Impact of the implementation of a vaccination strategy on hepatitis B virus infections in China over a 20-year period

International Journal of Infectious Diseases 16 (2012) e82–e88

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Review

Impact of the implementation of a vaccination strategy on hepatitis B virus infections in China over a 20-year period Zhuanbo Luo, Lanjuan Li, Bing Ruan * National Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qing-Chun Road, Hangzhou 310003, People’s Republic of China

A R T I C L E I N F O

S U M M A R Y

Article history: Received 13 May 2011 Received in revised form 22 October 2011 Accepted 26 October 2011

Hepatitis B virus (HBV) vaccination has been recommended for all neonates in China since 1992. This article reviews the impact of HBV vaccination throughout the past 20 years in China. Before the introduction of the HBV vaccination program, approximately 9.8% of the general Chinese population tested positive for hepatitis B virus surface antigen (HBsAg). Since 1992, vaccination coverage has increased each year. In 1999, a National Expanded Programme on Immunization (EPI) review showed that the immunization coverage with three doses of HBV vaccine was 70.7%, and reached 99.0% in Beijing. The HBsAg carrier rate in the general population decreased to 7.2% in 2006. In particular, the prevalence of HBsAg decreased to 2.3% among children aged 5–14 years and to 1.0% among children younger than 5 years. In addition, the administration of the HBV vaccine may have reduced the risk of hepatocellular carcinoma among adults. Despite the administration of hepatitis B immunoglobulin and the HBV vaccine to children with HBsAg-positive mothers, the failure rate of HBV immunoprophylaxis was 5–10%. In China, vaccine failure was related to HBV S gene mutation and inadequate administration of HBV vaccine. The prevalence of HBV carriers in China was markedly reduced after the introduction of the universal HBV vaccination program. If we immunize all susceptible individuals with the hepatitis B vaccine (especially children), interrupt transmission, and provide antiviral treatment for existing HBV carriers, the number of new cases may be reduced to close to zero in the future and this may eventually result in the eradication of HBV. ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Corresponding Editor: Jane Zuckerman, London, UK Keywords: Epidemiology Hepatitis B vaccine Hepatitis B virus China

1. Introduction Hepatitis B virus (HBV) infection is a serious public health problem worldwide and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).1 At least 2 billion people are infected with HBV and among them 350–400 million are chronic HBV carriers. An estimated 1 million people die each year from acute and chronic sequelae secondary to HBV infection.2 Approximately 4.5 million new cases of HBV infection occur worldwide each year, and 25% of these cases progress to liver disease.3 There is a marked difference in the geographic distribution of carriers, ranging from 10–20% in Southeast Asia and SubSaharan Africa to less than 1% in Northern Europe and America.1,4 Approximately 75% of chronic carriers live in Asia and the Western Pacific.1,4 In low endemic areas, most HBV infections are acquired via horizontal transmission among adolescents and young adults. Regarding areas of high endemicity, the infection is often acquired during the preschool years, and the most common route of

* Corresponding author. Tel.: +86 571 87236585; fax: +86 571 87236585. E-mail address: [email protected] (B. Ruan).

transmission in Asiatic countries is perinatal and in African countries is horizontal during childhood.2,4 The risk of becoming an HBV carrier is 90% in cases of perinatal infection, between 25% and 30% for infected infants and children under 5 years of age, and less than 10% for infected adults.2,4 More than a quarter of infants and older children who acquire an HBV infection will eventually develop HBV-related HCC or cirrhosis. Adults who have had a chronic HBV infection since childhood develop HCC at a rate of 5% per decade, which is 100–300-times the rate among uninfected persons.1,4 In the People’s Republic of China, HCC is the second leading cause of cancer mortality. Approximately 110 000 persons die each year from HCC, which accounts for 45% of the deaths from HCC worldwide.5,6 In China, the standardized annual death rate from HCC was 11.00 per 100 000 persons in 1973–75, increasing to 17.83 per 100 000 persons in 1990–92, then remaining steady at 17.86 per 100 000 persons in 2004–05.7 Aging has contributed to this increase in the death rate during the past 30 years, because HCC develops most frequently in persons aged 40 years and older.8 However, since the introduction of HBV vaccination in 1992, the mortality rate has remained steady in the setting of aging. The major risk factor for HCC in China is clearly chronic HBV infection,

1201-9712/$36.00 – see front matter ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2011.10.009

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followed by hepatitis C virus (HCV) infection. The odd ratios for these two etiological agents are 11.34 for HBV and 4.28 for HCV (p < 0.05).9 More than 70–80% of HCC cases in China are attributable to HBV and approximately 20% of HCC patients test positive for HCV RNA.10–12 Because less than 10% of HCC cases are non-B and non-C, surveillance of hepatitis carriers is the most important tool for the prevention of HCC in China. Although current antiviral treatments using interferons or nucleoside/nucleotide analogs are effective against chronic HBV, chronic carriage of the virus is more difficult to eliminate. Considering that most HBV infections in China occur perinatally, universal infant vaccination is the key to the elimination and subsequent eradication of HBV. The first HBV vaccine, derived from human carrier plasma, was approved for use in the USA in 1981. In 1991, the World Health Organization (WHO) recommended that all countries implement a policy of universal HBV vaccination by 1997.13 Most countries have incorporated universal HBV vaccination into their national infant immunization programs. The estimated global coverage rate of infant HBV vaccination increased from less than 1% in 1990 to 30% in 2000, and from nearly 50% in 2004 to 69% in 2008.14 As of 2008, 177 of the 193 WHO member states (92%) had initiated HBV vaccination programs.15 This program has reduced not only the rate of persistent infection and the total prevalence of HBV in the younger generation, but also the occurrence of childhood HCC and fulminant hepatitis.16 In China, hepatitis B has significantly declined in the past decades as a result of the HBV vaccination program and the introduction of other public health measures, such as the use of universal precautions in medical settings and blood screening tests. Thus, this article reviews the impact of HBV vaccination in China over the past 20 years.

this is not mandatory, and provide the vaccine for the high-risk populations, increasing the vaccine dosage and number of shots for patients or non-responders. (4) Provide immediate care to individuals exposed to HBV by accident. For those who are negative or who have an unknown status for the antibody to the hepatitis B surface antigen (anti-HBs), a combination of the hepatitis B vaccine and HBIG are given immediately after exposure to the virus. In China, the hepatitis B immunization coverage rate has increased each year since 1992. Infant vaccination coverage with both the timely birth dose and the complete vaccine series was substantially higher among children born during 2003 than among those born during 1997; timely birth-dose coverage increased from 29.1% to 75.8%, and the HepB series completion increased from 70.7% to 89.8%, with the highest in Beijing at 99%.19 A study conducted in Zhejiang Province, which is located in the southeast of China, showed that by 1997, the hepatitis B immunization coverage rate for newborns receiving their first dose reached 96.1%, and for those receiving three doses reached 93.0%.20 In general, a protective antibody response occurs after the first dose in 30–50% of healthy adults aged 40 years or younger. This protective response occurs in 75.0% of healthy adults after the second dose, and in more than 90.0% of healthy adults after the third dose.16 Data obtained from a Chinese survey revealed that after completion of the three-dose HBV vaccination regimen, approximately 90–95% of healthy individuals exhibited protective concentrations of the anti-HBs antibody.21

2. Strategy for the prevention of HBV infection in China

According to a national study published in the early 1990s, the overall prevalence of chronic HBV carriage was approximately 9.8% in 61 702 subjects in 30 provinces of China (range 4.5–17.9%) before the introduction of the HBV vaccine.22 Liang et al.23 reported that the prevalence of HBsAg positivity in 2002 was 8.5% in a population of 46 167 people aged 10 years, born before the vaccination program was introduced. Zhou24 launched a survey of 7451 public employees between 2003 and 2004 to evaluate HBV infection. The results showed that the vaccinated population had a lower HBsAg prevalence compared with the unvaccinated individuals (3.1% vs. 8.3%). The study further discovered that the risk of becoming an HBV carrier in the vaccinated cohort was significantly associated with incomplete HBV vaccination (for those who received fewer than three doses of HBV vaccine). Tian et al.25 made a comparison of the HBV prevalence in 1983 and 2005 in Hebei Province. They reported that the overall prevalence of HBsAg among 5460 subjects aged 1 year was 8.6% in 1995. However in 2005, after 19 years of immunization with the vaccine, the average HBsAg positive rate of 10 010 subjects was 5.3%. A subgroup analysis revealed that the rate of HBsAg carriage among subjects aged 1–19 years was 9.4% in 1995, while it was 1.5% in 2005. Hence, the rate of HBsAg carriage declined from 9.4% in 1995 to 1.5% in 2005, a reduction of 84.4%. Most of the subjects aged 1–19 years in the 2005 survey were born after the introduction of the universal vaccination program. However, the rates of HBsAg carriage among subjects older than 20 years during the same years were 7.6% and 7.0%, respectively, a reduction of 8.4% from 1995 to 2005. For all years, the rates of HBsAg carriage were significantly lower among subjects aged 1–19 years than among subjects older than 20 years. Wu et al.26 also conducted a study on the HBV prevalence in people aged 1–49 years in 1999. They found that the prevalence of HBsAg among children (age range 1–13 years; born between 1986 and 1999) who were vaccinated as infants was below 1%. The rate of HBsAg carriage among junior and senior high

China is classified as an area of high HBV endemicity, and the HBV vaccine has been available in China since 1982. The Ministry of Health of China has implemented a series of regulations on the management of hepatitis B vaccination since 1992. As a result, the routine HBV immunization of infants was recommended in 1992; however unlike other Expanded Programme on Immunization (EPI) vaccines, families had to pay for the HBV vaccine. In 2001, the central government of China decided to integrate HBV vaccination into the EPI, requiring local authorities at all levels to provide free HBV vaccine to all infants from 2002; however the families had to pay the service fee for the vaccination procedure. The Chinese government finally adopted a completely free HBV vaccination program for all neonates in 2005.17 In China, most cases of HBV infection occur when the virus is transmitted from carrier mothers to infants during the perinatal period, and from other horizontal sources to infants and children. Over the past 20 years, China has adopted a series of strategies to eliminate HBV infection and prevent transmission of the virus.18 These strategies are outlined as follows: (1) Consistently strengthen general newborn hepatitis B vaccination. To prevent perinatal transmission, neonates born to hepatitis B surface antigen (HBsAg)-positive mothers should receive a combination of immunization with the hepatitis B vaccine (either 10 mg recombinant yeast vaccine or 20 mg Chinese hamster oocyte (CHO) vaccine) and hepatitis B immunoglobulin (HBIG; 100 IU) within 24 h after birth; within 12 h after delivery is also an option. By combining hepatitis B vaccine together with the HBIG injection, a 95–97% protective rate could be achieved in those neonates born to HBsAg-positive mothers. (2) Create a nationwide program that provides ‘catch-up’ immunization with the HBV vaccine for children who were not vaccinated at birth. (3) Encourage pregnant women to determine their HBsAg status in hospital even though

3. Impact of HBV vaccination in China over a 20-year period 3.1. Changes in the prevalence of chronic HBV carriers

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Prevalence of HBsAg(%)

12 10 8

1992

6

2006

4 2 0 10

10- 19 20- 29 30- 39 40- 49 50- 59 Age(years)

Figure 1. Comparison of the prevalence of hepatitis B surface antigen (HBsAg) in 1992 and 2006; HBV vaccination has been recommended for all neonates in China since 1992.

school students (born between 1982 and 1985) was 3.0%, which was significantly lower than the rate of HBsAg in people aged 20 years. People born between 1982 and 1985 were vaccinated as school-age children, but people older than 20 years had not ever been vaccinated. Although many epidemiological studies have assessed HBV infection in China, most of the studies have been based on unrepresentative or small populations from selected communities. The Chinese Ministry for Health, Center for Disease Control and Prevention, performed national hepatitis serosurveys in 1992 and 2006 among the population aged 1–59 years to investigate the epidemiological characteristics of HBV infection in China.27 As the surveys were based on a representative sample of the entire nation and used a stratified multistage probability sampling design, these data provide a comprehensive picture of the distribution of HBV in China. Data obtained from the first national survey in 1992 revealed that the rates of HBsAg seropositivity in children aged 4 years were 10.7% in males and 8.5% in females. Among children and adolescents aged 5–14 years, the seropositivity rates were 12.4% in males and 8.9% in females. The peak age for seropositivity was 10–14 years for both males and females, after which time the rates remained the same until the subjects reached 50–59 years. The rates then decreased in both males and females.28 Data obtained from the most recent national HBV survey in China, which was undertaken in 2006,27 after 14 years of HBV vaccination implementation, revealed that the prevalence of HBsAg in the general population was 7.2% in 2006 and was 1.0% among males and females aged 4 years (Figure 1). The prevalence of HBsAg was 2.3% in children and adolescents aged 5–14 years, and the total number of HBV carriers was estimated to be more than 93 million, among whom 30 million were patients with chronic hepatitis B. According to these nationwide surveys, the prevalence of HBsAg positivity in persons aged 4 years decreased from 9.7% in 1992 to 1.0% in 2006. The rate of HBsAg carriage among subjects aged 5–14 years declined from 10.7% in 1992 to 2.3% in 2006. A sustained decline in HBV infection is expected in the future, whereupon the prevalence of HBV infection in China will eventually be as low as that in Western countries. 3.2. Changes in HBV surface antibody and HBV core antibody positivity In 1992, the first national hepatitis serosurvey found that the weighted anti-HBs seropositive rate was 27.4%: 27.5% in males and 28.9% in females.28 The rate of HBV surface antibody (anti-HBs) in 3419 children aged 1–14 years increased sharply, from 37.2% in 1992 to 65.0% in 2002 in Guangdong Province following the introduction of the hepatitis B vaccine into the EPI in 1992.29 In

1999, Ma et al.30 also examined the prevalence of anti-HBs among 1727 children in Hebei Province and found that the anti-HBs seropositive rate was 93.9% among children aged 1–3 years, 57.8% among children aged 4–10 years, and 16.2% among children aged 11–14 years. Lei et al.31 reported in the middle 2000s that the serological epidemiology of anti-HBs for children aged 1–6 years in the Zhujiang Delta Area was 65.8%, which was similar to that in Guangdong Province. In 2005, Yu et al.32 reported that the anti-HBs positive rate in Wuhan City was 42.4% in 1992 in children aged 1–3 years, increasing to 79.1% in 1999. By 2003 it reached 83.2%; the positive rate increased by 49.0% when compared with that of children of the same age in 1992. A 2006 survey of national immunity conducted by the Chinese government revealed that the anti-HBs prevalence was 60.0% among children born during the period 1992–2005 (aged 1–13 years).33 Regarding the change in antibody to the hepatitis B core antigen (anti-HBc) positivity, during the 1980s, the proportion of chronic HBsAg carriage attributable to perinatal transmission was estimated at 13–20%. Thereafter, the prevalence of anti-HBc increased with increasing age. The anti-HBc positivity rate was nearly 30.0% among children younger than 10 years. Among adults in their forties, the infection rate reached approximately 60.0%.34 After the introduction of the vaccine program, Chen et al.35 reported that the anti-HBc seropositive rate in 2002 was 11.9% among children aged 3–5 years, 9.5% among children aged 6–10 years, and 12.7% among children aged 11–15 years. During the late 2000s, the prevalence of anti-HBc decreased with decreasing age and was less than 10% in the population younger than 15 years.36 These data may reflect the effects of universal HBV vaccination in China. In the national survey of 2006,27 the proportion of anti-HBc was highest in adults aged 50–59 years (50.0%) and decreased with decreasing age (Figure 2). 3.3. Changes in hepatitis B e antigen (HBeAg) status among HBsAgpositive persons In the national survey of HBV in 1992, the age-specific prevalence of HBeAg among HBsAg carriers was 32.7%. Children aged 1–14 years had the highest prevalence of 53.3%. After that, the prevalence decreased with age to 12.3% in people aged 40–59 years.28 In the most recent survey in 2006, we found that among HBsAg-positive children aged <15 years, the proportion positive for HBeAg was still high (>68%). HBeAg decreased with age to 15.0% among persons age 40–59 years. These are similar to percentages found in 1992. Hence, over the past 20 years, a change in the HBeAg-positive rate is not evident. The currently available hepatitis B vaccines should continue, particularly ensuring that timely birth doses are given to all children.

70

Prevalence of Anti-HBc(%)

e84

60 50 40

1992

30

2006

20 10 0 10

10- 19

20- 29

30- 39

40- 49

50- 59

Age(years) Figure 2. Comparison of the prevalence of antibody to hepatitis B core antigen (antiHBc) in 1992 and 2006; HBV vaccination has been recommended for all neonates in China since 1992.

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3.4. Changes in the incidence of HCC 0.7

HCC is one of the most common cancers worldwide (ranking within the top 10). In some parts of Asia it represents the first or second most common cancer and is a major public health problem.37 The treatment of liver cancer may be difficult because most patients, especially those in less developed areas, are diagnosed at an advanced stage, at which time the disease is not amenable to potential curative therapy. Thus prevention is the key to reducing the occurrence of liver cancer and its related mortality. With respect to liver cancer, hepatitis B vaccination early in life before infection occurs provides a good example of a primary prevention measure. At a WHO meeting in 1983, the evidence for an association between the carrier state of HBV infection and liver cancer was sufficiently strong to justify the use of a vaccine against this infection as a means of preventing this cancer.38 In 1998, a large-scale cohort study39 performed in Korea reported that HBV vaccination protected against the development of HCC in adult men. This study found that the incidence of HCC was lower in the vaccinated group than in the unvaccinated group and suggested that HBV vaccination significantly decreases the incidence of HCC, even in adulthood. Importantly, a Taiwanese study demonstrated a decline in the incidence of HCC in children after the implementation of universal hepatitis B vaccination.40 Mass vaccination against hepatitis B was launched in 1984 in Taiwan. The study reported that the average annual incidence of HCC in children aged 6–14 years 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), after the vaccination program was started (Figure 3). The corresponding rates of mortality from HCC also decreased. A more recent study from Taiwan by Chang et al.41 also revealed the effectiveness of the universal HBV immunization program to prevent HCC. In each of the study age groups, the incidence rates of HCC were significantly (p < 0.001) lower in the vaccinated birth cohorts compared with the unvaccinated (Table 1). The data suggest that 75% of HCC in children in Taiwan might be prevented by hepatitis B immunization. These are long-term follow-up studies that can verify that hepatitis B vaccination not only protected children from becoming carriers but also protected them against HCC. Along with a decrease in HBsAg carrier status, the development of HCC is expected to decrease in the near future. 4. Failure of immunoprophylaxis Before the introduction of the HBV vaccine, nearly 90% of infants born to HBeAg-positive mothers were infected at birth.42,43 By administering HBIG and the HBV vaccine to all neonates born from HBsAg-positive mothers, 88–95% of all cases of perinatal

0.6 0.5

Annual 0.4 Average Incidence/100 000 0.3

0. 7 0. 57 0. 36

0.2 0.1 0

1981-1986

1986-1990

1990-1994

Year Figure 3. Average annual incidence of hepatocellular carcinoma in children aged 6–14 years before and after the start of the HBV vaccination program; HBV vaccination was recommended in 1984 in Taiwan.

transmission of HBV could be eliminated.43,44 However, despite the adequate administration of HBIG and the HBV vaccine at birth, about 5–10% of cases of perinatal transmission of HBV could not be completely prevented.44,45 Although the cause of prophylaxis failure is still unclear, high levels of maternal viremia and intrauterine infections probably contribute.44–49 According to studies reported in China,50,51 vertical transmission in infants was uniquely associated with the mother’s HBeAg titer and HBV DNA levels. HBsAg-positive rates in infants according to the HBeAg status and HBV DNA levels of their HBsAg-positive mothers are shown in Tables 2 and 3.51 Among the 178 neonates born to mothers whose HBeAg titer was 1:100 or greater and HBV-DNA was 125 pg/ml or greater, 31 (17.4%) were HBsAg-positive. Conversely, of the infants born to mothers whose HBeAg titer was less than 1:100 or HBV-DNA load was less than 125 pg/ml, one was HBsAg-positive. Wang et al. also reported that the mean HBV DNA level of mothers whose babies became infected with HBV was significantly higher than the mean level of those mothers whose babies did not become infected with HBV (2.14  105 copies/ml vs. 2.39  106 copies/ml; p = 0.04).52 Liu et al.50 reported that a high HBV DNA viral load (107 copies/ml) was the most important risk factor for the failure of immunization; they determined that the danger of vertical transmission was low when the HBV DNA load was less than 105 copies/ml in the mother, but increased as the level rose to 107, 108, and 109 copies/ml. These studies reveal the importance of perinatal transmission of HBV from HBeAg-positive and high HBV DNA level mothers to their children. The same conclusions have been reached in other countries. In Korea, Song et al.53 evaluated the failure of HBV immunoprophylaxis in 144 children who received HBIG and the HBV vaccine, and who were born to HBsAg-positive mothers with detectable HBV DNA. Among the 144 participants, 17 (11.8%) experienced

Table 1 Incidence rates of hepatocellular carcinoma in Taiwan among children aged 6–9, 10–14, and 15–19 years, born before and after the launch of the Taiwanese universal hepatitis B virus vaccination program in 1984 Age at diagnosis, y

6–9

10–14

15–19

95% CI, 95% confidence interval.

Birth year

1973–1979 1979–1984 1984–1998 1968–1979 1979–1984 1984–1994 1963–1979 1979–1984 1984–1989

Hepatocellular carcinoma

p-Value

Incidence rate (per 100 000 person-years)

Rate ratio (95% CI)

0.51 0.47 0.15 0.60 0.50 0.19 0.52 0.80 0.16

1 (referent) 0.93 (0.59–1.46) 0.30 (0.18–0.42) 1 (referent) 0.84 (0.60–1.17) 0.32 (0.21–0.49) 1 (referent) 1.55 (1.17–2.04) 0.30 (0.16–0.58)

0.74 <0.001 0.29 <0.001 0.001 <0.001

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Table 2 Changes in vaccine failure rate in the newborn according to maternal HBeAg titer Maternal HBeAg titers

Mother–child pairs

Vaccine failure rate, n (%)

<1:50 1:50 1:100 1:200 1:400

56 20 16 16 70

0 0 2 5 25

(0) (0) (12.5) (31.3) (35.7)

HBeAg, hepatitis B e antigen.

Table 3 Changes in vaccine failure rate in the newborn according to maternal HBV DNA titer Maternal HBV DNA titers (pg/ml)

Mother–child pairs

Vaccine failure rate, n (%)

<125 125–1000 1000–8000 8000

86 24 60 8

1 6 21 4

(1.2) (25) (35) (50)

HBV, hepatitis B virus.

immunoprophylaxis failure. The rate of HBV immunoprophylaxis failure was 12% among children born to mothers who were HBsAgpositive, 0% in those born to HBeAg-negative mothers, 21% in those born to HBeAg-positive mothers, 0% in those born to mothers with undetectable HBV DNA, and 27% in those born to mothers with detectable HBV DNA. A study by Kang et al.54 reported that the failure rate of HBV immunoprophylaxis was 7.4% and that all such cases had been born to HBeAg-positive mothers. According to a national survey in 2006,33 among the neonates born in 2005, the rate of weighted three-dose coverage of hepatitis B vaccine reached 93.4%. Despite the high rate of three-dose coverage, the positivity rate of anti-HBs was only 84.5%. Approximately 10% of newborns experienced immunoprophylaxis failure, defined as anti-HBs seronegativity. These reports confirm again that maternal transmission is the primary reason for vaccine failure and that it is this primary problem that must be addressed. Therefore, maternal HBeAg and HBV DNA levels should be assessed prior to childbirth to identify children at high risk of immunoprophylaxis failure. The effectiveness of strategies to reduce maternal HBV activity during the perinatal period should also be further elucidated. Another mechanism of vaccine failure involves HBV surface gene mutants. The immune pressure of hepatitis B immunization and HBIG promotes the selection of HBV surface gene mutants. In particular, S gene HBV mutants (i.e., the prototype G145R mutation, in which a single amino acid substitution of glycine to arginine occurs at amino acid 145 of the ‘a’ determinant of the surface antigen) have been identified in Italy and elsewhere.55–57 Such mutants can potentially escape neutralizing anti-HBs antibodies and infect vaccinated people. In Taiwan, the prevalence of surface gene mutants was found to be approximately 20.0% in HBsAg carrier children.56 However the prevalence of HBV surface gene mutants across the nation of China remains unclear. A survey undertaken in eastern China50 found that the total mutation rate was only 12.5% (2/16) in vaccination failed children. Hu et al.58 reported that among immunoprophylaxis failed children, the prevalence of amino acid substitutions was 20.0%. Wang et al.59 also reported that nucleotide diversity rates were 11.4% in the children of Jiangsu Province. This might be because the HBV S gene mutation rates differed with the geography and the years of HBV vaccination. However, the mutation rate was clearly lower than that in children who failed to be protected by perinatal prophylaxis in other countries (Singapore 39.0%, Japan 30.8%, USA 25.5%),60–62 and higher than that in Korea.63 Therefore, compared with previous studies in other nations, gene surface variants do not

appear to play an important role in perinatal immunoprophylaxis failure in China. Chen reported that the presence of vaccine escape mutants does not seem to threaten the ongoing hepatitis B control strategies worldwide.16 Worthy of note is the fact that the current hepatitis B vaccines can protect chimpanzees from infection with a mutant virus.64 Hence, the currently available hepatitis B vaccines can be continued in all countries including China. Inadequate administration of HBV vaccine may be a cause of perinatal immunoprophylaxis failure. A national survey undertaken in 200565 reported that the coverage with a timely birth dose was only 69.6% in rural areas and 86.9% in urban areas. Furthermore, most hospitals refrained from administering HBIG to mothers of unknown HBsAg status until a complete report was obtained. Such a delay in providing the initial dose of the vaccine increases the risk of HBV infection in the child. Increasing the HBIG coverage rates among infants born to HBsAg-positive mothers is also an important way to prevent mother-to-infant transmission. Data obtained from the national study also revealed that the HepB series completion rate of infants was approximately 90.7% in rural areas and 95.0% in urban areas.65 Therefore, the rate of vaccination coverage must be increased to minimize the risk of HBV transmission, and the timely administration of the HBV vaccine must be ensured. These data suggest that considerable variation exists in the administration of perinatal prophylaxis and that failure to provide appropriate immunoprophylaxis remains an important cause of perinatal HBV infection, especially among infants born in rural areas of China. 5. Strategies towards the eradication of hepatitis B As is known to us, infection with HBV consists of three components: an infectious source, a susceptible host, and an established route of transmission.66 Because humans are the only reservoir of HBV, it is not impossible that a comprehensive control strategy could eventually lead to the eradication of the virus. To begin with, existing HBV carriers can now be treated effectively67 and viral load can decrease to undetectable levels, so that infection does not spread rampantly. However, prolonged use of current nucleos(t)ide analogs against HBV still poses the problem of viral resistance, and the cost of long-term treatment is still high.67 Another important strategy is to interrupt the transmission route through education of the public and medical personnel, although changes in high-risk human behaviors are often difficult to achieve. In China, we should place an emphasis on more and better screening of HBsAg in pregnant women. Screening pregnant women will result in the early detection of high-risk infants for HBV infection, so that measures to prevent mother-to-infant transmission can be taken. The most effective strategy, however, is to immunize all susceptible individuals with the hepatitis B vaccine, especially children.66,68 Universal hepatitis B vaccination in childhood can prevent not only chronic HBV infection in high endemic areas, but also acute HBV infection in low endemic areas of China. Therefore, it should be recommended at all levels of government, regardless of HBV endemicity. A recent survey revealed that HBIG may also play an important role. Xu et al.69 reported that it is effective and safe to prevent intrauterine infection of HBV with HBIG from the 28th week of pregnancy in women who are positive for HBeAg and HBsAg. This is particularly significant in China, as most HBV carriers are infected by motherto-infant transmission. Many researchers from China70 and other countries71 have also reported that the addition of HBIG to the recombinant vaccine for neonates will significantly increase the prevalence of anti-HBs and the protection against HBV infection in comparison with HBV vaccine alone. In summary, the combined efforts of universal vaccination, HBIG, antiviral treatment, and interruption of transmission make

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the elimination of HBV infection plausible and may eventually result in the eradication of HBV. To reach this goal, all efforts need to be supported adequately, and a long-term commitment from both government and non-governmental organizations is essential. This support should be lasting and overcome the existing backlog of HBV carriers in the population of China. The goal of eradicating HBV is plausible, but every endeavor should to be pursued to make this become a reality. 6. Conclusions Hepatitis B vaccination has effectively reduced the infection and chronicity rates of HBV and related complications. However, despite adequate administration of HBIG and the HBV vaccine in children with HBsAg-positive mothers, the vaccine failure rate was 5–10%. Vaccine failure was related to HBV S gene mutation and inadequate administration of HBV vaccine in China. Despite considerable efforts to reduce HBV infection via the universal vaccination of all newborn and school-age children, a large proportion of the population was previously infected with HBV and still harbors the virus. Although difficult, the eradication of HBV remains possible in China in the future, considering that humans are the only reservoir of HBV. Acknowledgements This study was supported by Mega-projects of Science Research for the 11th and 12th Five-Year Plan of China; the epidemiology, prevention, and control of major infectious diseases (2009ZX10004-901, 2011ZX10004-901), Ministry of Science and Technology. Ethical approval: Our study was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, China. Conflicts of interest: None. References 1. Cha C, Dematteo RP. Molecular mechanisms in hepatocellular carcinoma development. Best Pract Res Clin Gastroenterol 2005;19:25–37. 2. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004;350:1118–29. 3. Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol 2005;34:1329–39. 4. Lok AS. Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 2004;127:S303–9. 5. Wang JS, Huang T, Su J, Liang F, Wei Z, Liang Y, et al. Hepatocellular carcinoma and aflatoxin exposure in Zhuqing Village, Fusui County, People’s Republic of China. Cancer Epidemiol Biomarkers Prev 2001;10:143–6. 6. Shi J, Zhu L, Liu S, Xie WF. A meta-analysis of case–control studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma in China. Br J Cancer 2005;92:607–12. 7. Chen JG, Zhang SW, Chen WQ. Analysis of liver cancer mortality in the national retrospective sampling survey of death causes in China, 2004–2005. Chin J Prev Med 2010;44:383–9. 8. Bosch FX, Ribes J. The epidemiology of primary liver cancer: global epidemiology. In: Tabor E, editor. Viruses and liver cancer. Amsterdam, the Netherlands: Elsevier; 2002 . p. 1–16. 9. Luo RH, Zhao ZX, Zhou XY, Gao ZL, Yao JL. Risk factors for primary liver carcinoma in Chinese population. World J Gastroenterol 2005;11:4431–4. 10. Xin YN, Xuan SY. Hepatitis B virus, hepatitis C virus infection and primary liver cancer research. Chin J Clin Hepatol 2006;22:64–5. 11. Nguyen VT, Law MG, Dore GJ. Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat 2009;16: 453–63. 12. Lavanchy D. Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol 2005;34(Suppl 1):S1–3. 13. World Health Organization: Expanded Programme on Immunization. Global Advisory Group. Weekly Epidemiol Rec 1992;67:11–6. 14. World Health Organization. Global immunization 1989–2010, 3rd dose of hepatitis B coverage in infants. Geneva: WHO; 2010. Available at: http:// www.who.int/immunization_monitoring/diseases/HepB_coverage.jpg (accessed November 2011).

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