Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in taiwan

Hsu, Hong–Yuan; Liaw, Shwu-Jen; Ni, Yen‐Hsuan; Chen, Huey‐Ling

doi:10.1002/hep.510300511

Cited by 246 publications

(175 citation statements)

References 36 publications

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“…1,36 This program provides protection to virtually the entire population born each year, successfully reducing hepatitis B prevalence as reported in several countries. [37][38][39] However, it would take about 15-20 years to obtain whole community protection using this strategy alone. 40,41 Adolescents and young adults who were born before the initiation of universal infant immunization program would remain susceptible to HBV infection; many might even have acquired the disease in early childhood and are at risk of developing advanced chronic diseases later in their life.…”

Section: Discussionmentioning

confidence: 99%

High Prevalence of Hepatitis B Virus Infection in Young Adults in Ternate, Eastern Indonesia

Ie¹,

Turyadi²,

Sidarta³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. The incidence of hepatitis B virus (HBV) infection has been declining thanks to the universal hepatitis B infant immunization program. Nevertheless, young adults born before the program implementation might have acquired HBV in early childhood or remain susceptible to infection. This study aimed to evaluate hepatitis B epidemiology in asymptomatic young adult population in Ternate, eastern Indonesia. Serum samples of 376 subjects (aged 17-25, mean 19.82 ± 1.69 years; male/female 138/238) were screened for HBV parameters serologically (HBV surface antigen [HBsAg]; its antibody [anti-HBs]; anti-core antigen [anti-HBc]), and molecularly (HBV DNA). HBsAg, anti-HBc, anti-HBs, and HBV DNA prevalence were 15.7%, 36.2%, 24.2%, and 27.9%, respectively, with male predominance. Of all subjects, 13.0% were HBsAg negative with detectable HBV DNA (occult hepatitis B [OHB]), and 56.4% showed negativity for all seromarkers. This population showed high hepatitis B prevalence with substantial occurrence of OHB. However, a high percentage of the population were still susceptible and at risk of HBV infection. This study emphasizes the necessity to improve prevention strategies to screen and manage HBV carriers, including the adoption of catch-up or booster vaccination targeted to young adult populations. Investigations on the roles of host-virus interactions associated with OHB and its implications are warranted.

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Section: Discussionmentioning

confidence: 99%

High Prevalence of Hepatitis B Virus Infection in Young Adults in Ternate, Eastern Indonesia

Ie¹,

Turyadi²,

Sidarta³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…The clinically relevant S-escape, precore stop codon, and BCP mutations all consist of G-A mismatches. [24][25][26][27][28][29] However, Tm shifts can also occur as a result of natural polymorphisms within the probe hybridization region of different HBV genotypes. Thus, according to the principle involved, the mismatches associated with natural polymorphism would result in larger Tm shifts than the single base-pair mismatches associated with the identified mutant, thereby allowing the mutant to be further distinguished from the wild-type virus.…”

Section: Discussionmentioning

confidence: 99%

Rapid detection of hepatitis B virus mutations using real-time PCR and melting curve analysis

2002

Hepatology

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Current methods of detecting hepatitis B virus (HBV) mutations are time consuming, labor intensive, and not suitable for screening large numbers of samples. In the present study, we documented the advantages of a system that exploits differences in thermal stability between perfect match and mismatch hybrids, and thereby distinguishes between wild-type and mutants. Hybridization probes were designed complementary to specific wild-type HBV sequences in surface (S), precore, and basal core promoter (BCP) regions of the HBV genome (nt 587, 1896, and 1762/1764, respectively). Two probes were designed for each mutation: anchor probes were 3 labeled with fluorescein and sensor probes, 5 labeled with LC-Red 640, and 3 phosphorylated. Temperatures for each probe melted from amplification products were then determined in a melting program. Sera from 12 patients, each containing identified HBV mutants (6 S-escape, 1 precore, 1 BCP, and 4 mixed precore and BCP), and 5 control sera from patients with wild-type virus were analyzed. Genomic sequences of mutant and wild-type viruses were confirmed by direct sequencing. Real-time polymerase chain reaction (PCR) with fluorescent hybridization probes accurately identified each mutant and wild-type genome. Melting temperatures obtained from probe-product duplexes for the 3 mutants were distinguished from wild-type (>4.0°C, minimal) within 45 minutes. The sensitivity of the system was 100 copies/mL and as few as 5% of mutant among wild-type virus were detected. In conclusion, real-time PCR with fluorescent hybridization probes is a specific, sensitive, quantitative, and rapid means of detecting clinically relevant HBV mutants. (HEPATOLOGY 2002;36:723-728.) T he hepatitis B virus (HBV) is one of the most common infectious agents in humans and a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. [1][2][3] It is a partially double-stranded DNA molecule virus that replicates through an RNA intermediate by reverse transcription. 4,5 The reverse transcriptase enzyme responsible for this aspect of the replication cycle lacks proofreading function and, therefore, mutations to the genome are common. Indeed, it is now recognized that the majority of chronic HBV infections are associated with emergence of mutations throughout the viral genome. Some of these mutations result in the generation of diverse viral populations and different clinical outcomes. Those in the surface, core, precore, and basal core promoter (BCP) regions appear to have the greatest clinical relevance. 6,7 Additional mutations have also been described after therapeutic interventions such as antiviral therapy and vaccination. 8,9 Thus, the ability to detect these mutants is essential to further our understanding of the natural history of HBV and its response to antiviral therapy and immunoprophylaxis.Presently, the detection of HBV mutants is largely performed by restriction fragment length polymorphism analysis, 10,11 gap ligase chain reaction assay and/or direct sequencing. 12,13 These methods ...

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“…[2][3][4] The mutant by far most frequently detected all over the world in vaccinated individuals and liver transplant recipients treated with monoclonal or polyclonal anti-hepatitis B surface antigen (HBsAg) hyperimmunoglobulin carries a glycine to arginine substitution at amino acid position 145 (G145R). 3,[5][6][7][8][9][10][11] There is no doubt that despite selection of immuneescape variants, vaccination programs have so far been highly effective in reducing the incidence of de novo HBV infections. [12][13][14] However, in the future the prevalence of the G145R variant certainly will increase with global application of vaccination programs.…”

mentioning

confidence: 99%

“…In Taiwan, for example, a country with a vaccination program for children since 1984, the prevalence of a-determinant mutants in HBV-DNA-positive children increased from 7.8% in 1984 to 28.1% in 1994. 7 Notably, several cases of G145R mutant infections are not routinely diagnosed because mutant HBsAg may escape detection by some conventional HBsAg screening tests. 15,16 Despite future development of better diagnostic tests and further improvement of commercially available vaccines, concern remains that the growing selection pressure may allow the G145R variant to reach an even comparable prevalence as Wt virus in the world population.…”

mentioning

confidence: 99%

Deficiency in Virion Secretion and Decreased Stability of the Hepatitis B Virus Immune Escape Mutant G145r

et al. 2003

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Hepatitis B virus with a G145R mutation in the small surface protein is considered the quintessential immune escape mutant because it frequently is found in vaccinated individuals with breakthrough infections and liver transplant recipients under anti-hepatitis B surface antigen (HBsAg) immunoglobulin prophylaxis. Nowadays the prevalence of the variant progressively increases. However, because spread of a virus depends not only on immune pressure but also on the viral phenotype, we investigated the biologic properties of the G145R variant. The G145R mutation was introduced into wild-type (Wt) virus genome by in vitro mutagenesis. After transfection into human hepatoma cells, the DNA, RNA, and protein synthesis and viral secretion ability of the mutant were studied. Furthermore, cotransfection studies were performed with the G145R variant and a Wt virus S-protein expressing construct and vice versa. Production and stability of viral messenger RNAs (mRNAs), DNA, and proteins were not affected by the G145R mutation. In contrast, secretion of mutant virions was reduced significantly. Only 20% of virions were found in the medium of G145R variant-transfected cells compared with Wt virus. Furthermore, mutant virions were more sensitive to detergent treatment suggesting a diminished stability. In cotransfection studies, Wt virus S-protein rescued secretion of mutant virions, whereas mutant S-protein had a transdominant negative effect on secretion of Wt virus. Both mechanisms may support persistence of the defective mutant in a mixed population with Wt virus. In conclusion, the significant defect of the G145R mutant for secretion of infectious virions and the diminished stability of mutant virions may limit global spread of the mutant. H epatitis B virus (HBV) exhibits a mutation rate more than 4 orders of magnitude higher than that of other DNA viruses. 1 Naturally occurring variants may accumulate over time if they have a survival benefit over wild-type (Wt) virus, such as a higher ability to replicate DNA, an enhanced secretion ability, an increased infectivity or stability of virions, and so forth. In addition, certain variants may be selected under immune pressure or therapy with antiviral drugs.Nowadays, immune-escape variants that emerge under active and/or passive vaccination and are responsible for vaccination-breakthrough infections are of particular clinical relevance. Several such mutants carrying single or multiple amino acid substitutions in the major antigenic region of the virus, the a-determinant of the small surface protein, have been described. [2][3][4] The mutant by far most frequently detected all over the world in vaccinated individuals and liver transplant recipients treated with monoclonal or polyclonal anti-hepatitis B surface antigen (HBsAg) hyperimmunoglobulin carries a glycine to arginine substitution at amino acid position 145 (G145R). 3,[5][6][7][8][9][10][11] There is no doubt that despite selection of immuneescape variants, vaccination programs have so far been highly effective in reduci...

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Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in taiwan

Cited by 246 publications

References 36 publications

High Prevalence of Hepatitis B Virus Infection in Young Adults in Ternate, Eastern Indonesia

High Prevalence of Hepatitis B Virus Infection in Young Adults in Ternate, Eastern Indonesia

Rapid detection of hepatitis B virus mutations using real-time PCR and melting curve analysis

Deficiency in Virion Secretion and Decreased Stability of the Hepatitis B Virus Immune Escape Mutant G145r

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