International disease burden of acute viral hepatitis among adolescents and young adults: An observational study

Adolescents and young adults are the driving force of social development, and the prevalence of acute viral hepatitis (AVH) in this population cannot be ignored. At present, there are few studies on the disease burden of AVH in this age group, and most studies focus on chronic liver disease. In this study, we identified global trends in the burden of AVH among adolescents and young adults (15–29) to help policymakers implement precise disease interventions. In this observational study of disease trends, we collected data exclusively from the Global Burden of Disease (GBD) 2019 study. This study examined the trends in the prevalence, incidence and mortality of AVH among adolescents and young adults in 21 regions of the world from 2009 to 2019. Age‐specific disease trends were analysed with a joinpoint regression model. The overall global disease burden of AVH declined. The prevalence rate per 100,000 people decreased from 316.13 in 2009 to 198.79 in 2019, the incidence rate decreased from 3245.52 in 2009 to 2091.93 in 2019, and the death rate decreased from 0.87 in 2009 to 0.43 in 2019. During the study period, the prevalence of hepatitis B virtues (HBV) in the young population decreased, but the downward trend of other types of hepatitis other than HBV was not obvious, especially HAV, which even showed an upward trend. Among adolescents and young adults aged 15–29 years, Western Saharan Africa had the highest prevalence of AVH in 2019. There were significant differences in mortality rates among different age groups; 20–24 was the age group with the highest mortality rate from 2009 to 2019, followed by the 15–19 and 25–29 age groups. Although the overall global AVH disease burden declined, some causes of AVH, such as HAV, showed an upward trend during the study period. In addition, the prevalence of AVH among adolescents and young adults in Asia and Africa was higher than that in other parts of the world and warrants more attention. Finally, more research should be conducted on mortality in the 20–24 age group.


| INTRODUC TI ON
Acute viral hepatitis (AVH) is a prevalent contagious illness on a global scale and has long affected people's health greatly. 1 Primary hepatophagocytic viruses, including hepatitis A, B, C, D and E, cause approximately 90% of AVH cases. 2 Worldwide, there was a substantial increase in the years lived with disability associated with AVH, with a 39.6% increase observed between 1990 and 2017. 3The number of new cases of AVH reached 340 million in 2017, and the incidence varied significantly in different countries and regions. 3The mortality rate of AVH is very low. 4 Hepatitis A virus (HAV) and hepatitis E virus (HEV) typically result in hepatitis that resolves on its own, but in some instances, they can lead to sudden and severe liver failure.Rare cases involve immunosuppression or chronic infection. 5On the other hand, hepatitis B virus (HBV) and hepatitis C virus (HCV) induce acute symptoms and more frequently progress to liver fibrosis and cirrhosis and elevate the likelihood of developing liver cancer, particularly hepatocellular carcinoma. 6Over the past two decades, substantial attention has been given to the treatment and prevention of HBV and HCV, whereas the urgency of addressing AVH has been less emphasized, resulting in this condition being oftentimes undervalued and neglected. 4e primary emphasis in the worldwide response to HCV has been directed toward the adult demographic, as they experience the greatest impact in terms of illness and death resulting from prolonged liver conditions. 7In contrast to the attention given to adults, the burden of hepatitis in children and adolescents has received relatively little consideration. 7However, children and adolescents are the most vulnerable groups and deserve special attention. 8Between 2009 and 2018, the yearly estimated cases of acute HCV infections in the United States tripled, particularly in the younger population. 9In 2019, the World Health Organization (WHO) reported that approximately 296 million people were impacted by HBV infection, with approximately 1.5 million new infections occurring each year. 10These statistics highlight the ongoing burden of this disease and the need for continued efforts to address its impact on public health.Detecting and treating HBV and HCV infections early in adolescents and children is crucial for preventing the development of lasting health complications associated with these chronic conditions. 11In addition, there have been widespread reports of a rising prevalence of HAV and HEV among adolescents across various regions worldwide. 12,13 2016, the WHO published an advocacy document outlining the objective of eradicating HBV and HCV infections by the year 2030. 14However, the burden of AVH in the younger population is still poorly understood.Therefore, this study aimed to outline the worldwide prevalence of AVH among individuals aged 15-29 years, employing data from the Global Burden of Disease (GBD) study encompassing the years 2009-2019.The objective was to provide valuable information for the purpose of shaping future strategies for intervention and mitigation.

| Overview
This study utilized data exclusively from the GBD 2019 study.The GBD 2019 study offers a comprehensive, organized and current evaluation of the worldwide impact in terms of prevalence, incidence, mortality and disability-adjusted life years (DALYs) for 256 causes of death, 369 diseases and injuries and 87 risk factors.This extensive assessment covers 204 countries and regions and spans the period from 1990 to 2019. 15The methodologies of the GBD studies are described in detail elsewhere. 16We assessed the prevalence, incidence and mortality of AVH, which can be found through the GBD data entry source tool. 17Regarding AVH, the data for this study were gathered through systematic reviews of the literature, manual searches on national health ministry websites, reports from antenatal clinics, information from the GBD collaborator network and case notifications.These sources are accessible through the GBD 2019 Data Input Sources Tool, which can be accessed at http:// ghdx.healt hdata.org/ gbd-2019.
The analysis was conducted using a Bayesian meta-regression tool called DisMod-MR.This tool operates within a geographical cascade framework, starting with a model that processes global data to generate initial global estimates.This model determines coefficients for predictor variables and adjustments based on various study characteristics. 18The initial global fit, alongside random effects values for each of the seven GBD superregions and coefficients for sex and country predictors, is then employed as input for subsequent models in each superregion. 16These subsequent models incorporate the specific input data for the respective region. 16This process iteratively continues, progressing from superregion to 21 region fits and eventually to 204 fits corresponding to individual countries.Earlier investigations have demonstrated that DisMod-MR yields robust and valid estimates when compared to actual surveillance data. 19
There is no clear age category classification, and we selected three age groups, 15-19, 20-24 and 25-29, to assess the cases of disease among adolescents and young adults. 15The GBD study divided the world into 21 regions based on the similarity of epidemiological data, geographical location characteristics and disease prevention and control. 21Cases from these 21 regions were used in this study.The sociodemographic index (SDI) is also included in the GBD study.The SDI includes fertility rankings, average education levels for individuals aged 15 years and older and per capita incomes and is a which comprehensive index used to evaluate the development position of different regions. 4The SDI ranges from zero to one, and the higher the value is, the better the development degree of social demography. 22

| Statistical analysis
To analyse shifts in mortality rate patterns, joinpoint regression was performed for each age and sex category using the Joinpoint Regression Program, specifically version 4.5.0.1 (developed by the Statistical Research and Applications Branch at the National Cancer Institute). 23e annual percent change (APC) in this paper was calculated by Joinpoint software.When the calculation result is greater than zero, it indicates an upward trend of disease development; when the result is less than zero, it indicates a downward trend; and when the APC TA B L E 1 AVH prevalence, death and incidence cases and rates of adolescents and young adults (15-29 years) by GBD regions: 2019. is close to zero, it indicates a stable trend. 24The software modelling method used the grid search method (GSM).The model was optimized using the default Monte Carlo permutation test in Joinpoint software. 25The maximum number of joinpoints was set as five.The best fit of joinpoints was determined by the joinpoint model when the trend change was statistically significant. 15The APC, average annual percent change (AAPC) and 95% CI were the main outcome indicators calculated by the joinpoint model.The APC is the percentage change in the dependent variable per year on average and is the recommended statistical tool for evaluating the trend within each independent segment of a piecewise function.Conversely, the AAPC is the preferred statistical method for comprehensively evaluating the overall trend across multiple segments.S1   and S2).
In terms of the regional distribution, the highest prevalence rate of AVH was observed in Western Saharan Africa in 2019, reaching 491.48 per 100,000 people.In the 15-19, 20-24 and 25-29 age groups, the prevalence rates were 412.46, 532.49 and 556.32, respectively (Tables 1 and 2).Other regions with notably high AVH prevalence rates (≥300 per 100,000 people) were Central Sub-Saharan Africa, East Asia, Oceania and Eastern Sub-Saharan Africa (Table 1).Conversely, the lowest prevalence rates of AVH were recorded in high-income North America, Western Europe and Australasia, with rates of 102.33, 106.67 and 142.99, respectively (Table 1).
Regarding mortality rates, the highest rates were observed in South Asia (1.43), Eastern Saharan Africa (0.97) and Central Saharan Africa (0.64) per 100,000 individuals.Conversely, the lowest mortality rates were reported in Western Europe, high-income North America, the high-income Asia Pacific region, and Australasia, all of which had a mortality rate of 0.01 (Table 1).

| Trends in AVH prevalence, incidence and death rates from 2009 to 2019
From

| AVH deaths due to liver disease between 2009 and 2019
Globally, from 2009 to 2019, the leading cause of AVH deaths was HAV.Among adolescents and young adults, the contribution of different etiologies to AVH deaths was similar between different age groups.HAV was the most common cause of death among those aged 15-19 years, followed by HBV.Deaths associated with AVH due to HCV and HEV were not significant worldwide.Similar patterns were observed among those aged 20-24 and 25-29 years (Figure 3).Importantly, although the death rate from HAV gradually decreased, an alarming finding was the rapid upward trend of AVH deaths with HAV in almost every age group compared with the lower mortality associated with other causes during the study period (2009-2019) (Figure 3).

| DISCUSS ION
To our knowledge, this study is the first all-encompassing analysis of the disease impact of AVH and the shifts in its patterns among individuals aged 15-29 years.This study covered the years 2009-2019 and offered insights at the global, regional and national levels.The results revealed important findings regarding the prevalence, incidence and mortality rates of AVH, as well as trends over a 10-year period from 2009 to 2019.This study found that the overall global burden of AVH decreased significantly, but the burden of AVH among adolescents and young adults remains substantial, and there are still significant variations for different regions.
This study found that in 2019, there were  This study also examined variations in the burden of AVH across different regions.Among these regions, Western Saharan Africa displayed the highest prevalence rate of AVH, followed by Central Sub-Saharan Africa, East Asia, Oceania and Eastern Sub-Saharan Africa.In contrast, the regions with the lowest prevalence rates were high-income North America, Western Europe and Australasia.These regional disparities highlight the need for region-specific strategies and interventions to address AVH.
Factors such as health care access, socioeconomic conditions and vaccination coverage may contribute to these regional differences and should be further investigated.According to the results, the regions with the highest incidence of AVH in 2019 were Africa and Asia, and the main reasons may include poor medical access and low vaccination coverage. 18In low-income countries; however, many barriers remain, including those mentioned above. 4In addi- The analysis of trends over the 10-year period revealed some important findings.Overall, there was a downward trend in AVH prevalence, incidence and mortality rates among adolescents and young vaccine coverage of 84% in 2017, globally. 29In many countries and regions, the prevalence, morbidity and mortality of AVH among young people decreased after the widespread introduction of vaccination programs. 30The HBV vaccination program stands out as a pivotal element in the prevention and control of HBV. 31 A compelling illustration of its impact is evident in China, where the prevalence of HBsAg decreased significantly from approximately 10% among children in the 1980s to less than 0.5% among those born after 2011. 32However, our study found that HBV prevalence in countries with insufficient vaccination, such as the Caribbean, South Asia and Sub-Saharan Africa, remained stable or showed a mild decrease.Thus, in nations lacking universal vaccination, we propose a campaign of universal vaccination of newborns and catch-up vaccination for adolescents could reduce the risk of HBV from parental transmission.
There was an upward trend in HAV prevalence, which was observed in more than half of the world.The increasing burden of HAV has been consistently reported in previous studies. 33The occurrence of HAV is linked to factors such as socioeconomic status, sanitation levels and limited availability of safe drinking water.The discrepancies in sanitary conditions and hygienic practices between high-income countries and low-and middle-income countries may account for the differences in HAV prevalence across different regions.
Enhancements in sanitation and hygiene measures have played an important role in combating HAV in low-and middle-income countries.Nonetheless, in more recent times, HAV outbreaks have become increasingly common across nations, regardless of their economic status.Within high-income countries, these outbreaks are frequently linked to the importation of frozen produce and the movement of infected travellers from regions where the disease is widespread. 34,35e upward trend in HAV prevalence emphasizes the need for ongoing endeavours to control and prevent HAV infections, particularly among adolescents and young adults.Vaccine is the same and effective way to prevent HAV.Several randomized controlled trials have demonstrated that the efficacy of the HAV vaccine for both preexposure prophylaxis and postexposure prophylaxis falls within the range of 95% to 100% in children. 36,37However, as of May 2019, only 34 countries worldwide had implemented or planned to introduce immunization with the HAV vaccine for children.Therefore, prioritizing the global health agenda to enhance HAV vaccine accessibility, particularly for children and adolescents, is crucial for fostering the well-being of populations worldwide.

| Strengths and limitations
The advantage of this study was the use of joinpoint analysis, which allowed us to intuitively analyse the incidence and trend changes of AVH caused by different causes from 2009 to 2019 so that single causes could be analysed independently and accurately. 15In addition, joinpoint analysis was used to analyse the differences between regions.As with all GBD studies, this study also had limitations.Although we used statistical methods to predict covariates to overcome the lack of data and low data availability, the main limitations were the heterogeneity of data sources and the variable accuracy of the data across countries and regions. 15The limitations of the GBD study biased our estimates in the current study, and the disease burden estimates may have been underestimated or overestimated in some regions.In these regions, we depended on trends observed in neighbouring countries, predictive factors, or a combination of both. 38Moreover, another limitation was the lack of HDV-related data in the GBD 2019 study, which may underestimate the disease burden of AVH. 4 The overall prevalence, mortality and morbidity of AVH among adolescents and young adults decreased worldwide.HAV was the leading cause of AVH deaths among adolescents and young adults, and the prevalence and mortality of AVH caused by HAV increased in recent years.The prevalence of HBV showed a downward trend.
HCV and HEV accounted for a small proportion of AVH.Although the overall trend was stable, the incidence of HCV and HEV demonstrated an upward trend in certain regions.These findings highlight the need for policymakers to design regional policies and targeted

F I G U R E 1
APC in age-specific AVH prevalence rate (per 100,000) due to HAV, HBV, HCV and HEV among adolescents and young adults from 2009 through 2019.AVH, acute viral hepatitis; APC, annual percent change.
tion, as indicated by the joinpoint regression model, 20-24 years was consistently the age group with the highest mortality rate during this study worldwide and more research is needed in the future to explore the possible reasons.Policymakers should target limited resources to those who need them most and better strengthen health infrastructure and health care systems to deliver targeted interventions.28 adults.These trends were mainly driven by a decline in HBV.Notably, the downward trend in HBV prevalence was more pronounced among those aged 15-19 years from 2015 to 2019.This could be largely attributed to the increased uptake of HBV vaccination programs in recent years, which have contributed to the reduction in HBV prevalence.Since 1984, countries have begun introducing the vaccine into their universal infant immunization program with an estimated HBV

F I G U R E 2
APC in age-specific AVH prevalent cases by HAV, HBV, HCV and HEV among adolescents and young adults from 2009 through 2019, globally and regionally.AVH, acute viral hepatitis; APC, annual percent change.

F I G U R E 3
APC in age-specific AVH death rate (per 100,000) due to HAV, HBV, HCV and HEV among adolescents and young adults from 2009 through 2019.AVH, acute viral hepatitis; APC, annual percent change.| 105 YANG et al. interventions for young people aged 15-29 years, particularly regarding HAV and its associated risk factors. 34Additionally, attention should be given to regions where HCV and HEV incidence is on the rise among adolescents and young adults, as this age group is a critical driver of future global development.More localized data are still needed, and comprehensive prevention and treatment of AVH in young people are necessary to achieve sustained reductions in adolescent and young adult mortality.

Table 2 ,
Tables 26Joinpoint software version 4.9.1.0was used.All data processing and visualization in this paper were performed by Python.The analysis adhered to the Guidelines for Accurate and Transparent Health Estimates adults aged 15-29 years was significant.There were 4.93 million prevalent cases of AVH, 51.91 million incident cases and 10,563 deaths attributed to AVH in this age group.The rates per 100,000 individuals for AVH prevalence, incidence and mortality were 198.79, 2091.93 and 0.43, respectively (Table 1).Further breakdown by age AVH prevalence rates (per 100,000) in 2009 and 2019 and APC of prevalence rates from 2009 to 2019, by age group and regions.