Ding-Shinn Chen

Universal Hepatitis B Vaccination in Taiwan and the Incidence of Hepatocellular Carcinoma in Children

BACKGROUND A nationwide hepatitis B vaccination program was implemented in Taiwan in July 1984. To assess the effect of the program on the development of hepatocellular carcinoma, we studied the incidence of this cancer in children in Taiwan from 1981 to 1994. METHODS We collected data on liver cancer in children from Taiwans National Cancer Registry, which receives reports from each of the countrys 142 hospitals with more than 50 beds. Data on childhood liver cancer were also obtained from Taiwans 17 major medical centers. To prevent the inclusion of cases of hepatoblastoma, the primary analysis was confined to liver cancers in children six years of age or older. Data were also obtained on mortality from liver cancer among children. RESULTS The average annual incidence of hepatocellular carcinoma in children 6 to 14 years of age declined from 0.70 per 100,000 children between 1981 and 1986 to 0.57 between 1986 and 1990, and to 0.36 between 1990 and 1994 (P<0.01). The corresponding rates of mortality from hepatocellular carcinoma also decreased. The incidence of hepatocellular carcinoma in children 6 to 9 years of age declined from 0.52 for those born between 1974 and 1984 to 0.13 for those born between 1984 and 1986 (P<0.001). CONCLUSIONS Since the institution of Taiwans program of universal hepatitis B vaccination, the incidence of hepatocellular carcinoma in children has declined.

Hepatitis B Genotypes Correlate With Clinical Outcomes in Patients With Chronic Hepatitis B

BACKGROUND & AIMS Six genotypes (A-F) of hepatitis B virus (HBV) have been identified; however, the genotype-related differences in the pathogenicity of HBV remain unknown. Therefore, we investigated the prevalence of HBV genotypes in Taiwan and the association between distinct genotypes and severity of liver disease in a cross-sectional study. METHODS Using a molecular method, HBV genotypes were determined in 100 asymptomatic carriers and in 170 patients with histologically verified chronic liver disease and hepatocellular carcinoma (HCC). RESULTS All genotypes except genotype E were identified in Taiwan, and genotypes B and C were predominant. Genotype C was prevalent in patients with cirrhosis and in those with HCC who were older than 50 years compared with age-matched asymptomatic carriers (60% vs. 23%, P < 0.001, and 41% vs. 15%, P = 0.005, respectively). Genotype B was significantly more common in patients with HCC aged less than 50 years compared with age-matched asymptomatic carriers (80% vs. 52%, P = 0.03). This predominance was more marked in younger patients with HCC (90% in those aged </=35 years), most of whom did not have cirrhosis. CONCLUSIONS Our data suggest that HBV genotype C is associated with more severe liver disease and genotype B may be associated with the development of HCC in young Taiwanese. However, additional large-scale longitudinal studies are needed to confirm the relationship of HBV genotypes to liver disease severity and clinical outcomes.

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.

STATEMENTS FROM THE TAORMINA EXPERT MEETING ON OCCULT HEPATITIS B VIRUS INFECTION

Giovanni Raimondo*, Jean-Pierre Allain, Maurizia R. Brunetto, Marie-Annick Buendia, Ding-Shinn Chen, Massimo Colombo, Antonio Craxi, Francesco Donato, Carlo Ferrari, Giovanni B. Gaeta, Wolfram H. Gerlich, Massimo Levrero, Stephen Locarnini, Thomas Michalak, Mario U. Mondelli, Jean-Michel Pawlotsky, Teresa Pollicino, Daniele Prati, Massimo Puoti, Didier Samuel, Daniel Shouval, Antonina Smedile, Giovanni Squadrito, Christian Trepo, Erica Villa, Hans Will, Alessandro R. Zanetti, Fabien Zoulim

Hepatitis B genotypes and the response to interferon therapy

BACKGROUND/AIMS Possible pathogenic differences among hepatitis B virus (HBV) genotypes have been observed; however, the response to interferon therapy among HBV genotypes remains unknown. We therefore analyzed the efficacy of interferon alfa in the treatment of chronic hepatitis B patients with different HBV genotypes. METHODS Fifty-eight genotype B or C infected chronic hepatitis B patients who had been treated with interferon alfa-2b were retrospectively studied. The response to interferon was defined as normalization of serum aminotransferase level, loss of hepatitis B e antigen and HBV DNA 48 weeks post-treatment. RESULTS Baseline data of both groups of patients were comparable; however, genotype C patients had a higher serum aminotransferase level and a higher frequency of core promoter mutation. The response rate was 41% and 15% in genotype B and C patients, respectively (p=0.045). In those with higher serum aminotransferase levels, the response rate was 50% and 17%, respectively (p=0.025). Additionally, younger age and genotype B infection may predict a better response to interferon alfa. CONCLUSIONS HBV genotype C, compared to genotype B, is associated with a higher frequency of core promoter mutation, and a lower response rate to interferon alfa therapy.

Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.

Background The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions. Methods From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 104 copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided. Results A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 104 copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% CI = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001). Conclusions HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Decreased Incidence of Hepatocellular Carcinoma in Hepatitis B Vaccinees: A 20-Year Follow-up Study

BACKGROUND Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma. This population-based study aimed to investigate whether prevention of hepatocellular carcinoma by the universal Taiwanese HBV vaccine program, launched in July 1984, has extended beyond childhood and to identify the predictors of hepatocellular carcinoma for vaccinated birth cohorts. METHODS Data on 1958 patients with hepatocellular carcinoma who were aged 6-29 years at diagnosis in Taiwan between 1983 and 2004 were collected from two national hepatocellular carcinoma registries. Age- and sex-specific incidence among vaccinated and unvaccinated birth cohorts were analyzed by using Poisson regression models. All statistical tests were two-sided. Records of 64 hepatocellular carcinoma patients and 5 524 435 HBV vaccinees who were born after the initiation of the vaccination program were compared for HBV immunization characteristics during infancy and prenatal maternal hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) serostatus. RESULTS Hepatocellular carcinoma incidence was statistically significantly lower among children aged 6-19 years in vaccinated compared with unvaccinated birth cohorts (64 hepatocellular cancers among vaccinees in 37 709 304 person-years vs 444 cancers in unvaccinated subjects in 78 496 406 person-years, showing an age- and sex-adjusted relative risk of 0.31, P < .001, for persons vaccinated at birth). The risk of developing hepatocellular carcinoma for vaccinated cohorts was statistically significantly associated with incomplete HBV vaccination (for those who received fewer than three doses of HBV vaccine, odds ratio [OR] = 4.32, 95% confidence interval [CI] = 2.34 to 7.91); with prenatal maternal HBsAg seropositivity (OR = 29.50, 95% CI = 13.98 to 62.60); with prenatal maternal HBeAg seropositivity (with administration of hepatitis B immunoglobulin at birth, OR = 5.13, 95% CI = 2.24 to 11.71; and without it, OR = 9.43, 95% CI = 3.54 to 25.11). CONCLUSION The prevention of hepatocellular carcinoma by this HBV vaccine extends from childhood to early adulthood. Failure to prevent hepatocellular carcinoma results mostly from unsuccessful control of HBV infection by highly infectious mothers.

Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.

The growth rate of 31 asymptomatic hepatocellular carcinomas (diameter less than or equal to 5 cm) discovered in 28 patients by a prospective screening program was determined by real-time ultrasonography over 36-860 days. Except for one tumor that shrank on follow-up, the doubling time ranged from 29 to 398 days, with a median of 117 days, an arithmetic mean of 136 days, and a geometric mean of 110 days. In 17 tumors with more than two measurements, the growth rate remained exponential in nine, declined in growth in seven, and showed an initial lag period in one. Doubling time correlated with initial tumor diameter but was independent of the patients age, sex, hepatitis B surface antigen status, tumor location, liver function tests, stage of liver cirrhosis, histologic type, or grade of malignancy. Although initial alpha-fetoprotein levels did not correlate well with growth rate, in 14 patients with an exponential increase of serum alpha-fetoprotein, the alpha-fetoprotein doubling time was closely related to the tumor doubling time. Based on the above data, the median detectable subclinical period of hepatocellular carcinoma was deduced to be 3.2 yr, and the suitable screening interval for its early detection in our area was 4-5 mo.

Hepatitis B Virus Infection in Children and Adolescents in a Hyperendemic Area: 15 Years after Mass Hepatitis B Vaccination

Hepatitis B virus (HBV) infection is an important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma in many parts of the world, including Taiwan (1, 2). Up to 15% to 20% of the general population in Taiwan are chronic carriers of hepatitis B surface antigen (HBsAg) (3, 4). Most chronic carriage of HBV results from infection in early childhood, especially before 2 years of age (57). Taiwan launched the worlds first nationwide universal vaccination program in 1984 to prevent infection in the early years of life (8). In addition to decreasing the proportion of carriers and the prevalence of HBV infection in the current young generation (9), the universal vaccination program has also resulted in a decreased incidence of childhood hepatocellular carcinoma (10). To study the effect of this universal vaccination program, we conducted a series of prospective seroepidemiologic surveys in Chung-Cheng District, Taipei City, Taiwan. The first survey was conducted shortly before the mass vaccination program began in 1984 (6), followed by similar surveys in 1989 (11) and 1994 (12). We report findings that extend our follow-up observations to 199915 years after the start of the program. Methods National Vaccination Program The national program of universal HBV vaccination in Taiwan began on 1 July 1984 (8). At that time, only the newborn infants of mothers who were HBsAg carriers were vaccinated. The vaccination program was extended in June 1987 to include all newborn infants and in July 1987 to cover all children of preschool age. The program was further extended to school children, teenagers, and then adults from 1988 to 1990. Since 1991, the vaccination records of first-grade children have been checked, and children without a complete set of previous vaccinations have been given catch-up HBV vaccinations. Before July 1992, four doses of plasma-derived vaccine were administered in children before 1 week of age and again at 1, 2, and 12 months of age; after July 1992, three doses of recombinant (yeast-derived) vaccine were administered before 1 week and at 1 month and 6 months of age. Since 1984, newborns whose mothers test positive for hepatitis B e antigen (HBeAg) have also received hepatitis B immunoglobulin, 0.5 mL (100 IU), within 24 hours after birth. The vaccination program has been described in greater detail elsewhere (8, 12). We defined the vaccination coverage rate as the percentage of children receiving at least three doses of HBV vaccine. We assessed the vaccination histories of the studied population by examining their vaccination cards and by taking a history from their parents. We classified the vaccination status as unknown for persons with a missing vaccination card or a vague vaccination history. Participants From March 1999 to October 1999, serum samples were collected from 1916 children and adolescents from two groups: 1) 1357 apparently healthy persons younger than 15 years of age [721 male participants and 636 female participants], who were born after the launch of the universal vaccination program, and 2) 559 persons (297 male participants and 262 female participants) 15 to 20 years of age, who were born before universal vaccination. We recruited participants for the baseline and follow-up seroepidemiologic studies in Chung-Cheng District, Taipei City. In 1999, Chung-Cheng had a population of 165 388 citizens; 35 005 of the citizens were younger than 15 years of age, and 47 565 were younger than 20 years of age. From 1994 to 1999, the population was stable, with an average annual migration rate of less than 4.8%. The annual family income,