversification and distinct geographical distribution has been proposed to be the result of the co-expansion of HBV with modern humans, after their out-of-Africa migration. HBeAg is a non-particulate protein of HBV that has immunomodulatory properties as a tolerogen that allows the virus to establish HBV infection in vivo. During the natural course of infection, there is seroconversion from a HBeAg-positive phase to a HBeAg-negative, anti-HBe-positive phase. During this seroconversion, there is loss of tolerance to infection and immune escape-HBeAg-negative mutants can be selected in response to the host immune response. The different genotypes and, in some cases, subgenotypes develop different mutations that can affect HBeAg expression at the transcriptional, translational and post-translational levels. The ability to develop mutations, affecting HBeAg expression, can influence the length of the HBeAg-positive phase, which is important in determining both the mode of transmission and the clinical course of HBV infection. Thus, the different genotypes/subgenotypes have evolved in such a way that they exhibit different modes of transmission and clinical manifestation of infection. Loss of HBeAg may be a sign of short-sighted evolution because there is loss of tolerogenic ability of HBeAg and HBeAg-negative virions are less transmissible. Depending on their ability to lead to HBeAg seroconversion, the genotype/subgenotypes exhibit varying degrees of short-sighted evolution. The “arms race” between HBV and the immune response to HBeAg is multifaceted and its elucidation intricate, with transmissibility and persistence being important for the survival of the virus. We attempt to shed some light on this complex interplay between host and virus.

• HBeAg seroconversion
• genotypes
• subgenotypes
• tolerogen
• transmission

We recently reported complex hepatitis B virus (HBV) drug resistant and concomitant vaccine escape hepatitis B surface antigen (HBsAg) variants during human immunodeficiency virus (HIV) co-infection and antiretroviral therapy (ART) exposure in Ethiopia. As a continuation of this report using the HBV positive sera from the same study participants, the current study further analyzed the HBV basal core promoter (BCP)/precore (PC) genes variability in patients with HBV drug resistance (at tyrosine-methionine-aspartate-aspartate (YMDD) reverse transcriptase (RT) motifs) and HIV co-infection in comparison with HBV mono-infected counterparts with no HBV drug resistant gene variants.

A total of 143 participants of HBV-HIV co-infected (n = 48), HBV mono-infected blood donors (n = 43) and chronic liver disease (CLD) patients (n = 52) were included in the study. The BCP/PC genome regions responsible for HBeAg expression from the EcoRI site (nucleotides 1653–1959) were sequenced and analyzed for the BCP/PC mutant variants.

Among the major mutant variants detected, double BCP mutations (A1762T/G1764A) (25.9%), Kozak sequences mutations (nt1809-1812) (51.7%) and the classical PC mutations such as A1814C/C1816T (15.4%), G1896A (25.2%) and G1862T (44.8%) were predominant mutant variants. The prevalence of the double BCP mutations was significantly lower in HIV co-infected patients (8.3%) compared with HBV mono-infected blood donors (32.6%) and CLD patients (36.5%). However, the Kozak sequences BCP mutations and the majority of PC mutations showed no significant differences among the study groups. Moreover, except for the overall BCP/PC mutant variants, co-prevalence rates of each major BCP/PC mutations and YMDDRT motif associated lamivudine (3TC)/entecavir (ETV) resistance mutations showed no significant differences when compared with the rates of BCP/PC mutations without YMDD RT motif drug resistance gene mutations. Unlike HIV co-infected group, no similar comparison made among HBV mono-infected blood donors and CLD patients since none of them developed the YMDD RT motif associated 3TC/ETV resistance mutations. However, HBV mono-infected blood donors and CLD patients who had no any drug resistance gene variants developed comparable G1862T (60.6% vs. 65.1%) and G1896A (24.2% vs. 11.6%) PC gene mutations.

No correlation observed between the BCP/PC genome variability and the YMDD RT motif associated HBV drug resistance gene variants during HIV co-infection. Nevertheless, irrespective of HIV co-infection status, the higher records of the BCP/PC gene variability in this study setting indicate a high risk of potential HBeAg negative chronic HBV infection in Northwest Ethiopia.

• Acute hepatitis
• HBeAg
• HBsAg
• Interferon
• Subtype

Although a successful vaccine against HBV has been implemented in 184 countries, eradication of hepatitis B virus (HBV) is still not on the horizon. There are over 240 million chronic carriers of HBV globally. The risk of developing chronic hepatitis ranges from >90% in newborns of hepatitis Be antigen (HBeAg)‐positive mothers, 25%–35% in children under 5 years of age and <5% in adults. HBeAg, a non‐particulate viral protein, is a marker of HBV replication. This is the only HBV antigen to cross the placenta, leading to specific unresponsiveness of helper T cells to the capsid protein and HBeAg in newborns. HBeAg is tolerated in utero and acts as a tolerogen after birth. Perinatal transmission is frequent when mothers are HBeAg‐positive, whereas it occurs less frequently when mothers are HBeAg‐negative. Sequence heterogeneity is a feature of HBV. Based on an intergroup divergence >7.5% across the complete genome, HBV is classified phylogenetically into at least nine genotypes. With between ~4% and 8% intergroup nucleotide divergence, genotypes A–D, F, H and I are classified further into subgenotypes. HBV genotypes/subgenotypes may have distinct geographical distribution and can develop different mutations in the regions of the HBV genome that code for HBeAg. These differences can be related to the role of HBV genotypes to the natural history of infection and mode of transmission. Thus genotypes/subgenotypes of HBV can be responsible for the different natural history of infection and modes of transmission in children, found in various regions of the world, where different genotypes/subgenotypes prevail. Copyright © 2016 John Wiley & Sons, Ltd.

• Argentina
• Epidemiology
• Genotypes
• HBV
• HBV/HIV co-infection
• Mutants

• Huh7 cells
• In vitro replication and protein expression
• Transfection

Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant.

• Adult
• Coinfection
• Female
• Genetic Heterogeneity
• Genotype
• HIV
• HIV Infections/diagnosis
• HIV Infections/immunology
• HIV Infections/virology
• Hepatitis B Core Antigens/genetics
• Hepatitis B Core Antigens/immunology
• Hepatitis B e Antigens/genetics
• Hepatitis B e Antigens/immunology
• Hepatitis B virus/classification
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/virology
• Humans
• Male
• Middle Aged
• Molecular Typing
• Phylogeny
• Promoter Regions, Genetic
• Viral Core Proteins/genetics
• Viral Envelope Proteins/genetics

Hepatitis B virus is hyperendemic in Sudan. Our aim was to molecularly characterize hepatitis B virus from Sudanese individuals, with and without liver disease, because genotypes play an important role in clinical manifestation and treatment management.

Ninety-nine patients - 30 asymptomatic, 42 cirrhotic, 15 with hepatocellular carcinoma, 7 with acute hepatitis and 5 with chronic hepatitis- were enrolled. Sequencing of surface and basic core promoter/precore regions and complete genome were performed.

The mean ± standard deviation, age was 45.7±14.8 years and the male to female ratio 77:22. The median (interquartile range) of hepatitis B virus DNA and alanine aminotransferase levels were 2.8 (2.2-4.2) log IU/ml and 30 (19–49) IU/L, respectively. Using three genotyping methods, 81/99 (82%) could be genotyped. Forty eight percent of the 99 patients were infected with genotype D and 24% with genotype E, 2% with putative D/E recombinants and 7% with genotype A. Patients infected with genotype E had higher frequency of hepatitis B e antigen-positivity and higher viral loads compared to patients infected with genotype D. Basic core promoter/precore region mutations, including the G1896A in 37% of HBeAg-negative individuals, could account for hepatitis B e antigen-negativity. Pre-S deletion mutants were found in genotypes D and E. Three isolates had the vaccine escape mutant sM133T.

Sudanese hepatitis B virus carriers were mainly infected with genotypes D or E, with patients infected with genotype E having higher HBeAg-positivity and higher viral loads. This is the first study to molecularly characterize hepatitis B virus from liver disease patients in Sudan.

• HBV
• Mismatch
• RNA
• Short hairpin

An online tool, which extracts and summarises nucleotide or amino acid sequence data at specified loci of interest, was developed and tested using the basic core promoter/precore (BCP/PC) region of the hepatitis B virus (HBV). The tool is aimed at researchers without specialist computer skills.

The tool consists of a web-based front-end, with a CGI script, which runs Python code to generate an output web-page. The Python code searches the input sequence data for a specified anchor motif, after which it generates summary tables and graphs of residue and motif distributions.

After the user provides an input file in FASTA format containing aligned sequence data (nucleotides or amino acids) and specifies an anchor motif at a known coordinate, the tool summarizes the nucleotides or amino acids at the specified loci, their frequency and analyzes motif patterns of the loci.The tool can output a graph that displays the frequency of mutations relative to a reference sequence. The tool was used to analyze the BCP/PC region of HBV belonging to subgenotypes A1, A2 and subgenotype D and to serotype HBV. The “Discovery Mode” ignores conserved loci and assists in identifying potential loci of interest.

Although HBV was used to demonstrate the utility of the Mutation Reporter Tool, the tool has wide application as it is genome-agnostic: nucleotide or amino acid sequence data from any organism can be processed. Rapid characterisation of many sequences can be achieved easily when the loci of interest are known. The tool is available online, without charge, at http://hvdr.bioinf.wits.ac.za/tools

Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are hyperendemic in sub-Saharan Africa. The HBV genotypes prevailing in HIV-infected Africans are unknown. Our aim was to determine the HBV genotypes in HIV-infected participants and to identify clinically significant HBV mutations. From 71 HBV DNA^+ve HIV-infected participants, 49 basic core promoter/precore (BCP/PC) and 29 complete S regions were successfully sequenced. Following phylogenetic analysis of 29 specimens in the complete S region, 28 belonged to subgenotype A1 and one to D3. Mutations affecting HBeAg expression at the transcriptional (1762T1764A), translational (Kozak 1809–1812, initiation 1814–1816, G1896A with C1858T), or post translational levels (G1862T), were responsible for the high HBeAg-negativity observed. The G1862T mutation occurred only in subgenotype A1 isolates, which were found in one third (7/21) of HBsAg^−ve participants, but in none of the 18 HBsAg^+ve participants (p<0.05). Pre-S deletion mutants were detected in four HBsAg^+ve and one HBsAg^−ve participant/s. The following mutations occurred significantly more frequently in HBV isolated in this study than in strains of the same cluster of the phylogenetic tree: ps1F25L, ps1V88L/A; ps2Q10R, ps2 R48K/T, ps2A53V and sQ129R/H, sQ164A/V/G/D, sV168A and sS174N (p<0.05). ps1I48V/T occurred more frequently in females than males (p<0.05). Isolates with sV168A occurred more frequently in participants with viral loads >200 IU per ml (p<0.05) and only sS174N occurred more frequently in HBsAg^−ve than in HBsAg^+ve individuals (p<0.05). Prior to initiation of ART, ten percent, 3 of 29 isolates sequenced, had drug resistance mutations rtV173L, rtL180M+rtM204V and rtV214A, respectively. This study has provided important information on the molecular characteristics of HBV in HIV-infected southern Africans prior to ART initiation, which has important clinical relevance in the management of HBV/HIV co-infection in our unique setting.

• Adolescent
• Adult
• Anti-HIV Agents/administration & dosage
• Child
• Child, Preschool
• Coinfection
• Female
• Gene Expression
• Genotyping Techniques
• HIV Infections/drug therapy
• HIV Infections/virology
• HIV-1/physiology
• Hepatitis B Surface Antigens/genetics
• Hepatitis B e Antigens/genetics
• Hepatitis B virus/classification
• Hepatitis B virus/genetics
• Hepatitis B virus/isolation & purification
• Hepatitis B, Chronic/virology
• Humans
• Male
• Middle Aged
• Mutation
• Phylogeny
• Sequence Analysis, DNA
• Sex Factors
• South Africa
• Time Factors
• Viral Load

• Adult
• Aflatoxin B1/toxicity
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/virology
• Case-Control Studies
• Female
• Gambia/epidemiology
• Genes, p53
• Genetic Variation
• Hepatitis B Surface Antigens/immunology
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/epidemiology
• Hepatitis B, Chronic/genetics
• Hepatitis B, Chronic/virology
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/virology
• Liver Neoplasms/epidemiology
• Liver Neoplasms/genetics
• Liver Neoplasms/virology
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Risk Factors
• Trans-Activators/genetics
• Tumor Suppressor Protein p53/genetics
• Viral Regulatory and Accessory Proteins

• MC_U190081996 Medical Research Council
• P01 ES006052 NIEHS NIH HHS

• Adult
• Aflatoxin B1/toxicity
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/virology
• Case-Control Studies
• Female
• Gambia/epidemiology
• Genes, p53
• Genetic Variation
• Hepatitis B Surface Antigens/immunology
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/epidemiology
• Hepatitis B, Chronic/genetics
• Hepatitis B, Chronic/virology
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/virology
• Liver Neoplasms/epidemiology
• Liver Neoplasms/genetics
• Liver Neoplasms/virology
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Risk Factors
• Trans-Activators/genetics
• Tumor Suppressor Protein p53/genetics
• Viral Regulatory and Accessory Proteins

• MC_U190081996 Medical Research Council
• P01 ES006052 NIEHS NIH HHS

• Adult
• Aged
• DNA, Viral/metabolism
• Female
• Frameshift Mutation/genetics
• Genotype
• Hep G2 Cells
• Hepatitis B virus/genetics
• Hepatitis B virus/pathogenicity
• Hepatitis B virus/physiology
• Humans
• Japan
• Liver Failure, Acute/virology
• Male
• Middle Aged
• Mutagenesis, Insertional/genetics
• Sequence Analysis, DNA
• Sequence Deletion/genetics
• Viral Core Proteins/genetics
• Viral Core Proteins/metabolism
• Virus Replication

AIM: To identify the prevalence of hepatitis B e antigen (HBeAg) and to assess the association of hepatitis B virus (HBV) core promoter mutations and viral load in Indonesian patients.

METHODS: Sixty-four patients with chronic hepatitis, 65 with liver cirrhosis and 50 with hepatocellular carcinoma were included in this study. HBeAg and hepatitis B e antibody (HBeAb) tests were performed using enzyme-linked immunosorbent assay and the mutations were analyzed by sequencing. Viral load was measured by real-time polymerase chain reaction.

RESULTS: Of 179 patients, 108 (60.3%) were HBeAg(-) and 86 (79.6%) of these HBeAg(-) patients had been seroconverted. The A1896 mutation was not found in HBeAg(+) patients, however, this mutation was detected in 70.7% of HBeAg(-) patients. This mutation was frequently found when HBeAg was not expressed (87.7%), compared to that found in HBeAg seroconverted patients (65.1%). The A1899 mutation was also more prevalent in HBeAg(-) than in HBeAg(+) patients (P = 0.004). The T1762/A1764 mutation was frequently found in both HBeAg(+) and HBeAg(-) patients, however, the prevalence of this mutation did not significantly differ among the two groups (P = 0.054). In HBeAg(+) patients, the T1762/A1764 mutation was correlated with lower HBV DNA (P < 0.001). The A1899 mutation did not correlate with HBV DNA (P = 0.609). In HBeAg(-) patients, the T1762/A1764 mutation alone was not correlated with HBV DNA (P = 0.095), however, the presence of either the T1762/A1764 or A1896 mutations was associated with increased HBV DNA (P < 0.001).

CONCLUSION: The percentage of HBeAg(-) patients is high in Indonesia, and most of the HBeAg(-) patients had been seroconverted. The A1896 mutation was most likely the major cause of HBeAg loss. The T1762/A1764 mutation alone was associated with lower viral loads in HBeAg(+) patients, but not in HBeAg(-) patients.

• Hepatitis B e antibody
• Hepatitis B e antigen
• Hepatitis B virus
• Indonesia
• Precore/core promoter mutations
• Viral load

• Hepatitis B virus
• pre-S1
• precore mutation

• Adolescent
• Adult
• Alanine Transaminase/blood
• DNA, Viral/blood
• Female
• Hepatitis B Core Antigens/genetics
• Hepatitis B e Antigens/metabolism
• Hepatitis B virus/genetics
• Hepatitis B virus/metabolism
• Hepatitis B virus/pathogenicity
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/physiopathology
• Hepatitis B, Chronic/virology
• Humans
• Korea
• Male
• Middle Aged
• Mutation
• Promoter Regions, Genetic/genetics
• Protein Precursors/genetics
• Young Adult

• Adult
• Carcinoma, Hepatocellular/virology
• Codon, Terminator
• DNA, Viral/blood
• Female
• Genotype
• Hepatitis B Core Antigens/blood
• Hepatitis B e Antigens/blood
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/etiology
• Hepatitis B, Chronic/genetics
• Hepatitis B, Chronic/immunology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/etiology
• Hepatitis C, Chronic/genetics
• Hepatitis D, Chronic/complications
• Hepatitis D, Chronic/etiology
• Hepatitis D, Chronic/genetics
• Humans
• Liver Neoplasms/virology
• Male
• Middle Aged
• Molecular Sequence Data
• Mongolia
• Mutation
• Phenotype
• Phylogeny
• Promoter Regions, Genetic
• Viral Core Proteins/genetics
• Viral Load

• Cell Line
• DNA, Viral/genetics
• Genotype
• Hepatitis B/virology
• Hepatitis B e Antigens/biosynthesis
• Hepatitis B e Antigens/blood
• Hepatitis B e Antigens/genetics
• Hepatitis B virus/genetics
• Hepatitis B virus/physiology
• Humans
• Molecular Sequence Data
• Protein Biosynthesis
• RNA, Messenger/biosynthesis
• RNA, Viral/biosynthesis
• Recombination, Genetic
• Transcription, Genetic/physiology
• Virion
• Virus Assembly/physiology
• Virus Replication/genetics
• Virus Replication/physiology

• CA35711 NCI NIH HHS
• R21 DK066950 NIDDK NIH HHS
• CA95490 NCI NIH HHS
• DK28614 NIDDK NIH HHS
• DK066950 NIDDK NIH HHS
• CA109733 NCI NIH HHS
• R01 DK028614 NIDDK NIH HHS
• R01 CA035711 NCI NIH HHS
• R37 CA035711 NCI NIH HHS
• R01 CA109733 NCI NIH HHS

• Adolescent
• Adult
• Aged
• Child
• Child, Preschool
• DNA, Viral/genetics
• Female
• Gene Expression Regulation, Viral
• Genotype
• Hepatitis B e Antigens/physiology
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/epidemiology
• Hepatitis B, Chronic/physiopathology
• Hepatitis B, Chronic/virology
• Humans
• India/epidemiology
• Male
• Middle Aged
• Mutation/genetics
• Promoter Regions, Genetic/genetics

• Adult
• Aged
• Base Sequence
• Carrier State
• Genotype
• Hepatitis B/epidemiology
• Hepatitis B/virology
• Hepatitis B Surface Antigens/genetics
• Hepatitis B virus/genetics
• Humans
• Male
• Molecular Epidemiology
• Phylogeny
• Tanzania/epidemiology

• Adult
• Alanine Transaminase/blood
• DNA, Viral/chemistry
• DNA, Viral/genetics
• Female
• Genotype
• Hepatitis B/blood
• Hepatitis B/immunology
• Hepatitis B/virology
• Hepatitis B e Antigens/genetics
• Hepatitis B e Antigens/immunology
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Humans
• Male
• Middle Aged
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• RNA, Viral/blood
• Sequence Analysis, DNA
• Statistics, Nonparametric
• Viral Load

• Adult
• Analysis of Variance
• Cohort Studies
• DNA, Viral/genetics
• Disease Progression
• Female
• Gene Expression Regulation
• Genetic Markers
• Genetic Predisposition to Disease
• Genotype
• Hepatitis B, Chronic/epidemiology
• Hepatitis B, Chronic/genetics
• Hepatitis B, Chronic/physiopathology
• Hepatitis D, Chronic/epidemiology
• Hepatitis D, Chronic/genetics
• Hepatitis D, Chronic/physiopathology
• Humans
• Incidence
• Liver Function Tests
• Male
• Middle Aged
• Multivariate Analysis
• Probability
• Prognosis
• Retrospective Studies
• Risk Assessment
• Sensitivity and Specificity
• Severity of Illness Index
• Survival Rate
• Taiwan/epidemiology
• Viremia/epidemiology
• Viremia/genetics
• Viremia/physiopathology

• Gene Expression Regulation, Viral
• Genome, Viral
• Hepatitis B/virology
• Hepatitis B Core Antigens/genetics
• Hepatitis B virus/genetics
• Hepatitis B virus/physiology
• Humans
• Mutation
• Promoter Regions, Genetic/genetics
• Virus Replication

• AI54535 NIAID NIH HHS
• DK62857 NIDDK NIH HHS
• P20RR15578 NCRR NIH HHS

• Amino Acid Sequence
• DNA, Viral/biosynthesis
• Down-Regulation
• Gene Expression Regulation, Viral
• Hepatitis B e Antigens/metabolism
• Hepatitis B virus/genetics
• Hepatitis B virus/physiology
• Humans
• Molecular Sequence Data
• Mutation
• Nucleic Acid Conformation
• Viral Core Proteins/genetics
• Viral Core Proteins/metabolism
• Viral Envelope Proteins/genetics
• Virus Replication

• CA35711 NCI NIH HHS
• R03 AI054535 NIAID NIH HHS
• DK66950 NIDDK NIH HHS
• P20RR15578 NCRR NIH HHS
• AI54535 NIAID NIH HHS
• R21 DK066950 NIDDK NIH HHS
• R21 DK062857 NIDDK NIH HHS
• DK62857 NIDDK NIH HHS
• CA109733 NCI NIH HHS
• R01 CA035711 NCI NIH HHS
• R37 CA035711 NCI NIH HHS
• R01 CA109733 NCI NIH HHS

• hbv
• genotypes
• hbeag
• core promoter mutation
• 1858 variants
• precore stop codon mutation