Background
Hepatitis B virus (HBV) infection remains a huge public health burden in China [
1,
2] despite the success of HBV vaccination. Hepatitis B vaccine was first introduced into China in 1978 [
1]. In 1985, China initiated HBV vaccination in a small population with a plasma-derived hepatitis B vaccine [
3]. In 1992, the Chinese Ministry of Health recommended that infants be routinely vaccinated against HBV, but recipients were charged for both the vaccine and service [
4]. As a result, higher percentages of infants in the more affluent larger cities on the eastern coast of China received HBV vaccination compared to infants inland and in rural areas [
5]. In 2002, China integrated HBV vaccination into an expanded national immunization program in which HBV vaccines were free of charge [
6]. Furthermore, the service fees for HBV vaccination were waived in 2005 [
7]. In 2009, China enacted a new policy that enabled children < 15 years of age who had not been vaccinated to receive free vaccinations [
8]. In 2011, China started a new program that combined the prevention of mother-to-child transmissions of HIV, syphilis, and HBV in 1156 counties (representing 44% of pregnant women in China) and then expanded it nationwide to cover all pregnancies in 2015 [
9].
Since this universal HBV vaccination strategy was implemented among infants from the early 1990s, HBsAg seroprevalence in China has decreased, particularly among children [
10]. In 1992, just before the implementation of the universal HBV vaccination of infants, a nationwide survey sampling 61,702 participants across 30 provinces in mainland China found that the overall HBsAg positivity was 9.8% (range: 4.5–17.9%) [
11]. In that survey, HBsAg positivity in male and female children aged ≤4 years was 10.7 and 8.5%, respectively; for male and female children aged 5–14 years the figures were 12.4 and 8.9%, respectively. Peak HBsAg positivity occurred in both males and females aged 10–14 years, but similar HBsAg-positive percentages remained until 50–59 years of age. In 2006, another national survey of HBsAg seroprevalence was conducted among individuals aged 1–59 years to update HBV epidemiology in China. The 2006 study found that HBsAg positivity had fallen to 7.2% in the general population (sample size: 81,775). Although 2.42% positivity was found in children aged 5–14 years, only 1.0% of children aged ≤4 years were HBsAg positive [
4]. The latest national survey of hepatitis B virus infection conducted in 2014 (sample size: 31,713) only covered people aged 1–29 years. HBsAg prevalence among participants aged 1–4, 5–14, and 15–29 years was 0.3, 0.9, and 4.4%, respectively [
3].
Sample sizes of the three prior national surveys were relatively small considering the population of mainland China is nearly 1.4 billion people. Moreover, few studies had larger sample sizes with wide range of age recently.
To update the current HBV infection in northeast China, we performed a serological survey of HBV infection in a large number of inpatients. This study also consisted of specialized disease cohorts. Admitted patients routinely received HBV-infection screening if high-risk factors for HBV infection were identified; if blood transfusions were received during surgeries, invasive procedures, dialysis, or pregnancy; or if iatrogenic infection and transmission were possible [
12‐
14].
Discussion
The number of participants enrolled in previous national surveys was 61,702 in 1992, 81,775 in 2006, and 31,713 in 2014, representing relatively small sample sizes for a national survey. The current study investigated HBV infection in a much larger sample of 218,627 hospitalized patients, and HBV serological markers were determined by CLIA, giving a higher sensitivity than enzyme-linked immunosorbent assay(ELISA) [
15]. Results of this study reflect current HBV infection rates in northeast China. The main findings were (1) 6.2% of women at childbearing age were HBsAg positive; (2) HBsAg positivity in middle-aged male patients was 13.36%, which was the highest among all the age groups; and (3) 60% of patients aged under 20 years were only positive for HBsAb, which was the highest among all age group. Overall, nearly 40% of the study population lacked protection against HBV infection.
HBsAg positivity among participants aged 1–20 years was 1.1%. These patients were born after 1992 when hepatitis B vaccination of infants was first recommended. A dramatic decrease of HBV infection was seen in those patients born after 2002 when hepatitis B vaccination was formally integrated into routine immunization of infants. The impact of HBV vaccination on reducing HBV vertical transmission identified by this study was consistent with previous international studies [
16‐
19]. In addition, the reduced HBsAg prevalence also reduced the incidence of liver cirrhosis and hepatocellular carcinoma [
20]. The highest HBsAg positivity rate was detected in patients aged 41–50 years, reflecting the fact that they were likely infected before 1992 and continued to carry HBV infection until this study [
21,
22]. Another factor was that those participants aged over 20 years tend to experience more risky behaviors, like unsafe injection and blood tranfusion, making them more vulnerable to HBV infection, compared with patients aged under 20 years.
The percentage of HBsAg positivity was higher in in the male age groups > 20 years than their female counterparts, and the difference between both genders increased with age. These results were consistent with the 2006 national survey and other studies [
4,
23‐
25]. Androgen may inhibit both cellular and humoral immune responses. However, estrogen appears to only inhibit the cellular immune response while it may enhance the humoral immune response. In addition, progesterone promotes the transformation of cellular immunity to the humoral immune response [
26,
27]. The sex hormones may contribute to the diverse between genders with age growing. Females were more likely to have HBsAg seroconversion. A notable finding among subjects aged under 20 years was that there was no significant difference in HBsAg positivity between males and females, as they had the same opportunity to access HBV vaccination independent of gender.
HBsAg positivity in women of childbearing age was 6.2%, which was much lower than the figure (11.8%) recorded from Fujian Province [
28], which has a more developed economy than Jilin Province. This study conducted in 2013 explained that the high prevalence of HBsAg attributed to lack of consciousness from insufficient educational attainment and rural residency. HBsAg-positive pregnant women remain a significant challenge in blocking HBV vertical transmission as regular HBV vaccination schedule may fail to protect newborns from perinatal HBV infection.
Among patients aged under 20 years, HBsAg positivity increased with older age while HBsAb positivity decreased with older age. 60% of this population were HBsAb positive, reflecting successful HBV vaccination. This protective percentage resembled the result from Chengdu City [
29]. Some factors, including low HBV vaccination coverage rate of 3 doses in rural areas, the quality of vaccines and cold chain operation for vaccine storage and transport, failed to make the HBsAb positivity higher in patients aged under 20 years. However the most important factor could be waning protection over time after the scheduled HBV vaccination. A previous study concluded that booster doses should be unnecessary for children after a full primary immunization owing to long lasting immune memory [
30]; 41.64% of this population were negative for any HBV markers, suggesting they were neither exposed to HBV, nor vaccinated. If they were at high risk for HBV infection in the future, then HBV vaccination is highly recommended.
HBcAb positivity increased with age, independent of gender. As reported, HBcAb positivity increased with older age in younger age groups. However it then decreased in the oldest age groups [
31], which is likely a consequence of spontaneous clearance, antiviral therapy, or increased mortality of cirrhosis and hepatocellular carcinoma [
32]. HBsAg-negative/HBcAb-positive status is generally interpreted as having previous HBV exposure, but it could also indicate occult HBV infection [
33], as defined as undetectable serum HBsAg accompanied by detectable HBV-DNA in serum and/or liver tissue [
34]. A study from Italy found that more than 50% of HBcAb-positive subjects had detectable HBV DNA in their liver tissues [
35]. In the current study, HBcAb positivity among HBsAg-negative patients was 19.29%, although we were unable to determine exactly how many of them had occult HBV infection. A recent study from Heilongjiang Province (a northeast neighbor to Jilin Province) [
36] showed that nearly 1 out of 10 patients with negative HBsAg had occult HBV infection. Immunotherapy or chemotherapy may reactivate occult HBV infection and outcomes can be fatal. HBsAg-negative/anti-HBc-positive patients should therefore be closely monitored if their immunity is expected to be compromised by such a treatment or procedure.
Most surveys utilized ELISA for detecting HBV serological markers. However, CLIA was used in this study. Both ELISA and CLIA could equally detect HBV antigen and antibody titers. However, there is a significant difference in detection sensitivity between the two: CLIA is more sensitive (96.45%) compared to ELISA (77.3%) [
37,
38] when serum HBsAg level is low [
15].
Consistent with earlier studies [
39,
40], nearly 14% of middle-aged male patients had HBV infection in this study and they were considered at high risk for advanced liver diseases and should be closely monitored. Many of these patients are unaware of their HBV-infection status, so a routine HBV marker test should be carried out in this group.
There are a few limitations in this study. First, the participants enrolled in this study are not representative of all inpatients or the general population since only patients who met the criteria for screening HBV infection were included. This population was based in a single hospital. The patients enrolled were not from random sampling. HBV infection prevalence detected in this inpatient population was expected to be higher while HBsAb positivity was lower comparing to the general population. Second, the patients in the study were only from Jilin Province, with no representation from outside this province. In future studies, we will include participants from throughout China to update HBV infection at a national level.
Our results highlight the critical impact of universal HBV vaccination of infants and young children on HBV infection prevalence in mainland China. Our findings reaffirm many previous studies, which showed significant decreases in HBsAg positivity mainly driven by the successful implementation of universal hepatitis B vaccination policy. Indeed, China has evolved from high to intermediate HBV endemicity. It is expected that endemicity will decrease further. Despite this remarkable achievement, China still faces an enormous challenge to manage nearly 100 million people with chronic HBV infection of who only 1% received standard antiviral treatment. One goal in managing HBV infection is to diagnose 90% of HBV infected cases by 2030 [
41].