Mankind has been fighting for hundreds of years against infectious diseases, which has resulted in a significant burden on communities across the global [1
]. The United Nations set the 2030 agenda for Sustainable Development in 2015, defining an ambitious goal for infectious disease control and prevention. With a particular interest in a few kinds of diseases (Health Target 3.3), the UN proposed to fight against infectious diseases with specific actions across the economic and social dimension [2
]. Evidently, to accelerate the achievement of this magnificent health target, certain kinds of infectious diseases, which have brought great harm to societies and their economies, have been identified as the priority among priorities.
Viral hepatitis, which is commonly transmitted through the fecal-oral route (types A and E) or exposure to infectious blood or fluids (types B, C and D), is a liver inflammation resulting from a viral infection. Due to the high incidence and severe consequences, viral hepatitis has been an international public threat for almost all countries, especially in Asia and Africa [3
]. As hepatitis B and C can always cause cirrhosis or liver cancer, viral hepatitis is also a major cause of death, with about 1.45 million people being killed by different kinds of viral hepatitis infection per year [1
]. Besides, viral hepatitis is also a growing cause of mortality among people living with HIV, with a large amount of AIDS patients showing co-infections with hepatitis B and C virus [3
As the most populous country in the world, China has been threatened by and fighting against viral hepatitis for a long time. The Chinese government began to report the cases of viral hepatitis in the 1960s. Over the subsequent 30 years, hepatitis A and B dominated the viral hepatitis epidemics in China. However, reported cases of viral hepatitis other than type A and B have increased swiftly in recent decades, and as a result, the government decided to report viral hepatitis as A, B, Non-A and B, unspecified (clinical viral hepatitis cases which cannot be clearly detected as infected by which kind of virus) in 1990 [4
]. In the middle 1990s, the incidence of hepatitis B began to surpass hepatitis A and became the most widespread hepatitis infection in China, while more and more cases of Non-A and B hepatitis were reported [5
]. In order to systematically monitor and control the epidemics of viral hepatitis, the Chinese Center for Disease Control and Prevention (China CDC) decided to classify the reported cases of viral hepatitis as hepatitis A, B, C, E, and unspecified viral hepatitis, while it decided not to report hepatitis D infections as they usually present as co-infections with hepatitis B. Nowadays viral hepatitis is listed as the class B notifiable infectious disease in China (Specified in the Law of the People’s Republic of China on the Prevention and Treatment of Infectious Diseases [6
]), which is under strict control and surveillance by the infectious disease reporting system developed by the China CDC. According to the latest China Health and Family Planning Statistical Yearbook (CHFPSY), the number of reported cases of viral hepatitis in 2015 ranked first (1,218,946 cases) and accounted for 40.01% of the reported cases (3,046,447 cases) among all 42 notifiable infectious diseases in that year.
Numerous researchers have studied the epidemiology of viral hepatitis in China. On the one hand, some studies have focused on the temporal trends of different types of viral hepatitis. Ren et al. [7
] compared the epidemiology of hepatitis A and E from 2004 to 2014 and concluded their converse temporal trends in China. Zhang and Wilson [5
] reviewed the national trends of hepatitis A, B, C, E at the national level and unspecified hepatitis and compared them with other 7 types of notifiable infectious diseases in China. Sumi et al. [8
] analyzed and predicted the temporal trends of hepatitis A, B, C, E in Wuhan, which is a medium-scale Chinese provincial capital city. On the other hand, some scholars focused on the hepatitis epidemiology at a time point or among a short time period, exploring the age-specific, gender-specific or space-specific epidemiology of viral hepatitis in China. Lu et al. [9
] compared the prevalence of hepatitis A, B, C, E in different age and gender groups based on the cross-sectional data of six regions in China. Zhang and colleagues [10
] investigated and conduct laboratory hepatitis infection tests (hepatitis B surface antigen and anti-HCV first, if positive, then further test HBV DNA and HCV RNA) for 227,808 study participants and thus concluded the prevalence of HBV and HCV with gender, age, ethnic group and education level. Jia et al. [11
] mapped the prevalence of HEV antibodies in the Chinese population based on the third National Viral Hepatitis Prevalence Survey (NVHPS III). Wang et al. [12
] did a spatial cluster analysis of hepatitis C virus infection in China and detected the hot spots and cold spots of HCV infections in China.
To conclude, most of the previous studies either paid their attention to the temporal trends of viral hepatitis or focused on the investigation-based epidemics of viral hepatitis, but few did the analysis from the spatio-temporal perspective and systematically compared the epidemics of all the types of viral hepatitis. It is well known that the epidemiology of all the infectious diseases differs across space and also changes with time, only a spatio-temporal analysis can provide a complete understanding of the situation of viral hepatitis prevention and control in China. Besides, different types of viral hepatitis still share similarities in prevention and control measures despite their different transmission routes and health outcomes. Therefore, the aim of this study is to study and visualize the spatio-temporal epidemiology of different types of viral hepatitis in China. To be more specific, we conduct this study from three dimensions. First, this study explores the temporal trends of viral hepatitis. Second, this study investigates the spatial clusters of viral hepatitis in China. Third, this study compares the spatio-temporal epidemiology of viral hepatitis in China. Based on the results, we could systematically discuss the situation and policy implications for the prevention and control of viral hepatitis in China.
This study conducted a comparative spatial-temporal epidemiology of different types of hepatitis viruses (A, B, C, E and unspecified), which provided much evidence for making area-targeted hepatitis prevention and control strategy in China. We would like to discuss the spatial-temporal epidemiology for different types of viral hepatitis first and then focus on the future prevention and control strategy.
Globally, China is still facing the severe threats of all types of viral hepatitis, with the reported cases of each kind of viral hepatitis distributed in all the provincial units. The global Moran’s I of the incidence of hepatitis A, B, C, E all reached the 0.05 significance level at all the time points, indicating the spatial concentration of the reported cases, which met our expectations and echoes the previous studies on infectious diseases distribution [12
], while it is obvious that the spatio-temporal epidemiology of different types of hepatitis viruses (A, B, C, E and unspecified) in China are quite different, with different epidemiologic trends affecting different locations and revealing different spatial changing patterns.
On the one hand, the fecal-oral transmitted hepatitis forms (A and E) showed opposite trends and distinct spatial distribution characteristics. The incidence of hepatitis A was on a declining curve from 2003 to 2015, with the high-high cluster area remaining relatively stable and gradually shrinking. During 2003 to 2015, Yunnan and Sichuan successively moved out the high-high cluster area. In 2015, the high-high cluster area was mainly situated in the undeveloped areas, namely, Xinjiang, Xizang, Qinghai, Gansu. The space-time scan analysis also indicated the severe epidemics of hepatitis A in earlier years. This pattern can be attributed to two major factors. First, in the 1990s, there was a massive campaign to promote the vaccination of HAV. The HepA-L (Hepatitis A Attenuated Live Vaccine) and, HepA-I (Hepatitis A Inactivated Vaccine) are both listed in the class A vaccines of the national immunization program (the national immunization program includes two classes vaccines, for class A vaccines, all the citizens are duty-bound to vaccinate and can be vaccinated for free, while the class B vaccines are at citizens’ own expense, people can choose vaccine or not based on their own free will). Second, the overall sanitation and hygienic conditions in China have been improving substantially, breaking the contamination cycle of viral hepatitis, which also helps to explain why the high-high cluster area mainly concentrated in the undeveloped west China. Owing to the relatively underdeveloped economy and worse living conditions, west China is confronted with more difficulties to ensure the food and water safety. Therefore, it is still important to keep promoting the access to clean food and water as well as the hygienic living environment in undeveloped areas to contain the spreading and epidemics of type A hepatitis. In contrast, it is seemingly that the epidemics of type E hepatitis, whose incidence kept rising during the research period, has not been tamed as well. Therefore, it is believed that hepatitis E has not received due attention as other diseases posing a comparable burden of disease, such as HAV and HBV. Regarding its hotspots, HH or HL clusters are not widespread in 2003 yet later the Yangtze River Delta region began to display high-high cluster feature until now. It is also echoed by the spatial-scan analysis. In China’s Context, hepatitis E infection occurred, under most circumstances, as sporadic cases and occasional food-borne outbreaks, which results from poor sanitation conditions, including contamination of water and food from animal reservoir and human [11
]. In consideration of the fact that the HH clusters of Hepatitis were mainly distributed in the Yangtze River Delta region, which is one of the three biggest integrated and dynamic city-regions in China, it is reasonable to recommend a stricter food and sanitation supervision in big cities. Beyond that, as effective vaccines also exist for hepatitis E infections [3
], it is not unrealistic to introduce targeted vaccination campaign owing to the fairly strong economy and medical conditions in coastal areas.
On the other hand, the blood-borne transmitted hepatitis forms (B and C) also differ in epidemiologic trends and spatial changing patterns. Hepatitis B displayed a relatively stable status during the past decade. There were almost no significant clusters detected by spatial autocorrelation analysis and space-time scan analysis, indicating the effective control of the epidemics of hepatitis B in recent years. It is widely believed that the progress mainly results from the implementation of HBV vaccine programs in China [10
]. Up to now, the childhood hepatitis B vaccination (three-dose, 0-1-6-month schedule) has been listed in class A vaccines of the national immunization program with the coverage rates of birth-dose and three-dose hepatitis B vaccine being both higher than 90% [28
]. However, the universal newborn vaccination is not enough for the control of hepatitis B in China. Up to now, there is not yet a united strategy, either a plan or coverage by the health insurance [29
], for hepatitis B vaccine among adults and adolescents older than 14 years old who have not been vaccinated. This results in low active hepatitis B vaccination rate among adults [29
]. Besides, the measures to protect the most-at-risk populations (MARPs) should be strengthened. China still faces the challenge of mother-to-child transmission of hepatitis B [30
]. In addition, in the contexts of growing mobility and increasingly open attitudes towards sex, the young people and adolescents, men who have sex with men (MSM), female sex workers (FSW), drug users and also the mobile populations should be paid more attention [32
]. In particular, the epidemics of hepatitis D should also be taken seriously as about one-tenth of HBV infections are simultaneously infected with HDV in China [34
]. In contrast to Hepatitis B, the epidemics of hepatitis C became much more severe from 2003 to 2015. In 2003, the prevalence level of hepatitis C was quite low, the high-high cluster area mainly concentrated in Northeast China, while with the increase of its incidence, the high-high cluster area began to move towards the west. In 2015, the median incidence among all the provincial units has exceeded 10/100,000 and only Gansu displays high-high cluster feature, indicating serious epidemics of hepatitis C in Gansu and its surrounding areas. While, it is also important to note that the epidemics of hepatitis C in Hainan should also be paid much attention as it had become the second highest in 2015 (Due to the boundary-based strategy of spatial weight matrix in this study, Hainan cannot be identified each type of cluster as it does not border with other units). In addition, the space-scan analysis also indicates the severe epidemics of hepatitis C in west China during 2010 to 2015. Now, HCV infection has not received enough attention in China, with a lot of people unaware of their infection, which potentially accelerated the transmission of hepatitis C [35
]. Even the mandatory HCV screening has been implemented in blood donors control the HCV transmission in blood or blood product transfusion. However, it is believed that the paid blood donors, patients on hemodialysis, patients with hemophilia are still at higher risk of hepatitis C virus infection [36
]. In particular, Since HBV and HCV can both be transmitted through the exchange of body fluids, HCV may either be co-infected with HBV and HIV, or both, thus sharing similarity in MARPs in China, such as the drug users and MSMs [37
The unspecified viral hepatitis displayed a downward trend, which was mainly contributed to the development of diagnostic techniques [41
]. Now, the diagnostic techniques for hepatitis B have been well-rounded, which makes it easy to diagnose. The diagnosis for hepatitis A and C is also easy with the combination of their clinical characteristics. Therefore it is believed that the unspecified viral hepatitis in China is mainly hepatitis E or other viruses, which should once again arouse our attention to tackle the epidemics of hepatitis C in China [4
]. Anyhow, the accurate diagnosis of viral hepatitis is crucial for the treatment and epidemics control in latter stages, a powerful laboratory and diagnostic system vis-a-vis each type of viral hepatitis matters a lot in the reporting and treatment of infected cases.
Despite the widespread reported cases of all types of viral hepatitis, the number of deaths and morbidity due to viral hepatitis is decreasing with the development and treatment, which makes viral hepatitis fade away from the eyes of policy makers. Now it is quite clear about the measures to prevent and control each type of viral hepatitis. Recently in 2016, WHO released the strategies to deal with viral hepatitis infections worldwide, which partially contributes to the fulfillment of the 2030 SDGs [3
]. As a national response, the central government of PRC has launched a program named National Prevention and Control Plan, led by the National Commission of Health and Planning and 10 other departments and ministries. While the prevention and control of viral hepatitis is a complex job owing to the various epidemiologic trends and spatial distribution characteristics. Therefore, it is suggested that every provincial unit should make its evidence-based plan which identifies the priority measures and enables meaningful inputs from all key stakeholders, such as the health sector, food sector, CDC, and so on. For those adjacent provincial units displaying HH or HL cluster features in 2015, it could more efficient if they can collaborate and formulate some joint measures. In particular, the measures to tackle viral hepatitis in China should not be limited to its prevention and control. Different from HAV and HEV, whose infections tend to be acute rather than chronic, HCV and HBV infections often cause chronic hepatitis and may develop into cirrhosis and hepatocellular carcinoma, which always require lifelong treatment. Patients infected with hepatitis B and C suffer from lifelong medical treatment, deteriorating their social and economic conditions even with the coverage of social and medical welfare [42
]. Therefore, the government should not only ensure safe and effective prevention, care and treatment services but also their affordability together with multiple health security policies, such as health insurance and medical aids.