Introduction

Hepatitis A, caused by hepatitis A virus (HAV), is mostly transmitted via the fecal–oral route either by the contaminated food or water ingestion or via person-to-person contact [1]. Hepatitis A infection is usually an acute, self-limiting liver disease; however, its clinical severity is closely correlated with increasing age [2,3]. In case of children aged below 6 years, approximately 50% of children are asymptomatic; meanwhile, in children aged above 6 years and adults, 75% of infections are usually accompanied by symptoms such as jaundice and dark urine. People older than 50 years may have higher case fatality ratios (1.8%) [3–6].

Globally, symptomatic hepatitis A cases accounts for 1.4 million each year [7], with tens of millions of infections in total [8]. In China, hepatitis A is a common public health issue [9,10]. However, reported incidence rate of HAV infected cases varied across China. Historically, the average reported number of HAV infected cases in the eastern provinces of China (78,720 cases per province per year) was higher than that in the western provinces (nearly 50,000 cases per province per year) during 1990–1994 [11,12].

The above difference on geographical distribution is closely related with population density, sanitary condition, and other socioeconomic indicators [13]. Zhejiang Province is a developed eastern province in China. Compared with the provinces from western parts of China, Zhejiang Province is one of China’s smallest and most densely populated provinces, with a total area of 101,800 km² and population of 54,980,000 in 2014 [14].

The most recently published study on the epidemiology of hepatitis A in Zhejiang Province was reported in 2000 [15]; according to the findings of this study, hepatitis A was highly endemic between 1991 and 1998 in Zhejiang Province, with an average number of acute hepatitis A cases per year of almost 25,000. Moreover, the highest incidence rate of hepatitis A was observed among pre-school children with a rate of >100 cases per 100,000 pre-school children.

Hepatitis A is a vaccine-preventable disease. Hepatitis A vaccines are reportedly safe and effective. In Zhejiang, these vaccines were introduced in the market in 1995. Initially, hepatitis A vaccines were available only to children whose parents were willing to voluntarily pay. Between 1996 and 2007, about 80% of hepatitis A vaccines were given to pre-school children. Since 2008, hepatitis A vaccines have been integrated in the national childhood routine immunization program, which means children aged between 18 months and 7 years are immunized free of charge. Since hepatitis A vaccines have been available for nearly two decades, it is worthwhile to reassess the evolving epidemiological profile of hepatitis A; this is critical to gather evidence for ongoing policymaking to prevent and control this disease.

In this study, we provided an update of the epidemiological characteristics of hepatitis A in Zhejiang based on population-based surveillance data collected from the National Notifiable Disease Reporting System (NNDRS) during 2005–2014. In addition, strategies for the future prevention and control of hepatitis A were discussed.

Methods

Results

From January 1, 2005 to December 31, 2014, a total of 18 duplicated records were removed. Consequently, 8923 laboratory-confirmed cases were reported to the NNDRS in Zhejiang Province (Range: 423–1696 cases per year; Mean:892.3 cases per year) during the study period. The annual incidence rate was 1.7 cases per 100,000 population (Range: 0.8–3.4 cases per 100,000 population). The mean age of reported HAV cases was 38.8 years.

Overall trend of hepatitis A incidence rate

Linear regression analysis revealed that a decreasing trend of HAV reported incidence rate in Zhejiang Province during the study period (P<0.001), although the trend was observed to be upward during 2005–2007 and then be downward between 2008 and 2014 (Fig 1).

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Fig 1. Hepatitis A incidence rate by year.

https://doi.org/10.1371/journal.pone.0153804.g001

Age distribution

During 2005–2007, the incidence rate increased in individuals aged ≤19 years and those aged ≥20 years (P< 0.001, Fig 2). However, between 2008 and 2014, the incidence rate declined in the two age groups (P< 0.001, Fig 2). The most drastic decrease was observed among those aged ≤19 years; the incidence rate sharply decreased by 87.0%, which represented a decline from 1.68 cases per 100,000 individuals in 2008 to 0.22 cases per 100,000 individuals in 2014.

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Fig 2. Hepatitis A incidence rate by age group and year.

https://doi.org/10.1371/journal.pone.0153804.g002

The mean age of reported hepatitis A cases shifted by >10 years during the study period, with a right shift from 36.8 years in 2005 to 47.2 years in 2014 (P< 0.001).

Gender distribution

During the study period, the incidence rate of reported hepatitis A cases were higher in males than in females (P< 0.05, Fig 3). The male-to-female ratio was 2:1 during 2005–2007; the gap slowly narrowed from 1.8:1 in 2008 to 1.1:1 in 2014.

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Fig 3. Hepatitis A incidence rate by gender and year.

https://doi.org/10.1371/journal.pone.0153804.g003

Occupational distribution

The hepatitis A cases in 2005–2014 were reported among population from different occupations (Table 1). Every year, laborers made up the vast majority of HAV cases during the study period. The proportion of laborers appeared to tower over the proportions of other occupations: Laborers, 68.8%; Professionals, 5.1%; Workers, 4.2%; Managers, 3.2%; and Others, 18.7%.

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Table 1. Percentages of hepatitis A cases by occupation.

https://doi.org/10.1371/journal.pone.0153804.t001

Hepatitis A vaccines used

Due to a limited number of vaccines available in 2008, one dose of live attenuated hepatitis A vaccine was initially used for 18–24-month children in a few cities which had a higher prevalence of HAV. Subsequently, throughout Zhejiang Province, hepatitis A vaccines began to be given to children 18 months to 7 years of age by 2010. During 2005–2014, there was no a specific catch-up vaccination program implemented to any certain age cohort in Zhejiang Province.

From 2008 to 2014, the number of hepatitis A vaccines used was noted to continuously increase from 100,000 doses in 2008 to 800,000 doses in 2014 (P< 0.001, Table 2). From 2011 to 2014, the average number of vaccines used each year (700,000 doses) appeared to be sufficient for one child birth cohort (500,000–600,000 children).

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Table 2. Dose of Hepatitis A vaccines used and new-born population by year.

https://doi.org/10.1371/journal.pone.0153804.t002

Discussion

This study describes a changing trend in the incidence rate of reported HAV infections that occurred before and after massive introduction of hepatitis A vaccine. Before the national childhood routine vaccination program was introduced in 2008, the overall incidence rate continuously increased from 2.5 cases per 100,000 individuals in 2005 to 3.4 cases per 100,000 individuals in 2007. Nevertheless, a significant decline in the incidence rate was noted from 2.2 cases per 100,000 individuals in 2008 to 0.9 cases per 100,000 individuals in 2014. These upward and downward trends could be explained by the following two factors. First, before introducing childhood vaccination program, hepatitis A was endemic and characterized by cyclical periods of approximately every 7–10 years [18–20]. Previously, in Zhejiang Province, a higher prevalence of hepatitis A infection was seen in 1960, 1967, 1981, 1988, and 1996 [15,21]. Therefore, the slightly higher reported incidence rate in 2007 is presumably related to the cyclical epidemiology; a few outbreaks occurred in primary schools in this province as a result of drinking contaminated water [22,23]. Second, a large number of doses of hepatitis A vaccines administered to children each year is believed to be responsible for this steady decline, and this is in agreement with data published by a previous study [24].

During 2013–2014, the annual average incidence rate of reported HAV infections declined to the historically lowest record of <1.0 case per 100,000 individuals; this rate was similar to that in developed countries with low endemicity, such as the United States of America (0.4–0.6 per 100,000 population between 2009–2013) [25], Germany (1.0/100,000 in 2012) [26], Denmark (1.0/100,000 in 2012) [26], and the Netherlands (0.7/100,000 in 2012) [26]. Zhejiang Province may therefore be classified as a low-endemic area. This hypothesis needs further support from studies on the seroprevalence of antibodies to HAV among the general population.

Our results showed that the reported incidence rates for each age group declined between 2008 and 2014, although only children aged ≤19 years appeared to benefit directly from the province-wide routine vaccination programs. The decline in the hepatitis A incidence rate is closely correlated with the level of socioeconomic development and improvement in living conditions [27,28]. With urbanization policies being extensively implemented throughout China, more people are relocating from rural to urban areas. During 2007–2012, in Zhejiang Province, >50% of the rural adult population had significantly improved their living conditions and sanitary infrastructures by migrating [29]. In addition, the booming economy and changing lifestyles contribute to disrupting the fecal–oral transmission of HAV, thereby reducing the likelihood of getting infected [30].

The difference in incidence rate by gender occurred during the study period, with a higher incidence rate in males than in females, which is consistent with the findings of other studies [31–33]. There is no reported biological evidence to support that males are more susceptible to HAV infection than females. The difference may be explained by gender disparities with regard to access to healthcare resources. Usually, females tend to have poorer access to healthcare resources than males due to their comparably limited opportunity for education and paid labor.

The present study also showed that majority of the reported HAV infections were seen among the Worker class; this finding conspicuously differed from the national research study results obtained in 2005–2007 [1]. The current study identified adults with a low socioeconomic status to be the most susceptible population, whereas the national research study identified peasants and children of <10 years as the most susceptible populations [1]. This difference may be explained by the provincial inequality of economic development. In western, underdeveloped provinces in China, HAV transmission predominately occurs among children, whereas in eastern, developed provinces, HAV transmission primarily occurs among adults. The mean age of infection was noted to shift by 10 years in the present study, which depicted an increased risk with regard to the potential severity of infection in the aging population. Therefore, we strongly recommend that adults with a low socioeconomic status should be the focus of hepatitis A immunization, along with the continued implementation of the current country-wide routine vaccination program in children.

Conclusions

This study reflected the change of epidemiological features of HAV infection between 2005 and 2014 in Zhejiang Province. The mean age of infected HAV cases shifted from 36.8 to 47.2 years. The reported incidence rate in individuals aged ≤19 years declined to the historically lowest record in 2014. The vast majority of reported hepatitis A cases were observed in the Worker class. Our findings highlight the importance of future public health efforts that focus on protecting the Worker class from hepatitis A.

Hepatitis A infection risk is closely related with the poor sanitation, lack of safe drinking water, consumption of contaminated food with HAV, and underdeveloped economic areas [34–38]. Therefore, improved sanitation, safe food and hepatitis A vaccines are considered to be the most efficient ways to combat this disease. In addition, future research are needed to explore the sources of exposure to HAV for the susceptible population and determine the level of HAV exposure. On the basis of the current massive routine vaccination program, we suggest additional measures are needed to prevent and control HAV infections among the population at risk, such as, health education for improved personal hygiene practices, providing sustainable access to safe drinking water or food, and improved sanitation for living space.

Supporting Information

Acknowledgments

The authors would like to specially thank those who provided data for this study, including physicians and health care workers in district hospitals and CDC staff at several levels and in many laboratories. The authors also would like to thank two anonymous reviewers for their helpful comments, valuable suggestions, and language editing which have greatly improved the quality of the manuscript.