Influences of Hepatitis B Virus (HBV) Genotypes, Core Promoter Mutations and HBeAg/anti-HBe Titers on HBV DNA Levels (original) (raw)
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Mutations of Basal Core Promoter and Precore Regions in Hepatitis B Virus Genotypes B and C
Hepatitis Monthly, 2014
Background: Mutations in basal core promoter (BCP) and precore regions of hepatitis B virus (HBV) are associated with course and treatment outcomes of chronic HBV infection. While BCP and precore mutation analysis have been carried out in adult patients between different genotypes, this analysis has rarely been performed for chronically infected children. Objectives: The aim of this study was to assess the mutation profiles of BCP and precore regions in different HBV genotypes in chronically infected children. Patients and Methods: A cohort of 245 children and 92 adults with chronic HBV infection was included in this study. BCP and precore regions were analyzed by PCR amplification and sequenced. Results: Ten nucleotide positions, including nt1679, nt1721, nt1753, nt1757, nt1758, nt1762, nt1764, nt1775, nt1856 and nt1858 in BCP/precore regions of HBV genome, showed obviously higher frequencies of mutation in genotype C subjects than in genotype B subjects among children, while there were only three positions, including nt1679, nt1758 and nt1775 showing higher mutation frequencies in genotype C subjects than in genotype B subjects in adults. Several combined mutations were obviously highly distributed in children with chronic HBV genotype C infection, such as G1721A/A1775G/T1858C triple mutation; a novel combined mutation type, exclusively detected in children with chronic HBV genotype C infection. In addition, G1721A/A1775G/T1858C combined mutation was associated with higher viral load and lower age distribution. Conclusions: The mutation ratio difference between genotypes B and C in children was higher than that of adults and several combined mutations were exclusively detected in children with chronic HBV genotype C infection associated with higher viral load.
Hepatitis B virus infection: Precore mutants and its relation to viral genotypes and core mutations
Hepatology, 1995
The precore-core gene of hepatitis B virus (HBV) was directly sequenced from serum samples of 42 patients with chronic B hepatitis (19 hepatitis B e antigen [HBeAg]+ and 23 anti-me+). Viral genotypes were determined by comparison with ll reference sequences and by restriction analysis. Genotype A was identified in 16 cases, genotype D in 24 cases, and other genotypes in 2 cases. Precore mutations, mainly M1 (stop at codon 28), were differently distributed among the viral genotypes: 3 cases (18.8%) with genotype A and 18 cases (75%) with genotype D. In sequences with precore mutants, the encapsidation signal was more stable (negative stabilization energy) than in sequences without precore mutants. In genotype A, the M1 mutation coexisted with a second mutation (C + T at position 1858 in codon 15), and both mutations were paired in the secondary structure of the RNA encapsidation signal, which justified the rare presence of precore mutants in this genotype. The analysis showed different distribution of mutations depending on the viral genotype; patients with genotype D were more likely to have persistent HBV infection by selection of precore mutants. Multiple amino acid substitutions were detected in the core region, mainly in two subsequences that have been previously described as epitopes (flanked by codons 11 to 27 and 74 to 83); the presence of these mutations was significantly related to the presence of precore variants which abolished the expression of HBeAg. The study of viral genotypes in chronic HBV infection may be valuable in predicting the persistence of viral replication after seroconversion to anti-HBe and suggest that the outcome of chronic infection may be affected by the HBV variability.
Clinical relevance and public health significance of hepatitis B virus genomic variations
World Journal of Gastroenterology, 2009
Ten hepatitis B virus (HBV) genotypes (A-J) and 34 HBV subgenotypes have been identified so far. HBV genotypes and subgenotypes have distinct geographical distributions, and have been shown to differ with regard to clinical outcome, prognosis, and response to interferon treatment. Infection with subgenotype A2 is frequently associated with high viral load, resulting in acute infection via horizontal transmission. Genotypes A and B are more sensitive to interferon treatment than genotypes D and C, respectively. Genotype B is more frequent in acute hepatitis than genotype C, whereas genotype C (C2) is more frequently associated with an increased risk of hepatocellular carcinoma (HCC), mostly cirrhotic, as compared with genotype B (B2). Genotype mixture is associated with high viral load and worse outcome of HBV infection. HBV mutations in the S genes, especially amino acids substitution at position 145 (G145R), are associated with immune escape, whereas mutations in the PreS or S genes which impair HBsAg secretion could present a risk to blood safety. HBV variants harboring mutations in the viral polymerase gene that confer resistance to nucleoside analogs may be selected during antiviral therapy. Different genotypes have distinct mutation patterns in the PreS and EnhⅡ/BCP/Precore regions. PreS deletions, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. HCCassociated HBV mutants may not transmit via motherto-child transmission, and are likely generated during HBV-induced pathogenesis. Examination of HBV mutations alone or in combination and host genetic susceptibility will be helpful in classifying the HBV-infected subjects who will develop HCC and need active antiviral treatments.
Hepatitis B Virus Promoter Regions, Genetic Mutations
2012
In this study, we evaluated the prevalence of the most common mutations occurring in Enhancer II (EnhII), Basal Core Promoter (BCP), Precore (PC), and Core (C) regions of hepatitis B virus (HBV) genome. Objectives: We also investigated the correlation between HBV variants, their genotypes, and patients' HBe antigen (HBeAg: soluble shape of the capsid antigen) status. Patients and Methods: We retrieved viral DNA from 40 serum samples of Tunisian patients positive for hepatitis B surface antigen (HBsAg) and HBV DNA, amplified the above mentioned regions using specific primers, and sequenced the corresponding PCR (polymerase chain reaction) products. For further analysis purpose, the patients were divided into two groups: Group1 including 34 HBeAg-negative patients and Group2 with 6 HBeAg-positive patients. Results: Twenty-one patients (52.5%) showed PC G1896A mutation and 11 (27.5%) carried A1762T/G1764A double mutations. These mutations were more frequent in HBeAg-negative patients than that in HBeAg-positive ones. Indeed, 58.8% of patients bearing G1896A mutation were HBeAg-negative while 16.7% were positive. In patients bearing T1762/A1764 double mutation, 29.4% were positive and 16.7% were negative. In addition, the A1896 mutation was restricted to HBV isolates that had wild-type T1858, while C1858 was rather linked to the occurrence of T1762/A1764 mutation. Interestingly, this study revealed a high frequency of genotype E. This frequency was important as compared to that of genotype D known to be predominant in the country as delineated in previous studies. Conclusions: Previous results supported and showed that HBV strains present in Tunisia belonging to genotype D and, to a lesser extent, to genotype E, were prone to mutations in BCP/ PC regions. This observation was more obvious in HBV isolates from asymptomatic chronic carriers (AsC). The high mutational rates observed in our study might result from a mechanism of viral escape that plays an important role in the loss of HBeAg.
Journal of Viral Hepatitis, 2000
The present study aimed to clarify how viraemia levels re¯ect the clinical stages of chronic hepatitis B virus (HBV) infection, in particular studying whether`healthy carriers' can be identi®ed by analysing HBV DNA levels with a highly sensitive quantitative assay. Histology activity index (HAI), alanine aminotransferase (ALT) level, genotype and precore mutations were compared with the 2 HBV DNA level, as measured using the Amplicor HBV Monitor assay in a prospective study. In 124 hepatitis B e antigen-negative (HBeAg ) ) patients, the majority with mild liver disease, log HBV DNA levels showed a Gaussian distribution around a geometric mean of 33 000 genome copies ml )1 , and increasing HBV DNA level was associated with signi®cantly higher in¯ammation (HAIin¯) and ®brosis (HAI®br) scores and higher ALTi (ALT¸the upper reference value). Severe in¯ammation (HAIin¯³ 7) was seen in 83% (®ve of six), 36% (eight of 22) and 3% (one of 37) of HBeAg ) patients with HBV DNA > 10 7 , > 2´10 5 and < 10 4 copies ml )1 , respectively. In severe HBeAg ) hepatitis, patients with precore wild-type infection had lower HBV DNA levels than those with precore mutants. In 36 HBeAg-positive (HBeAg + ) patients, no correlation between HBV DNA level and liver damage was seen. Ninety-six per cent of HBeAg ) patients with ALTi < 0.5 had HAIin¯£ 3. In HBeAg ) carriers with ALTi 0.5±1.0, the relative risk for severe in¯ammation, comparing HBV DNA > 2´10 5 copies ml )1 vs < 2´10 5 copies ml )1 , was 14.7. In conclusion, in HBeAg ) carriers, HBV DNA < 10 4 copies ml )1 or ALTi < 0.5 indicates mild in¯ammation, while > 2´10 5 copies ml )1 of HBV DNA may justify further investigations. Precore status may be relevant for the interpretation of viraemia.
Hepatology, 1999
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 F .01), while precore stop codon changes were exclusively found in patients infected with HBV who have T at nucleotide 1858 (87% vs. 0; P F .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 pre-clude the development of precore stop codon mutation. (HEPATOLOGY 1999;29:976-984.)
Journal of Clinical Microbiology, 2003
Hepatitis B virus (HBV) genotypes may influence HBeAg seroconversion rates, mutational patterns in the precore (PC) and core promoter (CP) regions, severity of liver disease, and response to antiviral treatment. Development of rapid, simple, and standardized assays to detect viral genotypes and common mutations in the PC and CP regions can accelerate research on the clinical significance of these variants. We aim to assess the accuracy of a line probe assay in determining HBV genotypes and detecting HBV PC and CP variants. HBV genotypes in 701 patients and PC and CP variants in 600 patients with chronic HBV infection from China and the United States were studied using the INNO-LiPA assay. All but one (99.9%) sample were classified by the genotyping assay. All eight genotypes, i.e., A to H, were found. The INNO-LiPA genotyping assay results were completely concordant with those of sequencing. Using the INNO-LiPA PC assay, 99.8 and 94.7% samples were classifiable in the PC and CP regions, respectively. The PC assay results were completely concordant with those of sequencing in all samples that showed either wild-type or variant sequence. The line probe assay was more sensitive in detecting mixtures than was direct sequencing. By INNO-LiPA, only 50 and 27% of the samples, with mixed wild-type and variant sequence in the PC and CP region, respectively, showed mixed sequence by direct sequencing. INNO-LiPA is rapid, sensitive, and reliable-thus enabling accurate determination of HBV genotypes and detection of PC and CP variants in a large population of patients.
Hepatitis monthly, 2013
More than two billion people have been exposed to hepatitis B virus (HBV) worldwide. Furthermore, four hundred million of them are infected with chronic HBV infection. The predominant mutation of the precore region involves a G to A change at nucleotide1896, which creates a premature stop codon at codon 28. Two mutations of A1762T and G1764A are reported as the most prevalent mutations in the basal core promoter (BCP). The purpose of this study was to investigate the relationship between mutations in precore (PC) and basal core promoter regions, and the viral load. Fifty serum samples from patients with hepatitis B were used. Levels of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured at the same time of serological markers of hepatitis B by ELISA. HBV-DNA was extracted from the sera, and then PCR performed on the HBV-DNA extracted with the use of specific primer of gene C. HBV viral load was determined by real-time PCR. The PC/ BCP muta...