Natural history of hepatitis B surface antigen mutants in children.
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Carrier State↗
Biomedical subjects
C J Oon
Publications and source records attributed to C J Oon.
Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma.
Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
Animals↗
Quantitation of hepatitis C viraemia by a competitive reverse transcription-polymerase chain reaction system.
Chronic hepatitis C infection is associated with the rapid development of cirrhosis and hepatocellular carcinoma. A quantitative assay to determine the level of hepatitis C (HCV) viraemia during treatment would be useful in determining the effect of antiviral agents. Such an assay has been developed with the principle of the method being the co-amplification of the viral genome isolated from the patient with an RNA competitor molecule (CM) using the competitive reverse transcription-polymerase chain reaction (RT-PCR). Known amounts of the CM compete for amplification with HCV RNA from the patient. To quantify each sample, 5 amplification reactions with titrated amounts of CM were performed. The CM can be distinguished from the normal HCV PCR product since it has been genetically altered to be a smaller molecule by the process of restriction digestion, ligation and reamplification. This quantitative method was used to monitor the viral load in 10 patients undergoing antiviral therapy with lymphoblastoid interferon. The level of HCV viraemia in these patients ranged from 10(9) to 10(12) genomes/ml serum. Declines in the level of viraemia were seen in 8 of the 10 patients after therapy. Since patients with low HCV viraemia levels are more likely to respond to interferon therapy in a sustained fashion, this method may also be employed to quantitate the level of viraemia in patients prior to interferon treatment, and may be an indicator of the dose and schedule of treatment. These results show that this quantitative method is useful in the monitoring of HCV viral load in patients.
Adolescent↗
Hepatitis E in Singapore--a seroprevalence study.
The seroprevalence of anti-HEV IgG was determined in a hospital-based population in a general medical unit. Patients who were otherwise well but admitted for acute, non-hepatological conditions represent the "healthy" general population, and those admitted primarily with liver disorders were studied. The seroprevalence of anti-HEV IgG was found to be 10.5% in the "healthy" population and 14.7% amongst those with liver diseases. The lack of travel history and past history of jaundice suggests presence of local cases and subclinical manifestation in some of the infected patients. There is an association between seroprevalence of hepatitis A and E, suggesting common predisposing factors for both infections. Anti-HAV IgG has a higher seroprevalence. Retesting of anti-HEV IgG in those who were initially positive found persistence of antibodies beyond twelve months. Both anti-HAV IgG and anti-HEV IgG were found more commonly in the older age groups.
Adolescent↗
Molecular epidemiology of hepatitis B virus vaccine variants in Singapore.
Perinatal infection with variants of hepatitis B virus occurs despite combined immunoprophylaxis with hepatitis B immunoglobulin and currently licensed plasma-derived and recombinant yeast hepatitis B vaccines. Several variants have been detected during a large study of infants born to carrier mothers in Singapore. The most frequent variant was a virus in which a single amino acid substitution Gly to Arg occurred at amino acid position 145 of the outer protein coat of the virus. Similar mutations have been described in Italy, Japan, the USA and a number of other countries. The emergence of antibody escape mutants is a cause for concern for the detection of virus and possibly for future immunization programmes.
Amino Acids↗
Long-term immunogenicity and efficacy of a reduced dose of plasma-based hepatitis B vaccine in young adults.
A cohort of seronegative preclinical medical and dental students and another cohort of seronegative national service recruits who were immunized intramuscularly with a reduced dose (10 micrograms) of plasma-based hepatitis B vaccine (Merck, Sharp & Dohme) at the start of the study and at 1 month and 6 months thereafter were followed up for 5 years and 6 years, respectively. Among the medical and dental students, antibody to hepatitis B surface antigen (anti-HBs) ( > or = 10 mlU/ml) was detected in 81% of the vaccinees at the end of the 5-year follow-up and the geometric mean titre (GMT) had dropped from 412.6 mlU/ml one year after completion of vaccination to 174.9 mlU/ml after 5 years. Antibody to hepatitis B core antigen (anti-HBc) was detected in 0.4-1.0% of the vaccinees but none was positive for hepatitis B surface antigen (HBsAg) during the follow-up period. Among the national servicemen, the anti-HBs seroconversion rate and GMT were considerably lower than those of the preclinical medical and dental students. At the end of the 6-year follow-up, 55% of the vaccinees were positive for anti-HBs ( > or = 10 mlU/ml) and the GMT had dropped from 80.7 mlU/ml one year after completion of vaccination to 30.4 mlU/ml after 6 years. Anti-HBc was detected in 8 (2.7%) and transient HBs antigenaemia in 2 (0.7%) of 293 vaccinees after 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Mutations in S region of hepatitis B virus.
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Genes, Viral↗
Immunogenicity of recombinant yeast-derived hepatitis B vaccine in nonresponders to perinatal immunization.
OBJECTIVE: Nonresponse to hepatitis B vaccine in the perinatal period occasionally occurs. This report documents the results of reimmunization of nonresponders to perinatal immunization. DESIGN: From a cohort of 1154 infants immunized with plasma-based vaccine in the perinatal period and followed up for more than 8 years, 45 nonresponders were identified. These children were reimmunized at 4 years of age. Each child received a yeast-derived recombinant hepatitis B vaccine on a 0-, 1-, and 5-month schedule, 33 children with 10-micrograms and 12 with 5-micrograms doses. Blood was sampled 1 month after the third vaccination and thereafter at 1, 2, and 4 years. SETTING: The follow-up clinic where the cohort of children was regularly seen. PATIENTS: Forty-five 4-year-old children who had no antibody to hepatitis B despite perinatal immunization. MAIN OUTCOME MEASURE: Antibody levels to hepatitis B surface antigen. RESULTS: Seroconversion with titers higher than 10 mIU/mL occurred in all children. More than 70% still had titers higher than 10 mIU/mL 4 years after vaccination. CONCLUSION: Nonresponders to perinatal hepatitis B vaccination respond well to subsequent vaccination.
Child↗
Partial sequence analysis of the hepatitis C viral genome in Singapore patients.
The distribution of hepatitis C viral (HCV) genotypes in Singapore has not been previously determined. We studied the sera of 40 Singapore patients which were PCR-positive for HCV. The HCV genotypes were determined by direct sequencing of amplified sequences of the 5' non-coding region, after reverse transcription. Of the 40 samples, 35/40 (87.5%) were of HCV type 1, 2/40 (5.0%) were of type 2 and 3/40 (7.5%) were of type 3. The most common HCV genotype in this study was the type 1 genotype. Our results confirm the wide geographical distribution of HCV genotypes.
Hepacivirus↗
Seroepidemiology of hepatitis A and hepatitis B virus infection in a Gurkha community in Singapore.
The overall prevalence of hepatitis A virus (HAV) infection among the Gurkhas and their families stationed in Singapore was 83.2%, with antibody to HAV detected in 67 (38.1%) of 176 children under 5 years of age, 121 (76.6%) of 158 children between 5 and 14 years, and 600 (97.9%) of 613 older children and adults over age 15 years. Children born in Singapore (102/223 or 45.7%) had a significantly lower crude prevalence than those born in Nepal (85/110 or 77.3%) (P < 0.000001). The age-adjusted difference in prevalence was also statistically significant (P < 0.001). Susceptible children had a high risk of acquiring HAV infection when they travelled to Nepal. As for hepatitis B virus (HBV) infection, the prevalence of hepatitis B surface antigen (HBsAg) was 2.8%, with a higher rate in males (20/560 or 3.6%) than in females (6/384 or 1.6%). The highest HBsAg prevalence (4/26 or 15.4%) was in young adult Gurkhas 15-19 years of age. No significant difference in the crude prevalence of HBV markers was noted between children born in Singapore (45/224 or 20.1%) and those born in Nepal (19/107 or 17.8%). Even after age adjustment, the difference remained insignificant. The prevalence of HBV markers of children of seropositive parents (27/156 or 17.3%) was not significantly higher than that of seronegative parents (19/131 or 14.5%). Married men had a significantly higher age-adjusted prevalence of infection than unmarried men (45.4% and 32.4%, respectively; P < 0.05). Seropositivity of one spouse was significantly correlated with the seropositivity of the other (P < 0.05), suggesting a role for heterosexual transmission of HBV infection.
Adolescent↗
Long-term survival following treatment of hepatocellular carcinoma in Singapore: evaluation of Wellferon in the prophylaxis of high-risk pre-cancerous conditions.
The present paper reviews several studies performed between 1977 and 1986 in Singapore on the 10-year survival outcome of treatment for stage I and II hepatocellular carcinoma (HCC). Of 801 HCC patients evaluated, only 2 survivors (0.3%) remained in complete remission for 13 and 14 years, respectively. One had received four weekly cycles of prednisolone, Adriamycin, vincristine and 5-fluorouracil for an inoperable HCC with a 10-cm diameter, and the other had received localised synchronised hepatic irradiation and Adriamycin. As follow-up, the use of localised hepatic irradiation consisting of 131I-labeled (30 mCi) iodised oil in lipiodol infused via the hepatic artery appeared to benefit patients with small residual tumours but did not affect larger tumours measuring 2 cm in diameter. Prophylactic, intermittent long-term administration of lymphoblastoid interferon-alpha (Wellferon) was carried out in pre-cancerous, high-risk hepatitis B surface antigen (HBsAg)-positive patients with cirrhosis, in immediate male relatives of liver cancer patients, and in persons who had undergone hepatic resection. In the untreated group, 10/162 (6%) cirrhotics, 3/18 (17%) male family members, and 6/10 (60%) post-resection cases developed single or multiple HCCs within 1 year of screening done at 3-month intervals on the basis of alpha-fetoprotein (AFP) levels and real-time hepatic ultrasonography. In contrast, none of the Wellferon-treated group consisting of 518 cirrhotic patients, 82 male relatives of HCC patients and 20 post-resection cases developed HCC. Two HBsAg-positive individuals who had not been treated with interferon (IFN) developed hepatic nodules which that showed dysplasia, AFP elevation and chromosomal changes. These studies demonstrate the poor results of late diagnosis and show that early intervention and prophylaxis with Wellferon can reduce the incidence of HCC in high-risk persons. In addition, transhepatic chemoembolisation and liver resection are suitable methods for treating small HCCs (single or multiple) that are detected by screening. However, some of these early-detected HCCs remain highly malignant. Prophylactic treatment of pre-cancerous conditions appears to be a better option as a long-term programme for HCC.
Adult↗
Comparison of the immune response of four different dosages of a yeast-recombinant hepatitis B vaccine in Singapore children: a four-year follow-up study.
The immunogenicity of four different dosages of yeast-derived hepatitis B vaccine (Merck, Sharp & Dohme: 0.6 micrograms, 1.25 micrograms, 2.5 micrograms and 5.0 micrograms), administered at 0, 1 and 6 months (0-1-6 schedule) intramuscularly, was evaluated in 122 seronegative healthy children 1-12 years of age. Three months after the first dose, 83.9-100% of the vaccinees seroconverted. Peak geometric mean titres (GMT) of between 1088 mlU/ml and 1699 mlU/ml were attained 3 months after completion of the vaccination schedule. After 24 months, anti-HBs (antibody to hepatitis B surface antigen) was detected in 93.1-100% of the vaccinees, but the GMT dropped to between 214.3 mlU/ml and 303.5 mlU/ml. After 48 months, 88.8-100% of the vaccinees continued to possess anti-HBs and 70.3-87% had titres above 10 mlU/ml. As expected, the GMT declined further to between 72.6 mlU/ml and 118.8 mlU/ml. There were no significant differences in seroconversion rates and GMT among the different dosage groups. All the vaccinees remained asymptomatic and free from hepatitis B virus infection. The study showed that reduced dosages of the vaccine (0.6 micrograms, 1.25 micrograms and 2.5 micrograms) were as immunogenic as the standard dose (5 micrograms); the 2.5-micrograms dose was recommended for the national childhood immunization programme in Singapore. No booster is necessary for at least four years after vaccination.
Antibody Formation↗
Independent emergence of a vaccine-induced escape mutant of hepatitis B virus.
We investigated the case of a child who was vaccinated at birth against hepatitis B and was also given hepatitis B immune globulin, but who nevertheless later became infected with the virus. Hepatitis B virus-specific deoxyribonucleic acid covering the region of the genome encoding the predominant a epitope of hepatitis B surface antigen was amplified using the polymerase chain reaction and the nucleotide sequence determined. We present evidence for the independent emergence of an escape mutant, similar to that previously identified in Italy, where a substitution of arginine for glycine has occurred in the second loop of the a epitope.
Amino Acid Sequence↗
Prevalence of antibody to hepatitis C in patients with liver disease.
We studied the seroprevalence of antibody to hepatitis C virus (HCV) in patients with liver disease using the Abbott HCV EIA. Twenty-four patients with acute sporadic nonA nonB hepatitis, 19 patients with chronic hepatitis, 28 patients with cirrhosis and 47 patients with hepatocellular carcinoma (HCC) were assayed. The seroprevalence was 8.3% (2/24) in acute hepatitis; 10.5% (2/19) in chronic hepatitis; 3.6% (1/28) in cirrhosis and 14.9% (7/47) in hepatocellular carcinoma. The seroprevalence rates were lower in all categories of liver disease compared to figures reported in developed countries. Possible reasons included a delayed or missed seroconversion in the acute hepatitis group. Other etiologies like hepatitis B and alcohol may play a more important role in chronic liver disease. On the other hand, the seroprevalence locally may actually be low. Sporadic, non-blood transfusion appears to be a common method of acquiring the infection.
Adult↗
Clearance of neonatal antiHBc following hepatitis B vaccination: relationship to antiHBs levels.
The persistence of antiHBc following hepatitis B virus (HBV) infection is sometimes regarded as evidence of a past infection, and the antiHBc inhibition of T-cell cytotoxic killing of HBV may be one way of tolerance leading to the carrier state. A model for studying the possibility of an immune tolerance occurring in the human situation was to observe the natural clearance rate of total antiHBc in babies who have acquired naturally maternal transferred antibodies, and to compare antiHBcIgG clearance and development of hepatitis B surface antigenaemia with the level of antibody to HBsAg (antiHBs), which is normally known to be virucidal. Two hundred and ninety-one normal infants who received hepatitis B vaccination in 1984 were followed and studied at six months, one, two and four years. AntiHBc was not found in any control infants born of HBsAg negative mothers. One child became antiHBc positive at four years reflecting acquired infection when antiHBs level had fallen to 36 mIU per ml. AntiHBc cleared in 66% of HBsAg pos./'e' neg. children at one year and completely by two years. In contrast, antiHBc clearance in children born of HBsAg pos./'e' pos. was inversely related to the antiHBs levels. Those with antiHBs levels over 50 mIU per ml cleared antiHBc more rapidly and were HBsAg negative, whereas in 28/49 (57%) HBs antigenaemia were associated more often with antiHBs under 10 mIU per ml and in 2/43 (5%) at levels between 11 to 50 mIU per ml. Two children who had later developed HBs antigenaemia in the presence of antiHBs after responding to earlier passive-active immunisation, suggest either defective antiHBs and/or the development of mutants or variants.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Anti-Idiotypic↗
Detection of tumour antigens in sera of patients with hepatocellular carcinoma using monoclonal antibodies.
A total of 70 serum samples taken from patients with hepatocellular carcinoma (HCC), acute viral hepatitis and cirrhosis and normal individuals were tested in a binding inhibition immunofluorescence assay using 5 mouse monoclonal antibodies (2G9, 3H11, 3H12, 1C7, 3H5) specific for hepatoma cells. Seven out of the 30 HCC sera (23.3%) inhibited the binding of one of these antibodies, 3H11. This detection of antigen 3H11 or antigens of similar structure in HCC sera was significantly more frequent than in control sera (1/40 = 2.5%) (Fisher's exact test, p = 0.009; df = 1, relative risk calculated by the odds ratio in a 2 x 2 table = 12.0). The presence of this antigen was unrelated to the hepatitis B surface antigen and alphafetoprotein status. Thus it would be of value particularly for the detection of hepatitis B negative or alphafetoprotein negative liver cancers.
Acute Disease↗
Primary liver cancer--the potential for prevention and elimination.
Primary liver cancer (PLC) is one of the top ten cancers in the world, and a leading cause of cancer mortality in Singapore and the Asia Pacific region. Chronic hepatitis B infection accounts for at least 80% of primary hepatocellular cancer. Other chemical carcinogens, such as aflatoxins, have been identified in foodstuffs and have also been found in the urine of normal human subjects. Aflatoxin and other chemical carcinogens, e.g. alcohol, cigarettes, also pose serious risks of hepatocarcinogenesis. Identification of small tumours (not necessarily early) may allow for earlier treatment to be instituted. Capsular lesions in general have a better prognosis than infiltrating cancers. In Singapore, if hepatitis B virus can be eliminated by the year 2000, at least 65% of hepatitis B related deaths can be saved. This would involve large scale hepatitis B immunisation to prevent the carrier state and the use of antiviral drugs earlier to eliminate hepatitis B infections.
Carcinoma, Hepatocellular↗