Recent updates in hepatitis vaccination and the prevention of hepatocellular carcinoma.
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Carcinoma, Hepatocellular↗
Biomedical subjects
Ding-Shinn Chen
Publications and source records attributed to Ding-Shinn Chen.
Prevalence and implication of a newly identified infectious agent (SEN virus) in Taiwan.
To investigate the prevalence and clinical relevance of a recently identified SEN virus (SENV) in Taiwan, 2 SENV variants (SENV-D and SENV-H) were studied in high-risk persons, patients with liver disease, and healthy adults. SENV-D and/or SENV-H (SENV-D/H) infections were more frequent in high-risk groups (54%-90%) and in patients with chronic hepatitis B (41%), hepatitis B-related hepatocellular carcinoma (HCC) (54%), chronic hepatitis C (67%), and hepatitis C-related HCC (76%) than in healthy adults (15%). The prevalence of SENV-D/H infection was comparable between patients with non-A to E fulminant hepatitis (30%) and healthy adults. Most subjects with SENV-D/H infection alone had no or mild hepatitis, and coinfection of SENV-D/H with chronic hepatitis B or C was not associated with increased evidence of liver disease and the risk of HCC. These results suggest that SENV-D/H infection is common in high-risk groups in Taiwan but that SENV-D/H infection is not associated with hepatitis.
DNA Virus Infections↗
Naturally occurring hepatitis B surface gene variants in chronic hepatitis B virus infection: correlation with viral serotypes and clinical stages of liver disease.
Virus variants escaping from host immunity may be implicated in the pathogenesis of hepatitis B virus (HBV) infection. In this cross-sectional study, the association was evaluated of the frequency of amino acid variation within the immunogenic epitopes of surface gene with different disease stages of chronic HBV infection. The surface gene of HBV encompassing the a determinant (amino acids 124-148) and the putative HLA class I restricted cytotoxic T lymphocyte (CTL) epitope (amino acids 28- 51) were amplified and directly sequenced in 33 asymptomatic carriers (Group I), 31 patients with chronic hepatitis (Group II), 22 with cirrhosis (Group III), and 36 with hepatocellular carcinoma (Group IV). The amino acid sequences were compared subsequently with the consensus sequences of HBV serotype adw or adr. The frequency of amino acid variation per site per sequence (FEQ) was analyzed by generalized estimating equation with Poisson model after stratification by clinical and virological features. The FEQ was 1.21% overall, and was highest in Group IV patients and in patients above 50 years of age. In contrast, nine Group IV patients aged below 50 years who were infected with serotype adw had an inversely higher FEQ than those above 50; the age effect among hepatocellular carcinoma patients was significantly different from that among non-cancerous patients (P = 0.04). Variation of amino acid clustered within a determinant and CTL epitope for serotype adw but was distributed at random for serotype adr. Mutation hotspots differed between serotypes adw and adr. The FEQ of HBV surface protein is correlated positively with advancing age and severity of liver disease, and certain variants may contribute to the persistence of HBV infection.
Adult↗
Sequence analysis of pre-S/surface and pre-core/core promoter genes of hepatitis B virus in chronic hepatitis C patients with occult HBV infection.
Although occult hepatitis B virus (HBV) infection in individuals without detectable hepatitis B surface antigen (HBsAg) may occur and has been reported to be common in patients with chronic hepatitis C, the related molecular mechanisms remain unknown. With the polymerase chain reaction, serum HBV DNA was sought in 100 HBsAg-negative patients with chronic hepatitis C virus (HCV)-infection. In those with occult HBV infection, possible genomic variability of HBV was evaluated by amplification and direct sequencing of pre-S, surface, and pre-core/core promoter genes. In total, 10 of the 100 patients (10%) had detectable serum HBV DNA, documenting an occult HBV infection. A deletion mutant in the pre-S gene was found in one patient and mutations of the a determinant of HBsAg were observed in 2. In addition, a novel core promoter mutant (a dinucleotide substitution: T-to-C at nucleotide 1,802 and T-to-G at nucleotide 1,803, T1802C/T1803G) was found frequently in patients with occult HBV infection as compared to sex- and age-matched HBsAg-positive patients (80 vs. 10%, P < 0.001). In conclusion, the data suggest occult HBV infection is not uncommon in chronic hepatitis C patients in Taiwan, and a novel core promoter mutant may be associated with the absence of circulating HBsAg in these patients.
Adult↗
Early acquisition of TT virus in infants: possible minor role of maternal transmission.
This study assessed the prevalence of TT virus (TTV) viremia in pregnant women and evaluated the role of maternal transmission in early acquisition of TTV in infants in Taiwan. Two groups of pregnant women were screened for TTV using polymerase chain reaction. The first group included 135 healthy pregnant women attending the obstetrics department for routine prenatal care and the second group from 25 GB virus-C/hepatitis G virus (GBV-C/HGV)-infected mothers. In both groups, when TTV infection was found in mothers, serial serum samples were collected for the infants at regular intervals until 1 year of age and were tested for TTV DNA. The results showed that 40% (54/135) of the women undergoing routine prenatal care and 56% (14/25) of GBV-C/HGV-infected pregnant women were positive for TTV DNA (P = 0.137). Of the 54 TTV-infected mothers in the routine prenatal group, 29 and their 30 infants received regular follow-up. The positive rate of TTV DNA in infants was 40% (12/30) in the routine prenatal group and 29% (4/14) in the group with GBV-C/HGV-infected mothers (P = 0.463). All but 2 of the 16 TTV-infected infants had normal serum alanine aminotransferase levels during follow-up. The phylogenetic analysis in 7 mother-infant pairs showed that the homology was diverse in each pair and a close genetic relatedness was found in 2 mother-infant pairs. In conclusion, TTV viremia is common in pregnant Taiwanese women and their infants. However, the results suggest that maternal transmission may play only a minor role in early acquisition of TTV in infants.
DNA Virus Infections↗
Co-delivery of GM-CSF gene enhances the immune responses of hepatitis C viral core protein-expressing DNA vaccine: role of dendritic cells.
Hepatitis C virus (HCV) infection has become a critical public health problem worldwide. In Taiwan, it has been estimated that more than 300,000 people, 2% of the general population, have HCV infection. It has been well documented that direct delivery of gene intramuscularly can generate both humoral and cellular immunity, which more closely simulates the conditions of infection. In this study, female Balb/c mice immunized with HCV core plasmid DNA with or without adjuvant GM-CSF cytokine gene could induce both cellular immune response and HCV core-specific antibody titers after injection. Furthermore, the mice immunized with HCV core plus GM-CSF genes showed higher antibody titer and cytotoxic T cell activity compared to those of mice immunized with HCV core gene only (P < 0.05). To explore the effect of GM-CSF gene, the mice were immunized with reporter gene and cytokine gene plasmid. Increased levels of reporter protein and infiltrating cells around muscle tissue were noted. Moreover, the protein could be detected in inguinal node 24 hr after injection, especially in mice immunized with HCV/core plasmid plus GM-CSF gene. It was also observed that reporter protein expressing CD11c(+) dendritic cells could be seen in the inguinal node. These data suggest that the GM-CSF gene did enhance HCV core specific immune response when co-immunized with HCV core DNA plasmid. Although more studies are needed, dendritic cells that appeared around the naked DNA injection area and that local lymph nodes might play a critical role in the immune response induced by naked DNA immunization.
Animals↗
Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B.
BACKGROUND: Mutations in the precore stop codon (G1896A) and the basal core promoter (A1762T and G1764A) are frequently found in hepatitis B envelope antigen (HBeAg)-negative chronic hepatitis B. However, the clinical significance of these mutations remains controversial. We therefore investigated the influence of hepatitis B virus (HBV) genotypes, as well as precore/basal core promoter mutants, on the clinical and virological features of patients with HBeAg-negative chronic hepatitis B. METHODS: Serum samples from 37 patients with HBeAg-negative chronic hepatitis B were collected for serological and molecular assays. The precore and basal core promoter regions were amplified by polymerase chain reaction and the amplicons were directly sequenced and analyzed. HBV genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Most of the patients had detectable serum HBV DNA, and genotypes B and C were the predominant strains. The overall prevalence of the precore stop codon mutant and basal core promoter mutant was 67% and 60%, respectively. The baseline clinical and virological features of patients with genotype B and genotype C infection were comparable. However, in the patients with precore/basal core promoter dual mutations there was a significantly lower proportion of individuals with a high detectable serum HBV DNA level (>100pg/ml) than in the patients with either the precore stop codon mutation alone or the basal core promoter mutation alone (P = 0.04 by the logistic regression test for the trend). CONCLUSIONS: Our data suggest a high prevalence of precore stop codon and basal core promoter mutation in Taiwanese patients with HBeAg-negative chronic hepatitis B, and the influence of the basal core promoter mutation on HBV replication is modulated by the emergence of the precore stop codon mutation.
Adolescent↗
Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B.
BACKGROUND: We carried out a study to predict the prognosis of acute hepatic failure in patients with chronic hepatitis B. METHODS: We studied 25 consecutive patients with severe acute hepatitis. Severe acute hepatitis was defined as the development of acute hepatitis with a total serum bilirubin level of more than 15 mg/dl, prolonged prothrombin time (PT) of more than 5 s, and hepatic encephalopathy (HE). All patients were assessed for King's criteria. Positivity for King's criteria was defined as PT more than 100 s, or any three of the following: (age < 10 years or >40 years; cryptogenic or drug-induced hepatitis; jaundice for more than 7 days before the onset of HE; PT > 50 s; and serum bilirubin > 17.5 mg/dl). All but 1 patient had serial serum alpha-fetoprotein (AFP) levels measured every 1-2 weeks. RESULTS: Eleven of 17 patients who died during the study met the King's criteria, whereas none of the surviving patients met the criteria. The sensitivity was 64.7% and the specificity, 100% for King's criteria in predicting a poor prognosis. In 16 of the 17 deceased patients, the AFP levels were reduced while their jaundice increased (sensitivity, 94.1%; specificity, 87.5%). All 17 deceased patients met the King's criteria and/or had reduced AFP levels while their jaundice increased (sensitivity, 100%; specificity, 87.5%). CONCLUSIONS: Our observations suggest that the combined use of follow-up AFP levels and King's criteria is helpful in predicting the poor prognosis of severe acute hepatitis superimposed on chronic hepatitis B.
Acute Disease↗
Hepatitis B viral genotypes and lamivudine resistance.
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Adult↗
Global control of hepatitis B virus infection.
Worldwide about 350 million people are chronic carriers of the hepatitis B virus (HBV). The infection can cause acute and chronic liver disease including cirrhosis and hepatocellular carcinoma (HCC). Hepatocellular injuries of HBV infection are predominantly immune-mediated, and the natural history of chronic infection can be divided into three phases based on virus-host interactions-namely, immune tolerance, immune clearance, and viral integration phases. Four serotypes (adw, ayw, adr, and ayr) and seven genotypes (A to G) of HBV have been identified, and they show some distinct geographic distributions. The HBV genotypes may have clinical relevance and are currently under investigation. On the basis of disease burden and the availability of safe and effective vaccines, the WHO recommended that by the end of the 20th century hepatitis B vaccine be incorporated into routine infant and childhood immunisation programmes for all countries. The efficacy of universal immunisation has been shown in different countries, with striking reductions of the prevalence of HBV carriage in children. Most important, hepatitis B vaccination can protect children against HCC and fulminant hepatitis, as has been shown in Taiwan. Nevertheless, the implementation of worldwide vaccination against HBV requires greater effort to overcome the social and economic hurdles. Safe and effective antiviral treatments are available but are still far from ideal, a situation that, hopefully, will be improved soon. With hepatitis B immunisation, the global control of HBV infection is possible by the end of the first half of 21st century.
Carrier State↗
Eight-year nationwide survival analysis in relatives of patients with hepatocellular carcinoma: role of viral infection.
BACKGROUND: Families of patients with hepatocellular carcinoma (HCC) carry a high risk of developing HCC. We determine the number of fatalities in relatives of HCC patients during an 8-year period to understand the risk and cause of HCC in relatives of patients with HCC. METHODS: From 1992 to 1997, 15 410 relatives of HCC patients in three generations were screened prospectively for HCC by ultrasonography, alpha-fetoprotein, liver biochemistry and viral markers. By using national citizen identification numbers, we searched the total fatalities in relatives of HCC patients between 1992 and 1999 from the national mortality data bank. The results were compared among different viral infection groups. RESULTS: Of the relatives studied, 37.8% were hepatitis B s antigen (HBsAg) positive (+), 4.3% were anti-hepatitis C virus (HCV) (+) and 1.7% were both HBsAg (+) and anti-HCV (+). A total of 399 fatalities, including 139 because of HCC (34.8%), 37 because of liver diseases (9.3%), 88 because of other cancers (22.1%) and 135 because of other diseases (33.8%), were found. Relatives who were HBsAg (+) or anti-HCV (+)showed a lower cumulative survival than did relatives who were negative for both HBsAg and anti-HCV. Relatives with dual infection of hepatitis B and C virus showed the highest mortality due to HCC or terminal liver diseases. CONCLUSIONS: Chronic viral infection rather than a hereditary factor is the main cause of a familial tendency for HCC. Dual infection of hepatitis B and C virus increases the risk of HCC or decompensated liver diseases.
Adult↗
Transfusion-transmitted HBV infection in an endemic area: the necessity of more sensitive screening for HBV carriers.
BACKGROUND: By NAT, HBV DNA is occasionally detectable in blood donors with past HBV infection but negative for HBsAg. Whether or not these donors can cause transfusion-transmitted HBV infections is uncertain. STUDY DESIGN AND METHODS: To determine whether or not donors with past HBV infection but negative for HbsAg can cause HBV transfusion-transmitted infections, recipients followed for blood transfusion in a university medical center in Taiwan were studied. HBV DNA and serologic markers were tested in donors and recipients. RESULTS: Of 1,038 enrolled recipients, 910 completed the 6-month post-transfusion follow-up visit. Of these, only 39 patients (4.3%) tested negative on the pretransfusion sample for HBsAg, anti-HBs, anti-HBc, and HBV DNA by PCR. These 39 HBV-naive recipients had been transfused with blood from 147 donations for which stored samples were available for HBV DNA testing by PCR; 11 of these HBsAg-negative samples tested positive for HBV DNA and anti-HBc. Two of the 11 patients who received the HBV-DNA-positive donations (18%) became positive for HBV DNA, and one seroconverted to anti-HBc and finally to anti-HBs, with a mild transient elevation of serum ALT activities. Based on the one confirmed case of HBV transmission, a projection was made that approximately 200 post-transfusion HBV infections could occur in one million units of transfused blood in Taiwan. CONCLUSIONS: In HBV-endemic areas like Taiwan, where blood donors are screened for HBsAg only, the risk of transfusion-transmitted HBV appears to be substantial. Implementation of NAT for blood screening in these settings warrants consideration.
Antibodies, Viral↗
Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: multistage hepatocarcinogenesis with multifactorial etiology.
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Carcinogens↗
Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: A pilot study.
Interferon alfa (IFN-alpha) therapy remains a mainstay of treatment in active hepatitis B. However, sustained remission rates remain relatively low, and the search for factors important for response to therapy continues. Our study aimed to identify the host single nucleotide polymorphisms (SNPs) that predict IFN response in hepatitis B patients. We selected genes in the IFN pathway involved in antiviral and signaling activities and sequenced 22 SNPs for each of our 82 patients. Our results identified 2 SNPs in the antiviral pathway that may influence IFN response. One SNP in the regulatory region of the eIF-2alpha gene revealed A/G alleles. The rate of A/G heterozygotes is 22% in nonresponders (NR) and 2% in sustained responders (R), with an odds ratio (OR) of 12.82 (95% CI: 1.52-107.85, P =.009). After adjustment for age, sex, and HBV DNA level, the OR reaches 14.94 (95% CI: 1.45-153.71, P =.023). This marker revealed greater significance than HBV DNA levels (OR: 5, 95% CI: 1.01-2.43, P =.033) as a marker for IFN response, suggesting its potential advantage over conventional predictors. In addition, borderline significance for the SNP in MxA gene promoter at nt -88 revealed G/T alleles, with the G/T heterozygote rate being 19% in nonresponders and 43% in sustained R (P =.061), concurring with a previous study involving hepatitis C patients. In conclusion, this pilot identified SNPs as potential markers that could predict hepatitis B patient response. These observations may help guide future large-scale studies in examining host SNPs for their clinical utility in predicting IFN response.
Adult↗
Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C.
Pathogenic and therapeutic differences among hepatitis B virus (HBV) genotypes have been documented. However, the association of virological characteristics with clinical differences among HBV genotypes remains unclear. We therefore studied the clinical and virological characteristics of Taiwanese volunteer blood donors infected with HBV genotypes B and C. HBV genotypes were determined in 300 candidate blood donors positive for HBV surface antigen (HBsAg), and sequences of the precore gene of the HBV genome were determined in 50 HBV e antigen (HBeAg)-positive and 50 HBeAg-negative blood donors. Of 300 HBsAg-positive blood donors, 10% had elevated serum aminotransferase levels and 27% were positive for HBeAg. HBV genotype distribution in 264 viremic carriers was as follows: B, 221 (83.7%); C, 39 (14.8%); F, 1 (0.4%); and mixed infection, 3 (1.1%). Blood donors with genotype C infection tended to have a higher frequency of HBeAg positivity and a higher serum HBV DNA level than those with genotype B infection. The frequency of precore stop codon mutation was significantly higher in HBeAg-negative blood donors than HBeAg-positive ones, irrespective of HBV genotypes. Meanwhile, only 5% of blood donors with genotype C infection had C-1858 strains. In conclusion, mixed infection of HBV genotypes indeed occurs, and genotype C has a higher serum HBV DNA level than genotype B. Precore stop codon mutation is common in HBeAg-negative HBV carriers, irrespective of HBV genotypes. In contrast, precore C-1858 strains are rarely identified in Taiwanese HBV genotype C.
Adult↗
Occult hepatitis B virus infection and clinical outcomes of patients with chronic hepatitis C.
Although occult hepatitis B virus (HBV) infections in individuals without detectable hepatitis B surface antigen (HBsAg) may occur and have been reported to be common in patients with chronic hepatitis C, the clinical relevance remains controversial. We searched for serum HBV DNA in 210 HBsAg-negative patients with hepatitis C virus (HCV)-related liver disease (110 patients with chronic hepatitis, 50 patients with cirrhosis, and 50 patients with hepatocellular carcinoma) by PCR. Most of the patients had detectable antibodies to HBsAg or HBV core antigen. All of the 110 chronic hepatitis C patients were treated with a combination therapy consisting of interferon plus ribavirin. In addition, 100 HBsAg-negative healthy adults served as controls. Thirty-one of the 210 patients (14.8%) had HBV DNA in their sera, as did 15 of the 100 healthy controls (15%). HBV DNA was not detected in the sera of those negative for serological markers of HBV infection. In patients with chronic HCV infection, the prevalence of occult HBV infection did not parallel the severity of liver disease (14.5% in patients with chronic hepatitis, 8% in patients with liver cirrhosis, and 22% in patients with hepatocellular carcinoma). In addition, the sustained response to combination therapy against hepatitis C was comparable between patients with and without occult HBV infection (38 versus 39%). In conclusion, these data suggest that occult HBV infection does not have clinical significance in chronic hepatitis C patients residing in areas where HBV infection is endemic.
Adult↗
Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection.
Genotype C of hepatitis B virus (HBV) has been shown to be associated with a poor clinical outcome, compared to genotype B. To explore the clinical phenotypes, with special reference to the seroconversion of hepatitis B e antigen (HBeAg) and frequency of acute exacerbation between patients infected with HBV genotypes B and C, a cohort of 272 Taiwanese patients with chronic HBV infection was analyzed. According to the status of HBeAg at enrollment and frequency of acute exacerbation during the follow-up period, five groups of patients with distinct clinical phenotypes were categorized. Of the 272 HBV carriers, 185 (68%) were infected with HBV genotype B and the remaining 87 (32%) were infected with genotype C. Among them, 150 (55%) were positive for HBeAg and patients with genotype C infection tended to have a higher positive rate of HBeAg than those with genotype B infection (63 versus 51%). Genotype B was more prevalent than genotype C in different groups of HBV carriers. However, the prevalence of genotype C in patients with multiple episodes of acute exacerbation who failed to have HBeAg seroconversion was significantly higher than in all 272 patients (50 versus 32%, P = 0.025), in those with HBeAg seroconversion after only one episode of acute exacerbation (50 versus 12%, P = 0.01), or in those negative for HBeAg at enrollment and without acute exacerbations (50 versus 23%, P = 0.002). In conclusion, patients with genotype C infection have a more aggressive clinical phenotype than do those with genotype B infection, which contributes to the former group's progressive liver disease and poor clinical outcomes.
Adult↗
Hepatitis D virus genotypes in intravenous drug users in taiwan: decreasing prevalence and lack of correlation with hepatitis B virus genotypes.
Of 368 hepatitis B virus (HBV)-infected intravenous drug users, 144 (39%) were positive for antibody to hepatitis D virus (anti-HDV). Anti-HDV-positive HBV carriers had a lower rate of positivity for HBV DNA than did anti-HDV-negative carriers (52 versus 73%, respectively). From 1986 to 1997, the average rate of decrease in the prevalence of HDV infection in this population was 4.7%/year.
Genotype↗