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Keywords:

  • epidemiology;
  • hepatitis B virus;
  • prevention;
  • transmission;
  • vaccine

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

Summary.  The concept of a hepatitis B vaccine was first introduced into China in 1978. China has been one of the first two developing countries to enact the universal hepatitis B vaccination programme for newborn babies in 1992, and has made tremendous achievements in the control of hepatitis B virus (HBV) infection since then. China now has both low and high endemic regions regarding HBV prevalence co-existing. Although China’s drive to stop HBV spread has resulted in changes in HBV epidemic patterns, for the eventual elimination HBV infection in China, it is important to understand the current status of its epidemiology and the aspects of HBV transmission in different regions. More efforts are needed to improve and develop strategies for the control of HBV infection in China, particularly after implementing the policy of universal HBV immunization for all newborns.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

Prevention of hepatitis B virus (HBV) infection has been amongst the highest priorities for healthcare in China. The concept of a hepatitis B vaccine was first introduced into China in 1978, only 2 years after Buynak and colleagues suggested using hepatitis B surface antigen (HBsAg) purified from HBsAg carrier serum as a vaccine to protect against HBV infection [1,2]. Demonstration programmes of an HBV vaccine performed in the mid-1980s in China produced an obvious positive outcome [3,4]. Consequently, in 1992, the year the World Health Assembly passed a resolution recommending global vaccination against HBV infection, China immediately enacted a policy of universal hepatitis B immunization for all newborns. Following the introduction of this policy, the overall HBV infection rate and HBsAg prevalence rate amongst the Chinese population, particularly in children under 15, have shown a dramatic decline [5]. This significant achievement in the battle against the HBV epidemic in the world’s most populated country makes it obvious that vaccination is a cost-effective measure to prevent HBV infection. Furthermore, as one of the HBV hyper-endemic areas in the world, China’s progress in controlling HBV infection has resulted in fundamental changes in the HBV epidemic pattern.

China is now recognized to have regions with low and high HBV endemicity co-existing. In some more developed areas, such as Beijing and Shanghai, the HBsAg carrier rate is as low as 3.03%, while in the less developed areas, such as western and southern provinces in China, serum HBsAg prevalence rate is still greater than 8% [6,7]. Thus, it continues to be important to understand the current status of HBV epidemiology in China. Only with this information to hand can immunization strategies be developed and comprehensive measures be implemented for the eventual elimination of HBV infection in China [6,8]. In this article, an overview of the current status of the epidemiology of HBV infection in China is given.

Decreases in HBV infection and HBsAg prevalence in the general population

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

The first nationwide sero-epidemiological survey on HBV infection in China was carried out in 1979. A total of 277 186 subjects (138 360 men and 138 826 women) from 209 counties and cities in 29 provinces were screened, making it the largest sero-epidemiological survey of viral hepatitis ever conducted in China. However, because the survey used a not very sensitive reverse passive haemagglutination (RPHA) assay to detect serum HBsAg, it was widely held that the 8.8% overall HBsAg prevalence rate seen among the general population underestimated the true prevalence of HBV in China at that time, and consequently the rate was never fully accepted by most experts [9]. Between 1984 and 1987, serum samples from a further 10 484 individuals were tested using a more sensitive radioimmunoassay (RIA), and this indicated that approximately 58.2% of the population showed evidence of having been infected by HBV, with the overall HBsAg prevalence rate being 10.1% [10,11]. China was therefore classified as a high endemic area under the World Health Organization (WHO)’s categorization, because it had ≥8% HBsAg prevalence in the general population.

The second nationwide HBV sero-epidemiological survey was conducted in 1992, as China began to enact the policy of universal infant immunization. The data showed that the HBV infection rate in the general population was 57.6% and the HBsAg carrier rate was 9.75% [12,13]. To evaluate the protective efficacy of HBV immunization, the third nationwide HBV sero-epidemiological survey was conducted in 2006 [5]. A total of 81 775 individual serum samples was collected at 160 disease surveillance sites from 31 provinces. To avoid bias, people from both rural and suburban areas were enrolled in the survey, and a multistage cluster-randomized sampling was used. This most recent sero-epidemiological survey revealed that the HBsAg carrier rate among the general population of the country had fallen by approximately one-quarter, from 9.75% in 1992 to 7.18% in 2006. Viewed in terms of infected individuals, this means that more than 30 million chronic HBV carriers have been prevented since 1992. China has now fallen from a high endemic area with HBsAg sero-prevalence ≥8%, into an intermediate endemic area where HBsAg prevalence in the general population is 2 ∼ 7%.

A more detailed analysis of serum HBsAg prevalence rates found in that fraction of the population affected by the introduction of universal infant immunization in 1992 shows that rates increased steadily from the lowest value of 0.96%, which was seen in the 1–4-year-old group through 2.42% in 5–14-year-old group and to 5.4% in 15–19-year-old group [14,15]. Figure 1 shows graphically the dramatic decrease in HBsAg prevalence among children younger than 15 years, who have had access to the HBV vaccine under the current expanded programme of immunization (EPI) in China [16,17]. This contrasts with the HBsAg prevalence in the 20–59-years-old cohort, which remains largely unchanged between the 1987 and 2006 sero-surveys (Fig. 1). This highlights that significant improvement in the public health consequences of chronic HBV infection cannot be expected until the current adult population is replaced by those who have been immunized against HBV under the ongoing universal infant immunization programme in China [14,18].

image

Figure 1.  Age-adjusted distribution of serum HBsAg prevalence rates from the 1987 and 2006 nationwide sero-epidemiological surveys.

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The shift of HBV sero-marker patterns

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

Due to the implementation of the universal infant HBV immunization programme in China, a shift in HBV sero-marker patterns has been observed. Among children younger than 15 years, the serum anti-HBc prevalence rate decreased, while the anti-HBs prevalence rate increased dramatically. The younger the children are, the more remarkable the changes. For instance, the anti-HBs prevalence rate in the 1–4-year-old group increased from 15.75% in 1992 to 72.25% in 2006, while the anti-HBc prevalence declined from 30.08% in 1992 to 3.76% in 2006 (Table 1) [8].

Table 1.   The shift of HBV sero-marker patterns
Age (years)YearNo. testedHBsAg (+)Anti-HBs (+)Anti-HBc (+)
No.%No.%No.%
1–19923 2883189.6751815.7598930.08
200616 3761771.0811 83272.256153.76
5–19926 39865410.221 37421.482 42637.92
200611 9091911.606 97558.576405.37
10–19926 31671211.271 57624.952 84445.03
200611 8443993.376 46054.541 27610.77

Decrease of acute hepatitis B incidence

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

A number of longitudinal cohort studies carried out in China have shown a steady decrease in the incidence of acute hepatitis B (AHB). For example, in Beijing the incidence of AHB in children of 0–4 and 5–9 years of age was 20.5/100 000 and 18.6/100 000, in 1990; respectively, at the time the HBV vaccine coverage was very low. This incidence was very close to the average incidence of hepatitis B in the whole population (22.1/100 000). The incidence of AHB in children remarkably decreased to less than 4/10 000 in 1995 and <1/10 000 in 2001, particularly in children of 0–4 years of age. However, the incidence of AHB in adults remained at a high level during those 12 years [19]. Data from Shanghai showed that the incidence of AHB dropped by more than 50% between 1993 and 2005 [20]. In Long’an county, an area of high endemicity with HBsAg sero-prevalence as high as 16% in the general population [21], the adoption of universal neonatal immunization in 1986 in Long’an county has had a dramatic effect on the incidence of AHB. A survey carried out in 2003 revealed AHB incidence among children of 1–14 years to be 1.5 cases per 100 000, a drop of more than 90% compared with the incidence seen in 1985 ∼ 1987 [3,21].

Changing patterns of HBV transmission

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

HBV is transmitted from person to person through percutaneous/mucous membrane exposure to blood or other body fluids of an infected person; that is, by sexual, perinatal and parenteral/percutaneous transmission. Convincing data have proven that the percentage of chronic HBV infection in a population has a strong impact on the transmission pattern of HBV infection.

Mother-to-child infection has been an important route of transmission and a major cause of high chronic infection in China; however, after more than 15 years of universal neonatal vaccination, a decrease in chronic HBV infection acquired vertically or during early childhood was observed in the 2006 sero-survey. For example, the HBsAg prevalence rate in children younger than 1 year decreased from 9.02% in 1992 to 0.69%, while that in the 5-year-old group decreased from 11.7% in 1992 to 1.2%. This indicates a big drop in HBV transmission during the neonatal period and early childhood since general neonatal hepatitis B vaccination in China.

Unsafe blood transfusion and/or the use of contaminated blood products had once been an important route of spreading HBV infection in China [22], and post-transfusion hepatitis occurred in up to 50% of all transfusions in the 1960s. Serological screening of blood donors was started in some blood centres from the late 1970s. Routine strict blood HBsAg screening was introduced to all blood centres by the Chinese Ministry of Public Health in the early 1980s. Since then, HBV infection due to unsafe blood transfusion has been satisfactorily controlled, particularly after the Law for Donating Blood was issued in 1998, and the later implementation of the Regulations for the Management of Blood in Clinical Facilities by the authorities. However, the relatively high presence of occult HBV infection (OBI) among blood donors in China reminds us that the possibility of HBV infection through blood transfusion still exists [23].

Sexual contact with chronically infected persons has been recognized as one of the most efficient routes of HBV transmission [24,25]. In regions of low prevalence, such as most of North America and Western Europe, where less than 1% of the population is chronically infected, most infections are acquired during adolescence to mid-adulthood due to unprotected sexual activity or intravenous drug use. Improper sexual behaviours had been repressed for many years in China before launching the opening-up policy in the 1980s. Therefore, sexual contact has been considered as an additional route of infection through transmission from infected husband to wife, or vice versa [26]. However, promiscuous sexual activity has increased in recent years following society’s more open attitude to sex. Consequently, HBV transmission attributed to sexual contact is increasing. The 2006 sero-epidemiological survey showed that in contradiction with the dramatic decline of HBV infection among children younger than 15 years, the HBsAg carrier rate in the 20–30-year-old group was the highest among all the age groups, at up to 10.5%, significantly higher than that of the 15–19-year-old group’s 5.4% prevalence rate [5]. This high rate of HBsAg prevalence suggests the role of sexual transmission among those sexually active persons from adolescence to mid-adulthood [27]. Data from the third nationwide sero-epidemiological survey showed high serum HBsAg prevalence among sexually active persons from adolescence to mid-adulthood, strongly suggesting the importance of HBV infection transmission via sexual activity in China currently (Fig. 1). Accordantly, a study on the incidence rates and sex- and age-specific incidence rates of hepatitis B from 1990 to 2007 in Shandong province found that 35.72% of the reported cases were aged between 15–29 years [28]. Therefore, it is worthwhile to note the urgent need to expand the coverage of the current HBV vaccination programme to sexually active young adults in China.

A population-based survey in Shanghai, the most developed area in China, revealed that undergoing an invasive medical procedure was also a major risk factor for AHB, as well as close household contact. Unsafe injections (both intramuscular and intravenous) or infusions, endoscopy, surgery, body care and beauty treatment in public places, including pedicures were associated with increased risk of acquiring HBV infection [19,29]. Although auto-disposable (AD) syringes have been widely used in socioeconomically developed urban areas in China in recent years, in some underdeveloped rural western areas, AD syringes were used in only 40.28% of clinics/hospitals [30,31]. An epidemiological retrospective study in Guangxi province showed that up to 63.6% of chronic HBV infections were caused by unsafe injection among unimmunized susceptible children [32]. Haemodialysis is another high risk factor for iatrogenic HBV infection; however, with regulations for infection control practices being enforced in recent years, we have witnessed an obvious decline in dialysis-related HBV infection. For those haemodialysis patients receiving continuous treatment, if with no blood transfusion history, the HBsAg rate dropped from up to 50% previously to the current 13.0 ∼ 35.0% [33,34]. In addition, the nosocomial spread of HBV infection in dental clinics has been recognized as a route of transmission, and has been becoming an important cause of HBV infection in recent years, as dental care is becoming affordable to people with increasing incomes.

Increased prevalence of HBeAg-negative chronic hepatitis B

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

HBeAg is a serum viral marker of active HBV replication in the liver, and a number of natural history studies have linked poor prognosis to the persistent detection of HBeAg [35,36]. Therefore, the loss of HBeAg in serum and the emergence of anti-HBe (termed HBeAg seroconversion) is normally accompanied by low HBV replication and is associated with positive disease outcome. Indeed, 90∼95% of HBeAg seroconversions are followed by clinical remission and a life-long inactive state with lower serum HBV DNA levels. However, even after HBeAg seroconversion, a small proportion of patients with chronic HBV infection may still have active viral replication defined by high serum HBV DNA, and continuous necroinflammation in the liver marked by elevated alanine aminotransferase (ALT) levels. Therefore, based on serum HBeAg status, CHB can be distinguished into two subcategories in clinical practice: HBeAg-positive and HBeAg-negative CHB. HBeAg-negative CHB is different from its HBeAg-positive counterpart regarding its clinical and histological background. The proportion of HBeAg-negative CHB has been increasing in recent years in China. The proportion was found to be 37.3% in 2000 [37] and 53.7% in 2006 [14]. Several reasons might account for this increasing proportion: (i) spontaneous HBeAg seroconversion (i.e. HBeAg negative and anti-HBe positive status) during a persistent HBV infection; (ii) selection of HBV precore (preC) and/or basal core promoter mutants during persistent immune pressure; (iii) the decrease of the incidence of AHB, patients of which normally have HBeAg-positive status, due to the universal HBV vaccination programme, screening of blood donors and improvement of safe injections; and (iv) the increased sensitivity of the anti-HBe detection assay. Patients with HBeAg-negative CHB are more likely to develop end-stage liver disease and hepatocellular carcinoma (HCC) and have poorer response to anti-HBV treatment. A study showed that cirrhosis and HCC were observed in 8% and 2% of patients after HBeAg seroconversion, respectively [35].

Decrease of morbidity and mortality of hepatocellular carcinoma

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

Chronic hepatitis B is a major cause of end-stage liver disease and mortality resulting from cirrhosis-related liver failure or HCC. In 1984, a HBV vaccination programme was launched in Taiwan. During the first 2 years of the programme, only newborns of high-risk (HBsAg-positive) mothers were vaccinated, while the vaccination programme was extended to all newborns after July 1986. The annual average morbidity rate of HCC in children in the 6–14-year-old group was 0.7 cases per 100 000 during 1981 to 1986 (before the vaccination programme) in Taiwan, which declined to 0.36 cases per 100 000 during 1990 to 1994 (after the vaccination programme) [38,39]. In 1985, a HBV vaccination programme for children aged 1–10 years was launched in Long’an county, Guangxi Province, China. In 1987, the programme was integrated into EPI for all newborns in the county. The coverage rates of HBV vaccine have kept constant at approximately 89.8%. The data obtained from the HCC Registration and Surveillance Systems in Long’an County showed that HCC mortality in children aged 10–19 years decreased dramatically from 5.7 cases per 100 000 during 1969 to 1988 to 0.4 cases per 100 000 during 1996 to 2001. HCC mortality in the other age groups did decrease to some extent, but not as dramatically as that in 10–19-year-old group [40].

Prevention of HBV infection has always been one of China’s highest priorities of public health. Since conducting the universal neonatal hepatitis B vaccine immunization programme and the endorsement of other comprehensive measures, the situation regarding HBV infection in China has been greatly improved. However, HBV infection still remains a serious public health problem in China. The estimated current chronic HBV infection among China’s 1.3 billion population still runs up to 93 million people, including 20–30 million patients with CHB. HBV and related liver cirrhosis and HCC cause approximately 300 000 deaths annually in China. Prophylactic HBV vaccination has been proven to be the most cost-effective strategy for the control of hepatitis B. For the control and eventual elimination of HBV infection, China has just launched a 15-year-long project with emphasis on the development of new immunization strategies [18,41]. The following issues will be addressed: (i) the urgent need to develop optimum immunization strategies characterized by the altering epidemiological features of hepatitis B; (ii) the development of different vaccine formulations to adapt to different populations at risk, such as those with difficulty in inducing a protective immune response after receiving the routine HBV vaccination; (iii) the establishment of more effective strategies to block vertical HBV transmission from HBsAg-positive mothers, particularly from those who are both HBsAg and HBeAg positive; (iv) the development of new generation HBV vaccines with long-term protection and better efficacy to simplify the procedure of vaccination; and (v) the needs for standard assay systems for humoral and cell-mediated immunity, which are essential for the evaluation of hepatitis B vaccine prevention efficacy and immunity persistence, if only so that the need for booster inoculation (how and when) can be addressed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References

The authors are grateful to Professor Malcolm A. McCrae from the University of Warwick for making some critical comments on the manuscript, and to Mr Leo Studach from Purdue University for English editing. This work was supported by grants from the Beijing Municipal Science and Technology Commission (no. D08050702870000), and the National S & T Major Project for Infectious Diseases Control (no.s 2008ZX10002-001, 2008ZX10002-004 and 2008ZX10002-012).

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Decreases in HBV infection and HBsAg prevalence in the general population
  5. The shift of HBV sero-marker patterns
  6. Decrease of acute hepatitis B incidence
  7. Changing patterns of HBV transmission
  8. Increased prevalence of HBeAg-negative chronic hepatitis B
  9. Decrease of morbidity and mortality of hepatocellular carcinoma
  10. Acknowledgements
  11. References
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