Molecular Epidemiology of an Outbreak of Fulminant Hepatitis B

A nosocomial outbreak of hepatitis B occurred among the inpatients of a hematology unit. Nine of the 11 infected patients died from fulminant hepatitis. An investigation was conducted to identify the source of infection and the route of transmission. Two clusters of nosocomial hepatitis B were identified. The hepatitis B virus (HBV) genome from serum samples of all case patients, of one HBsAg-positive patient with acute reactivation of the infection, and of eight acutely infected, unrelated cases was identified by PCR amplification of viral DNA and was entirely sequenced. Transmission was probably associated with breaks in infection control practices, which occurred as single events from common sources or through a patient-to-patient route, likely the result of shared medications or supplies. Sequence analysis evidenced close homology among the strains from the case patients and that from the patient with reactivation, who was the likely source of infection. Molecular analysis of viral isolates evidenced an accumulation of mutations in the core promoter/precore region, as well as several nucleotide substitutions throughout the genome. The sequences of all patients were compared with published sequences from fulminant and nonfulminant HBV infections.

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Recent High Incidence of Fulminant Hepatitis in Samara, Russia: Molecular Analysis of Prevailing Hepatitis B and D Virus Strains

Journal of Clinical Microbiology ◽

10.1128/jcm.38.9.3311-3316.2000 ◽

2000 ◽

Vol 38 (9) ◽

pp. 3311-3316 ◽

Cited By ~ 52

Author(s):

Erik Flodgren ◽

Susanne Bengtsson ◽

Mikael Knutsson ◽

Elena A. Strebkova ◽

Alistair H. Kidd ◽

...

Keyword(s):

Hepatitis B ◽

Viral Hepatitis ◽

Fulminant Hepatitis ◽

Core Promoter ◽

Direct Sequencing ◽

Serum Samples ◽

Genotype I ◽

Hepatitis D ◽

Promoter Sequences ◽

Far Eastern

Until 1991, the Russian city of Samara was largely isolated from other parts of Russia and the rest of the world. Very recently, Samara has seen an alarming increase in the incidence of hepatitis. The proportion of fulminant cases is unusually high. We wanted to assess the roles of hepatitis B virus (HBV) and hepatitis D virus (HDV) in acute viral hepatitis in this region by analyzing the prevailing strains of both and by determining their genotypes and possible origin. Serum samples were screened for different serological markers and by PCR followed by direct sequencing. Of the 94 HBV-positive samples (80% of which were acute infections), 37 (39%) were also HDV positive. Sixty-seven percent of the patients had anti-HCV antibodies. Twenty-five percent of all patients in the study had fulminant hepatitis. Statistically significant sex differences were found among fulminant cases. For HBV, the core promoter sequences of 62 strains were determined and all but one were found to be of genotype D. None of these had any deletions. Only one strain, from a patient with fulminant fatal hepatitis, showed multiple mutations. The pre-S2 region sequences of 31 HBV strains were also compared. Phylogenetically, these fell into two distinct groups within genotype D, suggesting different origins. For HDV, part of the region encoding the δ-antigen was sequenced from four strains. All proved to be of genotype I and were similar to Far Eastern and Eastern European strains. The contribution of intravenous drug use to the sharp increase in viral hepatitis in this unique setting is discussed.

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Fulminant hepatitis B: Induction by hepatitis B virus mutants defective in the precore region and incapable of encoding E antigen

Gastroenterology ◽

10.1016/0016-5085(91)90286-t ◽

1991 ◽

Vol 100 (4) ◽

pp. 1087-1094 ◽

Cited By ~ 178

Author(s):

Yoshitane Kosaka ◽

Kohjiro Takase ◽

Mineo Kojima ◽

Masaru Shimizu ◽

Kyoichi Inoue ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Fulminant Hepatitis ◽

Precore Region ◽

B Virus

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Hepatitis B Virus Mutants with Precore-Region Defects in Two Babies with Fulminant Hepatitis and Their Mothers Positive for Antibody to Hepatitis B e Antigen

Pediatric Research ◽

10.1203/00006450-199101000-00002 ◽

1991 ◽

Vol 29 (1) ◽

pp. 5-9 ◽

Cited By ~ 77

Author(s):

Sousuke Terazawa ◽

Mineo Kojima ◽

Tatsuru Yamanaka ◽

Shigeru Yotsumoto ◽

Hiroaki Okamoto ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Fulminant Hepatitis ◽

Hepatitis B E Antigen ◽

Precore Region ◽

B Virus

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Fulminant Hepatitis B Associated with a Specific Insertion in the Basal Core Promoter Region of Hepatitis B Virus DNA after Immunosuppressive Treatment

Clinical Infectious Diseases ◽

10.1086/427146 ◽

2005 ◽

Vol 40 (4) ◽

pp. e24-e27 ◽

Cited By ~ 17

Author(s):

R. Gerolami ◽

M. Henry ◽

P. Borentain ◽

P. Colson ◽

D. Botta ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Fulminant Hepatitis ◽

Promoter Region ◽

Core Promoter ◽

Immunosuppressive Treatment ◽

Basal Core Promoter ◽

Core Promoter Region ◽

B Virus ◽

Basal Core Promoter Region

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Genetic analysis ofprecore/coreand partialpolgenes in an unprecedented outbreak of fulminant hepatitis B in India

Epidemiology and Infection ◽

10.1017/s0950268812000349 ◽

2012 ◽

Vol 140 (10) ◽

pp. 1823-1829 ◽

Cited By ~ 3

Author(s):

S. KHARE ◽

S. S. NEGI ◽

S. SINGH ◽

M. SINGHAL ◽

S. KUMAR ◽

...

Keyword(s):

Hepatitis B ◽

Fulminant Hepatitis ◽

Stop Codon ◽

Core Promoter ◽

Sequence Similarity ◽

Genomic Analysis ◽

Core Gene ◽

Basal Core Promoter ◽

Rare Mutations ◽

Rapid Spread

SUMMARYWe investigated an unprecedented outbreak of fulminant hepatitis B virus (HBV) that occurred in Modasa, Gujarat (India) in 2009. Genomic analysis of all fulminant hepatic failure cases confirmed exclusive predominance of subgenotype D1. A1762T, G1764A basal core promoter (BCP) mutations, insertion of isoleucine after nt 1843, stop codon mutation G1896A, G1862T transversion plus seven other mutations in the core gene caused inhibition of HBeAg expression implicating them as circulatingprecore/BCP mutant virus. Two rare mutations at amino acids 89 (Ile→Ala) and 119 (Leu→Ser) in addition to other mutations in thepolymerase (pol)gene may have caused some alteration in either of fourpolgene domains to affect encapsidation of pregenomic RNA to enhance pathogenicity. Sequence similarity among patients' sequences suggested an involvement of a single hepatitis B mutant strain/source to corroborate the finding of gross and continued usage of HBV mutant-contaminated syringes/needles by a physician which resulted in this unprecedented outbreak of fulminant hepatitis B. The fulminant exacerbation of the disease might be attributed to mutations in the BCP/precore/coreandpolgenes that may have occurred due to selection pressure during rapid spread/mutation of the virus.

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Association of hepatitis B virus subgenotypes and basal core promoter/precore region variants with the clinical features of patients with acute hepatitis

Journal of Gastroenterology ◽

10.1007/s00535-008-2197-2 ◽

2008 ◽

Vol 43 (7) ◽

pp. 558-564 ◽

Cited By ~ 25

Author(s):

Kazuhiko Hayashi ◽

Yoshiaki Katano ◽

Yasushi Takeda ◽

Takashi Honda ◽

Masatoshi Ishigami ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Acute Hepatitis ◽

Clinical Features ◽

Core Promoter ◽

Basal Core Promoter ◽

Precore Region ◽

B Virus

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Biological features of hepatitis B virus strains associated with fulminant hepatitis

Future Virology ◽

10.2217/fvl-2020-0011 ◽

2020 ◽

Vol 15 (7) ◽

pp. 455-469

Author(s):

Ivana Lazarevic ◽

Ana Banko ◽

Danijela Miljanovic ◽

Maja Cupic

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Fulminant Hepatitis ◽

Core Promoter ◽

Clinical Manifestations ◽

Basal Core Promoter ◽

Biological Features ◽

B Virus ◽

Cytotoxic Proteins ◽

Virus Strains

Accumulating evidence suggests that hepatitis B virus (HBV) biological features may influence the course and clinical manifestations of infection and possibly the development of fulminant hepatitis (FH). Since HBV is not a cytocidal virus, virus-induced liver damage results from an interplay between the virus replication and the host's defense. Therefore, viral factors contributing to enhanced replication, induction of a stronger immune attack or apoptosis of hepatocytes could be crucial in development of FH. Numerous mutations in basal core promoter, pre-C, C and S regions of the HBV genome contribute to development of FH by different mechanisms, including enhanced viral replication, the loss of a decoy for immune response, unbalanced expression of viral proteins and retention of unprocessed cytotoxic proteins in hepatocytes.

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Low frequency of mutations in the X gene, core promoter and precore region of hepatitis B virus infected Vietnamese

Journal of Viral Hepatitis ◽

10.1111/j.1365-2893.2005.00560.x ◽

2005 ◽

Vol 12 (2) ◽

pp. 160-167 ◽

Cited By ~ 6

Author(s):

L. H. Song ◽

D. N. Duy ◽

V. Q. Binh ◽

A. J. F. Luty ◽

P. G. Kremsner ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Core Promoter ◽

Low Frequency ◽

Precore Region ◽

B Virus ◽

X Gene

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Molecular characterization of Hepatitis B virus basal core promoter and precore region of isolates from chronic Hepatitis B patients

Journal of the Pakistan Medical Association ◽

10.47391/jpma.1254 ◽

2021 ◽

pp. 1-18

Author(s):

Israr Ahmad ◽

Kafeel Ahmad

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Phylogenetic Tree ◽

Chronic Hepatitis B ◽

Stop Codon ◽

Core Promoter ◽

Direct Sequencing ◽

Basal Core Promoter ◽

Double Mutation ◽

Precore Region

Abstract Objective: The aim of this study was to analyze mutations in precore/core promoter region of HBV genome in chronic hepatitis B patients from three cities of Pakistan. Methods: A total of 50 treatment naïve chronic hepatitis B patients from Pakistan were selected. Viral load, HBeAg/antiHBe status, HBV ELISA and ALT levels were determined. Direct sequencing of BCP and PC region of HBV genome was carried out following a nested PCR approach. Phylogenetic tree was constructed using MEGA software version 6.0. Statistical analysis was carried out using SPSS version 16.0. Results: The G1896A precore stop codon mutation was detected in 19 (38%) isolates. The mutation was present in 17(34%) isolates from HBeAg negative patients and 2(4%) isolates from HBeAg positive patients. The Classic A1762T/G1764A double mutation was noted in 15 (30%) isolates. Mutation at position 1764 was observed in 12 (48%) samples. A rare G1764T mutation was also detected in 6 (12%) isolates. The CG1802-1803 mutation was detected in 47(94%) isolates. The T1858 mutation was detected in all 50 (100%) isolates. The GCAC Kozak sequence was present in 43(86%) isolates. The CAA1817-1819 mutation was observed in 49(98%) isolates and G1888 mutation was detected in 49(98%) isolates. Overall, 9(18%) isolates had wild-type sequences at all important loci including positions 1762,1764 and 1896. The pattern of sequences at genotype specific positions and phylogenetic tree revealed that majority of study isolates belonged to genotype D. Conclusions: Sequences results showed that precore region was comparatively more conserved than BCP region. Continuous...

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