Epidemiology of hepatitis B and hepatitis B virus infection in United States children

Before the era of routine hepatitis B vaccination, an estimated 24,000 children acquired hepatitis B virus (HBV) infection each year in the United States. Childhood hepatitis B immunization has led to significant declines in the incidence and prevalence of HBV infection in U.S. children. Because the greatest burden of hepatitis B is caused by complications of hepatocellular carcinoma and cirrhosis in adults who were infected with HBV as children, most of the benefits of vaccination have yet to be realized. Reaching the goal of eliminating HBV transmission to children likely will require increasing vaccination coverage, ensuring timely administration of postexposure immunoprophylaxis to prevent more perinatal infections, and continued evaluation of the impact of immunization recommendations.     

Hepatitis B in childhood: An update for the paediatrician

Hepatitis B virus (HBV) infection may lead to acute or chronic hepatitis, cirrhosis and hepatocellular carcinoma. The incidence rate of paediatric hepatitis B is 0.2/100,000 to 1.8/100,000 in Canada. Hepatitis B virus infection is acquired largely through mother-to-infant (vertical) or community-based (horizontal) transmission in early childhood, whereas older children are susceptible to HBV infection through exposure to contaminated blood during intravenous drug use or through sexual transmission. Immigrants from endemic areas and some Native Canadian populations are also at a higher risk for HBV infection. Infection with HBV may manifest in three forms: acute self-limited hepatitis, chronic hepatitis or massive hepatic necrosis causing acute liver failure. The identification of HBV infection and the characterization of the disease relies on serological and virological tests. The course of chronic hepatitis B may be classified into three phases: an immunotolerant phase, an active phase and an inactive phase. Current treatment options include interferon-alpha and lamivudine for individuals with elevated serum alanine aminotransferase levels and markers of persistent viral replication. Children with chronic hepatitis B require regular monitoring and age-appropriate lifestyle counselling. Paediatricians are well-positioned to promote vaccination and encourage testing of those who are at risk for hepatitis B. With effective universal vaccination against hepatitis B, this infection could be essentially eliminated in Canada.     

Hepatitis B virus mutation in children

Due to the lack of proof reading activity of hepatitis B virus (HBV) polymerase, mutation/variation of the viral sequence is frequently found during long term follow-ups. In the majority of children with chronic HBV infection, wild type HBV is the dominant viral strain during the natural course of chronic HBV infection. During long-term follow-up, HBV precore mutants developed spontaneously in approximately 10 to 24% of children before HBeAg seroconversion, and in around 50% of children after HBeAg seroconversion mutants. Occasionally, children may be infected primarily by mutant strains of HBV. Approximately 36% of children with fulminant hepatitis and 30% of children with acute hepatitis B were infected by precore mutants of HBV transmitted by their mothers or blood donors. In addition, after universal HBV vaccination, HBV surface gene variants emerge or are selected under the immune pressure generated by the host or by administration of hepatitis B immune globulin and hepatitis B vaccination. In HBV DNA positive children from four sequential surveys in Taiwan, the prevalence of hepatitis B surface gene a determinant mutants increased from 7.8% before the vaccination program, to 19.6%, 28.1%, and 23.1% at 5, 10, and 15 years after the program. Nucleoside analogue may also induce mutant strains, which reduces the antiviral effects. The most common example is the YMDD mutation of the HBV polymerase gene after antiviral therapy with lamivudine. It developed in 19% of the treated children. In conclusion, children may be infected primarily by mutant strains of HBV either naturally during acute HBV infection. Those infected with wild type HBV initially may develop mutant strains gradually during the course of chronic infection under the host immune pressure. Vaccine escape mutants may develop after immunoprophylaxis. In addition, antiviral therapy with nucleoside anlogues may also induce drug resistant mutant strains. Understanding the viral mutation status will help to design accurate strategies of immunoprophylaxis and antiviral therapy against HBV infection.     

Benefits of early hepatitis B immunization programs for newborns and infants

Despite the availability of safe and effective hepatitis B virus (HBV) vaccines for >20 years, strategies targeting risk groups failed to sufficiently control hepatitis B disease at the population level; this is mainly because of difficulties in risk identification and in program implementation. Hence, the global burden of disease of HBV still is substantial. The World Health Organization recommends universal vaccination against hepatitis B to ultimately eliminate HBV; this recommendation had been progressively implemented to reach 168 countries with a universal program by the end of 2006. However, hepatitis B immunization is currently becoming endangered of losing its place on the agendas of governments, agencies, and international organizations, mainly because of the increasing success of these immunization programs and the interest in newer vaccine-preventable diseases and the related programs.This publication aims to show that vaccination programs targeting newborns and infants are preferable to achieve this goal. The benefits of universal HBV vaccination for newborns and infants are: higher impact on chronic carrier rate and transmission; established potential of high vaccine coverage in this age group; opportunities to combine HBV vaccination with existing universal vaccination programs for newborns and infants; and impact on perinatal transmission, if vaccination is started shortly after birth. Moreover, the safety, immunogenicity, and long-term efficacy of newborn and infant HBV vaccination have been proven extensively. In summary, newborn and infant HBV vaccination programs should be considered the preferred strategy, capable of providing important and sustained impact on global HBV incidence, even if they have a delayed impact on sexual transmission of HBV.     

Chronic viral hepatitis

Among hepatitis A to E viruses, hepatitis B, C, and D viruses can cause chronic hepatitis, in both children and adults. Hepatitis B virus (HBV) infection is the most prevalent and important one. Perinatal transmission accounts for about 40–45% of chronic HBV infection in hyperendemic areas. Horizontal transmission through intramuscular injection using non-sterile needles and intrafamilial spread accounts for the other half of carriers. During the natural course of HBV infection, the host gradually clears HBV and hepatitis B e antigen (HBeAg), liver damage and elevation of aminotransferases occur during the process of HBV clearance. The most effective way to eliminate HBV infection is immunoprophylaxis starting since birth. It can prevent both HBV and hepatitis D virus (HDV) infections. Hepatitis C virus (HCV) infection in children occurs mainly in high risk children, such as those who received blood product or injection using non-sterile needles, or infants of HCV viremic mothers, etc. Screening of blood product reduced markedly the prevalence of post-transfusion HCV infection, but the prevention of sporadic cases requires HCV vaccination which is still under investigation.     

基于双生子样本的婴儿乙肝疫苗低/无免疫应答的围生期相关因素分析

目的 探讨围生期环境因素如喂养方式、生命早期营养状况等对婴儿乙肝疫苗低/无免疫应答的影响,为研究乙肝疫苗免疫失败机制提供依据。方法 采用病例对照研究设计,纳入来自5家协作医院儿童保健科参加常规体检的1周岁的双生子和无关个体组成两个独立样本,排除无关个体样本中低出生体重儿及两样本中乙肝表面抗原（HBsAg）阳性及母亲有乙肝病史的研究对象。通过病案调查及现场访谈,收集研究对象的父母健康状况、母亲孕产史、婴儿出生状况及1岁以内体检信息等可能的暴露因素资料。在分析乙肝疫苗低/无免疫应答的相关影响因素时,双生子样本采用XTGEE广义估计模型,无关个体样本采用Logistic回归模型和Tobit回归模型进行分析。结果 纳入分析的双生子样本为370人,无关个体样本为300人。19.2%（71例）双生子和11.7%（35例）无关个体在接种乙肝疫苗后发生低/无免疫应答。在双生子样本中,父亲吸烟(OR=4.50, 95%CI:2.52～8.03)和低出生体重(OR=2.55, 95%CI:1.33～4.87)可能增加乙肝疫苗低/无免疫应答风险, Apgar评分高和0～1周岁体重增长量大可能降低乙肝疫苗低/无免疫应答的风险。但在出生体重正常的无关个体样本中未发现上述因素与乙肝疫苗低/无免疫应答的相关性。结论 按照0-1-6方案接种乙肝疫苗后, 低出生体重、父亲吸烟、Apgar评分和0～1周岁体重增长量与婴儿发生乙肝疫苗低/无免疫应答相关。     

苏州市1500名5岁～10岁儿童乙肝病毒感染的调查研究

为了解乙肝疫苗接种预防儿童乙肝病毒（HBV）感染的效果，根据随机分层抽样原则，于1997年5月－10月对市区1500名5－10岁儿童进行乙肝病毒血清学检测和乙肝疫苗接种情况调查。结果表明，儿童HBV总感染率为3．60％（54／1500名），随年龄增大有上升趋势，接种组HBV感染率为1．65％，未接种组为19．63％（P＜0．001）；加强免疫的儿童抗HBs阳性率85．78％，HBV感染率0．73％；未进行加强免疫的儿童抗HBs阳性率为43．21％，HBV感染率为2．60％（P＜0．01）。提示儿童乙肝疫苗接种显著降低了儿童HBV感染率，但随年龄增长，50％以上儿童抗HBs滴度低于保护阈值，HBV感染率上升，加强免疫接种打破了这种趋势，值得提倡。     

乙型肝炎高危儿免疫预防效果及乙肝病毒母婴传播影响因素分析

目的 分析乙型肝炎病毒(HBV)母婴传播影响因素及乙肝高危儿免疫预防的效果,为儿童乙肝防治提供科学依据。方法 回顾性调查539例HBsAg阳性产妇及其6个月至5岁的乙肝高危儿551例,并检测乙肝高危儿的乙肝标志物,分析乙肝病毒母婴传播的影响因素。结果 乙肝疫苗接种率为100%,96.6%联合注射了乙肝疫苗和乙肝免疫球蛋白(HBIG)。各年龄段乙肝高危儿的HBsAg阳性率差异无统计学意义;HBsAb阳性率随年龄增长逐步下降 (P<0.01)。高危儿母亲为HBsAg、HBeAg双阳性者较单纯HBsAg阳性的乙肝感染率高 (15.1% vs 0.2%,P<0.01)。单纯接种乙肝疫苗的高危儿乙肝感染率 (28.6%)高于联合免疫注射者 (2.8%),P<0.01。结论 乙肝高危儿HBsAb阳性率随年龄增高逐渐下降。母亲HBsAg、HBeAg双阳性和出生未联合免疫注射是乙肝病毒母婴传播的危险因素。     

Persistence of antibody to hepatitis B and protection from disease among Alaska natives immunized at birth

BACKGROUND: Alaska Native (AN) children were at high risk of acquiring hepatitis B virus (HBV) infection before vaccination began in 1983. We evaluated the long-term protection from hepatitis B (HB) vaccination among AN children immunized when infants. METHODS: During 1984-1995, we recruited a convenience sample of AN children who had received a three dose series of HB vaccine starting at birth and had serum antibody to hepatitis B (anti-HBs) concentrations of >/= 10 mIU/mL at 7-26 months of age. We evaluated anti-HBs concentrations and the presence of anti-HBc in participants' sera every other year up to age 16 years. Anti-HB core antigen (anti-HBc)-positive specimens were tested for hepatitis B surface antigen and for HBV DNA. RESULTS: We followed 334 children for 3151 person-years (median, 10 years per child) with 1610 specimens collected. Anti-HBs concentrations dropped rapidly among all participants. Among children 2, 5 and 10 years of age, 37 of 79 (47%), 33 of 176 (19%) and 8 of 95 (8%), respectively, had anti-HBs concentrations of >/= 10 mIU/mL. Receipt of recombinant vaccine was significantly associated with a more rapid antibody decline (P < 0.001). Six (1.8%) children acquired anti-HBc, 3 of whom had definite breakthrough infections (at least 2 consecutive anti-HBc-positive specimens or at least 1 anti-HBc-positive specimen and HBV DNA detection by PCR). None of these children had detectable hepatitis B surface antigen, and none had symptoms of hepatitis. CONCLUSIONS: Anti-HBs concentrations declined over time among AN infants successfully immunized with HB vaccine starting at birth. Transient anti-HBc appeared in a small percentage of children; however, none developed clinical signs of hepatitis or chronic HBV infection.     

Efficacy of primary hepatitis B immunization in children with acute lymphoblastic leukemia

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) carry a high risk of hepatitis B virus (HIV) infection. The present study was conducted to see if prior routine hepatitis B vaccine received as a part of national immunization program could prevent HBV infection in these children. METHODOLOGY: Ninety-six children with ALL were screened for HBV. Children were divided into three groups according to their initial HBV serology; previously vaccinated children (Group I) (n=34) previously unvaccinated and seronegative children (Group II) (n=56),and unvaccinated but HBsAg negative and anti-HBs positive children (group III) (n=6). Sixty-seven of 96 (69.7%) children received vaccination. The schedule was initiated during the third month of maintenance therapy and each course consisted of three doses given at one month interval. RESULTS: Anti-HBs seroconversion following the first course of three doses of hepatitis B vaccination in group I, II and III was 57%, 33% and 100%, respectively. It increased to 97% in Group I, 62.5% in Group II, 100% in Group III. HBsAg positivity was found in 11 children (11.5%) and all of them developed chronic hepatitis B. Ten of them were in Group II whereas only one child was in Group I (P<0.04). CONCLUSION: This data reveals that routine HBV vaccination within the national immunization program plays an important role in decreasing subsequent hepatitis B infection in children with ALL.     

Asymptomatic viral hepatitis types A and B in an adolescent population.

Sera from 95 adolescents were examined for markers of hepatitis B virus (HBV) infection and hepatitis A virus (HAV) infection. HBV markers were found in eight adolescents (8%) and evidence of previous HAV infection was found in 18 adolescents (19%); none had a history of clinically recognizable hepatitis. These findings support the growing evidence that HBV and HAV infections are diseases of the pediatric age group, and that testing of HBV vaccines when they become available for patient use will have to include a pediatric population.     

Role of children with chronic hepatitis in the intrafamilial spread of hepatitis B virus infection

In order to evaluate the intrafamilial spread of hepatitis B virus (HBV) infection we studied the serological markers of HBV in 101 relatives of 35 children with chronic hepatitis B. Sixty per cent of relatives had markers of infection and 25% showed persistent HBs antigenemia. The high prevalence of HBeAg versus anti-HBe in chronically infected relatives suggests a close temporal relationship of the infection between adults and children. These results support the hypothesis that the child is the main carrier of HBV infection in his family.     

Delta-hepatitis

Investigations were conducted for serological evidence of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections in children suffering from acute viral hepatitis. A total of 52 serum samples were analysed by enzyme immunoassay. Of these, 18 (24%) were positive for hepatitis B virus markers and 34 (65.4%) were negative. Delta virus infection was detected in 6/18 (33%) hepatitis B patients. A significant finding was, that of the 34 patients negative for hepatitis B, 4 (12%) were positive only for HDV although the latter can only occur as a coexistent infection with hepatitis B virus. From the present study it may be inferred that delta virus infection is prevalent in children and absence of HBV markers does not rule out hepatitis D.     

Hepatitis B and C viruses in infants and young children

Advances during the past 20 years have led to a better understanding of the prevention, diagnosis, and treatment of acute and chronic hepatitis B (HBV) and hepatitis C (HCV) infections in the pediatric population. Universal vaccination and prenatal testing for HBV have decreased the incidence rate of acute HBV infections from more than 3/100,000 to 0.34/100,000 in all children. Diagnosis of chronic HBV is confirmed with positive serologic testing on two occasions at least 6 months apart. Current approved therapies with interferon alpha and lamivudine for children with chronic HBV infection have shown some efficacy, but results have been variable. In contrast, the lack of an effective HCV vaccine and the risk of mother-to-child transmission may increase the number of children with vertically acquired HCV that ultimately go on to develop liver fibrosis or cirrhosis. Diagnosis of HCV in the neonate should be postponed until after the child reaches 1 year of age because infants may have transient viremia. Treatment for HCV infected children has not been studied extensively. Peginterferon alpha-2a and Ribavirin are not currently approved for pediatric use; however, recent studies in children have shown potential benefit. More effective and less toxic therapies for young patients with HBV and HCV are needed, as are methods to interrupt perinatal transmission of HBV and HCV.     

Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation

Liver recipients who have antibodies to hepatitis B core antigen (anti-HBc) or received an anti-HBc positive liver graft are at risk of acquiring de novo hepatitis B infection so a life long prophylaxis is required. A post-transplant vaccination against hepatitis B virus (HBV) can offer a better alternative than either hepatitis B hyperimmune globulin (HBIG) or lamivudine. This study investigated the course of anti-HBs titer after vaccination and analyzed the factors that influence the response. Between October 1999 and February 2003, 37 pediatric patients were given a post-transplant vaccination when an anti-HBc positive graft was used, the recipient was anti-HBc positive, or when anti-HBs titer was below 20 IU/L irrespective of the serological status. Thirty-three patients responded to the vaccine and did not require further HBIG injections at a mean follow up of 33.6 months. Fifteen patients were good responder and only needed a single set of vaccines, and 18 were poor responder needing additional boosters. Two patients developed de novo hepatitis B infection and two required additional HBIG injections. Preoperative severity of liver disease, serological status of HBV of recipient or donor, use of HBIG or pulse steroid therapy, type of vaccines, and dose or time interval between doses had no influence on response rate. Recipients with a high preoperative anti-HB titer, small graft-recipient weight ratio (GRWR), greater catch up growth, heavier body weight, lower tacrolimus level at the time of vaccination, and longer time interval between transplant or steroid medication and vaccination yielded good response. If well tailored, post-transplant vaccination can be effective and offer patients prophylaxis against de novo hepatitis B infection for a prolonged period of time.     

Seroepidemiology of hepatitis B virus infection among children in Mongolia: Results of a nationwide survey

BACKGROUND: Because Mongolia is one of the highly endemic countries for hepatitis B virus (HBV) infection in the world, hepatitis B (HB) vaccine was introduced into the National Expanded Program on Immunization in 1991. However, relatively few data are available concerning HBV infection among children born after the start of the program, so far. The aim of the present paper was to describe the seroepidemiology of HBV infection among primary school children using representative national data. METHODS: In 2004, a nationwide school-based cross-sectional serosurvey was carried out throughout Mongolia, covering both urban and rural areas. Serum samples were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc) and hepatitis B e antigen (HBeAg) as well as for liver enzymes. RESULTS: A total of 1145 children aged 7-12 years were studied, which represents nearly 2% of the second grade population of elementary schools in Mongolia. The overall prevalence of HBsAg and anti-HBc was 5.2% (95% confidence interval [CI]: 3.9-6.5%) and 15.6% (95%CI: 13.5-17.7%), respectively. Among HBsAg-positive children 67.8% (95%CI: 55.9-79.7%) were also positive for HBeAg. The prevalence of chronic HBV infection increased by age and was significantly higher among children from rural areas compared to those from urban areas (7.7% vs 3.0%; P < 0.001). In the multivariate logistic regression analysis, rural residence (odds ratio [OR]: 2.57; 95%CI: 1.45-4.58), male sex (OR: 1.9; 95%CI: 1.08-3.26) and age (OR: 1.5; 95%CI: 1.10-2.05) were independent demographic predictors for chronic HBV infection. CONCLUSIONS: The prevalence of chronic HBV infection has been decreasing in the Mongolian young generation, most likely due to infant HB vaccination. However, significant rural-urban differences in the prevalence of HBV infection were found that demand further investigation to estimate the potential causes.     

Hepatitis B Vaccination in Children with Cancer

Between September 1991 and April 1993 the hepatitis B vaccination with recombinant hepatitis B vaccine was administered in 41 cancer patients following first diagnosis. All patients were under 16 year of age, with negative hepatitis B virus (HBV) serology and normal hepatic function. They received 40 μg of vaccine by injection into the deltoid muscle at 0, 1, and 2, months, with a fourth dose planned at the 4th month for nonresponders. At 1 year a booster dose was given. All the patients began vaccination within 1 month following diagnosis, and periodic serologic follow-up was performed immediately after each vaccination and also in the 6th, 9th, and 12th months after vaccination. Patients with production of anti-HBs at a titer equal to or greater than 10 mIU/L were considered seropositive. The seroconversion rates were 12.4%, 21.9%, 41.0%, and 48.7% after the first, second, third, and fourth monthly doses, respectively. Seroconversion rates were 56.0% at 6 months, 67.5% at 9 months, and 70.5% at 12 months. Geometric mean antibody titers were 212 and 373 mIU/L at 9 and 12 months, respectively. No serious side effects were observed. HBV vaccination is recommended for pediatric cancer patients.     

Effects of Booster HB Vaccine in Preventing Hepatitis B Virus Infection from Mother to Child

Hepatitis B immune serum 200 IU was injected intramuscularly to 127 infants born to hepatitis B e antigen positive mothers immediately after birth and at two months of age, and if necessary at four months. HB adjuvant vaccine 20 μg was injected subcutaneously at three, four, and six months. If antibodies to hepatitis B surface antigen were 2² or less, one to four doses of booster vaccine 20 μg were given. The first booster vaccination was given in 8.7% of cases by the age of one year, in 19.3% by 18 months, in 23.9% by 24 months, and in 36.2% by 30 months; thus 2-to-3-year-old infants were more frequently vaccinated than younger ones. This implies that 80%-90% of infants could be protected from vertical transmission of hepatitis B virus (HBV) up to the age of three years, if a booster vaccine was given to those born to HBeAg positive mothers not later than 24 months. Infants obtained enough antibody to prevent HBV infection by receiving one booster vaccination in 34 cases, by two in nine, by three in five, and by four in two.     

Current etiological structure of acute viral hepatitis in children

The etiological structure of viral hepatitides (VH) was defined in 345 children admitted to the clinic during one year with a diagnosis of acute viral hepatitis. It was established on the basis of clinico-laboratory studies and identification of serological markers of viral hepatitides A, B and delta. It has been demonstrated that in the structure of viral hepatitides in children living in Moscow, VHA accounts for 83.1%, acute VHB for 11.1%, HBV and HDV coinfection for 2.6%, and VH non A non B for 1.7%. In children of the first year of life, acute hepatitis was etiologically related to HBV-infection or to HBV and HDV coinfection. In a negligible part of the patients, VHA was diagnosed in the presence of chronic HBV-infection (1.2%) or exacerbation of chronic hepatitis B (0.3%). These data should be taken into consideration in planning and carrying out diagnostic, treatment and prophylactic measures aimed at solving VH problem in childhood.     

Hepatitis B e antigen positive mother hepatitis B e antigen long persistence in her non-infected baby

We report the case of a baby born to a hepatitis B virus (HBV) carrier mother. This infant had a hepatitis B e antigen (HBeAg) in the serum until 6 months of age. Serial sera samples were analysed for HBV markers. No breakthrough of HBV infection was detected. The origin of this HBV marker has been questioned. Conclusion: HBeAg can persist at a non-infected baby born to an HBeAg-positive mother up to the age of 6 months.