Precore stop codon mutant in chronic hepatitis B virus infection in children: its relation to hepatitis B e seroconversion and maternal hepatitis B surface antigen

doi:10.1016/S0168-8278(98)80337-1

Journal of Hepatology

Volume 28, Issue 6, June 1998, Pages 915-922

https://doi.org/10.1016/S0168-8278(98)80337-1 Get rights and content

Abstract

Background/Aims: The aims of this study were to investigate the significance of the precore stop codon mutant in the natural course of hepatitis B virus infection in children, and the influence of maternal transmission.

Methods: Sequential sera from 80 hepatitis B virus carrier children both before and after e seroconversion during long-term follow-up were studied using the polymerase chain reaction-amplification created restriction site method. Direct sequencing of the precore region was performed in 89 sera from 32 of the 80 children.

Results: The precore stop codon mutant coexisting with wild strain was found in 10% of children initially, and later in 25% of children before e seroconversion. After e seroconversion, wild type was still present in 75% and mutant in 39% of children at the end of follow-up. The mutant alone was present in 15% of anti-HBe positive children without concomitant aminotransferase elevation. Children with earlier emergence of this mutant tended to have higher peak aminotransferase levels. This mutant emerged less frequently in children of hepatitis B virus carrier mothers (37.5%) than in those of non-carrier mothers (65%) (p<0.05).

Conclusions: These observations suggest that this mutant is selected by host immune pressure, but is not an initiator in the loss of immune tolerance during childhood chronic hepatitis B virus infection.

References (32)

F Bonino et al.
Hepatitis B virus heterogeneity, one of many factors influencing the severity of hepatitis B
J Hepatol
(1993)
W Carman et al.
Viral genetic variation: hepatitis B virus as a clinical example
Lancet
(1993)
WL Chuang et al.
Precore mutations and core clustering mutations in chronic hepatitis B virus infection
Gastroenterology
(1993)
F Bortolotti et al.
Selection of a precore mutant of hepatitis B virus and reactivation of chronic hepatitis B acquired in children
J Pediatr
(1993)
T Laskus et al.
Nucleotide sequence analysis of the precore region in patients with fulminant hepatitis B in the United States
Gastroenterology
(1993)
MA Loriot et al.
Low frequency of precore hepatitis B virus mutants in anti-hepatitis B e positive reactivation after loss of hepatitis B e antigen in patients with chronic hepatitis B
Hepatology
(1995)
SP Tong et al.
Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal
Virology
(1992)
M Lindh et al.
Hepatitis B virus carriers without precore mutations in hepatitis B e antigen-negative stage show more severe liver damage
Hepatology
(1996)
WR Carman et al.
Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B virus infection
Lancet
(1898)
WF Carman et al.
Precore sequence variation in Chinese isolates of hepatitis B virus
J Infect Dis
(1992)

M Yoshiba et al.

Reactivation of precore mutant hepatitis B virus leading to fulminant hepatic failure following cytotoxic treatment

Dig Dis Sci

(1992)

M Omata et al.

Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis

N Engl J Med

(1991)

TJ Liang et al.

Hepatitis B virus precore mutation and fulminant hepatitis in the United States: a polymerase chain reaction-based assay for the detection of specific mutation

J Clin Invest

(1994)

HY Hsu et al.

Precore mutant of hepatitis B virus in childhood fulminant hepatitis B: an infrequent association

J Infect Dis

(1995)

H Okamoto et al.

Hepatitis B virus with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen

J Virol

(1990)

K Hamasaki et al.

Changes in the prevalence of HBeAg-negative mutant hepatitis B virus during the course of chronic hepatitis B

Hepatology

(1994)

Cited by (48)

Virological Determinants of Spontaneous Postpartum e Antigen Seroconversion and Surface Antigen Seroclearance in Pregnant Women Infected with Hepatitis B Virus
2016, Archives of Medical Research
Citation Excerpt :
Although the threshold level in our study is different due to the different follow-up durations and different detection agents used in the studies, both studies show that quantitative determination of HBeAg may be used to predict HBeAg seroconversion. HBeAg seroconversion is a host immunologically mediated event in which the host immune system brings a pressure to HBV, forcing the virus to evolve into the immune escape mutant strain (34,37). The G1896A mutation, which diminishes or abolishes HBeAg synthesis, is the most commonly occurring pattern (38).
We investigated the virological factors predicting spontaneous postpartum hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) seroclearance in pregnant women infected with hepatitis B virus (HBV).
We invited 419 HBV infected women whose sera had been collected during their pregnancy from August 2002–July 2004 and archived at −30°C, to participate the follow-up in October 2009–March 2010. Various virological factors were determined and compared in women with or without the seroconversion and seroclearance.
A total of 264 (63.0%) antiviral naive women participated in the follow-up with an average observation period of 6.4 years (5.4–7.4). Of 76 women who were HBeAg positive during pregnancy, 42 (55.3%) seroconverted to anti-HBe during follow-up. Compared to pregnant women with HBV DNA ≥3 × 10⁷ IU/mL or HBeAg ≥770 S/CO, those with HBV DNA <3 × 10⁷ IU/mL or HBeAg <770 S/CO had higher conversion rate, with odds ratios (OR) of 7.32 (95% confidence interval [CI], 2.00–26.78) and 5.94 (95% CI, 1.40–25.16), respectively. Thirty eight (14.4%) women cleared HBsAg; pregnant women with HBsAg levels of 100–999 and <100 IU/mL had higher HBsAg seroclearance rate with OR of 2.58 (95% CI, 1.03–6.43) and 13.33 (95% CI, 5.07–35.07), respectively, compared to those with HBsAg >1000 IU/mL.
HBeAg-positive pregnant women with HBV DNA <3 × 10⁷ IU/mL or HBeAg <770 S/CO are more likely to undergo postpartum HBeAg seroconversion. HBsAg <100 IU/mL is a strong predictor of spontaneous postpartum HBsAg seroclearance.
Human interleukin-10 genotypes are associated with different precore/core gene mutation patterns in children with chronic hepatitis B virus infection
2011, Journal of Pediatrics
Citation Excerpt :
There was no difference between different IL-10 -1082 SNP carriers in the prevalence of G1896A, C1913A, and G2304A. HBV precore/core gene mutations during HBeAg seroconversion are known to be the result of host immune selection.7,13 Mutations in the precore/core gene may change the amino acid sequence, protein structure, antigenicity, and the biological function of both HBeAg and HBcAg.10-12,17
To elucidate the association between human interleukin-10 (IL-10) genotypes and hepatitis B virus (HBV) precore/core gene mutation in children with chronic HBV infection.
The study group comprised of 21 children with chronic HBV infection with spontaneous hepatitis B e antigen (HBeAg) seroconversion who were followed for more than 10 years. Another nine children without HBeAg seroconversion served as the control subjects. Sera at the immune tolerance and inflammatory phase (alanine aminotransferase, >80 IU/L) were subjected to HBV precore/core sequence analysis. IL-10 -1082 polymorphism was also determined.
HBV precore/core gene mutation increased significantly more in the inflammatory phase than in the tolerance phase (G1896A, 76.2% versus 4.8%; C1913A, 33.3% versus 0%; C2189A, 28.6% versus 4.8%; G2304A, 52.4% versus 14.3%) in study group (n = 21) but not the control group (n = 9). Subjects with the G/G genotype at the IL-10-1082 polymorphism site had higher C2189A mutation rate than the A allele carriers (P = .02). C2189A mutation carriers are associated with more viral load decrement from tolerance to inflammatory phase (P = .01) and earlier spontaneous HBeAg seroconversion (P = .01).
The G/G genotype at the IL-10 -1082 polymorphism is associated with higher C2189A mutations, lower HBV viral load at immune inflammatory phase, and earlier spontaneous HBeAg seroconversion than A allele carriers.
Reply
2007, Gastroenterology
Viremia Profiles in Children With Chronic Hepatitis B Virus Infection and Spontaneous e Antigen Seroconversion
2007, Gastroenterology
Citation Excerpt :
We need to continue monitoring these patients to see if they develop persistent liver damage later in life. The precore 1896 stop codon mutant is an important factor for persistent viral replication after HBeAg seroconversion, and may prevail in one half to two thirds of HBeAg-negative children and adults with chronic HBV infection in Taiwan.8,9,19 An abnormal ALT level after HBeAg seroconversion is associated with the emergence of the precore mutant in adults.20
Background & Aims: This study investigated the viremia profiles in children with chronic hepatitis B virus (HBV) infection and spontaneous hepatitis B e antigen (HBeAg) seroconversion. Methods: Fifty-eight children with chronic HBV infection met the following criteria: normal alanine aminotransferase (ALT) level at enrollment, followed up for more than 10 years, no antiviral treatment, and having undergone spontaneous HBeAg seroconversion during follow-up evaluation. They were grouped according to the post-HBeAg seroconversion HBV-DNA levels: (1) low viremia: transient or never 10⁴ copies/mL or greater (n = 35) (2) fluctuating high viremia: 10⁴ copies/mL or greater at least twice at intervals more than 1 year apart (n = 23). Abdominal sonography, ALT, and HBV-DNA levels were assessed annually. Another 14 nonseroconverted children served as controls. The precore mutant (nt1896) and genotypes were examined. Results: The initial HBV-DNA level of the 58 seroconverters was 10^8.4±1.0 copies/mL and decreased to 10^2.9±2.0 copies/mL at the end of follow-up period. Their mean ages at enrollment, at peak HBV-DNA, at peak ALT, at HBeAg seroconversion, and at final follow-up were 7.0 ± 3.7, 13.4 ± 5.8, 16.3 ± 6.0, 17.2 ± 5.8, and 23.7 ± 4.1 years, respectively. The precore mutant appeared more often in the fluctuating-high-viremia group than in the low-viremia group (60.9% vs 22.9%, P = .004). HBV genotypes had no effect on the viremia profiles. After HBeAg seroconversion, none had persistent abnormal ALT levels. Conclusions: Generally, these young seroconverters had decreased viral loads, normal ALT levels, and uneventful courses after HBeAg seroconversion. A longer follow-up period is necessary to elucidate the significance of HBeAg seroconversion occurring in childhood and young adulthood.
Impact of hepatitis B vaccination on hepatitis B disease and nucleic acid testing in high-prevalence populations
2006, Journal of Clinical Virology
Hepatitis B virus (HBV) infection is highly prevalent in Asia, Africa, southern Europe and Latin America, HBV vaccination has effectively reduced the acute and chronic infection rates as well as related complications in the vaccinated children. The incidence of hepatocellular carcinoma in children has been reduced to approximately 25% of the incidence before the vaccination program, and fulminant hepatitis in children has also been reduced after universal hepatitis B vaccination. HBV DNA sero-positive rate was 98–100% in HBsAg positive vaccinated children, while the positive rate was only 11–20% in those vaccinees with a negative HBsAg but positive anti-HBc reaction. Hepatitis B surface gene mutants in HBV DNA positive children increased gradually from 7.8% before the vaccination program, to 19.6%, 28.1% and 23.1% at 5, 10 and 15 years after the vaccination program.
Long-term follow-up of vaccinated children has confirmed that universal HBV vaccination in infancy has produced adequate protection up to 14 years of age. The annual decay rate of hepatitis B surface antibody (anti-HBs) was 10.2% in children who did not receive a booster dose. The new HBV infection rate was not different between those who did and those who did not receive a booster dose of HBV vaccine.
During a follow-up period of seven years for 1200 vaccinated 7-year-old children in Taiwan, the mean annual hepatitis B core antibody sero-conversion rate was 0.2%. All were negative for HBV DNA. No new chronic HBV infections developed. A booster dose of HBV vaccine is not recommended in children under 15 years of age.
Systematic HBV DNA screening of a large population such as blood donors may be instrumental in following the long-term effect of the universal vaccination program on the incidence of silent HBV infection and vaccine escape mutants.
Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma
2004, Gastroenterology
Background & Aims: The aim of this study was to investigate the influence of hepatitis B virus (HBV) genotypes on the clinical outcome of chronic childhood HBV infection and hepatocellular carcinoma (HCC). Methods: A total of 460 HBV carrier children were followed-up for 15 years and 26 children with HBV-related HCC were recruited. HBV genotyping was examined at enrollment and the latest follow-up of these carrier children and at diagnosis in HCC children. Viral load was checked at enrollment for the carrier children. These carriers were grouped based on their initial hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) status. The HBeAg positive (+) group was divided further into an HBeAg(+/+) group and HBeAg(+/−) group, depending on whether spontaneous HBeAg seroconversion occurred during the follow-up period. Results: Genotype B constituted 73%, 86%, and 76% in the HBeAg(+/+), HBeAg(+/−), and anti-HBe(+) groups, respectively. Genotype C was found in 27%, 8%, and 6% in the HBeAg(+/+), HBeAg(+/−), and anti-HBe(+) group, respectively. Genotype C carriers were more prevalent in the HBeAg(+/+) group than the other 2 groups (P = .01), and had a delayed HBeAg seroconversion compared with the genotype B carriers (P < .001). Changes of genotype during the follow-up period were rare (2.8%). In those with HCC, genotype B was also the major type (74%). There was no difference in the baseline viral load between genotypes B and C. Conclusions: Although HBV genotype B dominates in children with chronic HBV infection and HCC in Taiwan, genotype C delays HBeAg seroconversion in pediatric chronic HBV infection.

View all citing articles on Scopus

View full text

Precore stop codon mutant in chronic hepatitis B virus infection in children: its relation to hepatitis B e seroconversion and maternal hepatitis B surface antigen

Abstract

J Hepatol

Lancet

Gastroenterology

J Pediatr

Gastroenterology

Hepatology

Virology

Hepatology

Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B virus infection

Lancet

Precore sequence variation in Chinese isolates of hepatitis B virus

J Infect Dis

Reactivation of precore mutant hepatitis B virus leading to fulminant hepatic failure following cytotoxic treatment

Dig Dis Sci

Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis

N Engl J Med

Hepatitis B virus precore mutation and fulminant hepatitis in the United States: a polymerase chain reaction-based assay for the detection of specific mutation

J Clin Invest

Precore mutant of hepatitis B virus in childhood fulminant hepatitis B: an infrequent association

J Infect Dis

Hepatitis B virus with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen

J Virol

Changes in the prevalence of HBeAg-negative mutant hepatitis B virus during the course of chronic hepatitis B

Hepatology