Epidemiology of Hepatitis A: Past and Current Trends

Hepatitis A virus is a common infectious etiology of acute hepatitis worldwide. It was not until World War II (1973) when hepatitis A virus was first identified by an American virologist, Stephen Mark Feinstone. The virus is most commonly transmitted through contaminated food, water, or sexual contact (oral-anal sex). The discovery of hepatitis A virus vaccine is considered a milestone in the history of acute viral hepatitis. Hepatitis A occurs worldwide and frequent outbreaks have been reported over the years. Major geographic differences have existed in endemicity of the disease depending primarily upon hygiene and sanitation practices. Some countries have experienced shifting of endemicity due to improvement of environmental hygiene, swelled International travel and national recommendations for hepatitis A vaccination. The age of acquiring hepatitis A virus is also shifting toward adolescents and adults. This has led to a more symptomatic disease, since hepatitis A infection among children is usually asymptomatic; this is known as the paradox of Hepatitis A epidemiology.


Introduction
The discovery of hepatitis viruses is one of the most mesmerizing scientific escapades of the last five decades. Their identification has been considered a milestone that revolutionized modern day medicine [1]. Disease outbreaks resembling hepatitis A have been known since ancient times. The earliest accounts of contagious jaundice are traced to ancient China [2]. Feinstone et al. were first to identify Hepatitis A virus (HAV) in the year 1973 [3]. Increasing globalization poses fresh challenges for prevention of HAV infections. This chapter is an attempt to decipher the evolution of the disease over the years and summaries the current HAV situation around the world.

The breakthrough
Outbreaks resembling hepatitis A have been reported from Europe in the 17th and 18th centuries during the period of war. The pathologists Bamberger and Virchow proposed the name "catarrhal jaundice", as they believed the disease to be caused by mucus blockage of common bile duct [4]. Viral origin of the disease was first indicated by McDonald [5]. The virus was identified when the focus of investigation changed from serum to feces [6]. It was first seen under immune electron microscope in fecal suspension from infected Joliet prison inmates [3].
It was not until early 1900s that the mode of transmission of hepatitis A was identified [7,8]. Although person-to-person contact was evident, the virus was thought to spread via droplet nuclei [9,10]. Voegt successfully transmitted hepatitis A through duodenal juice. He published his findings in Munich Medical Weekly in 1942 [11]. Havens et al., at Yale University, United States of America, successfully transmitted jaundice by feeding serum and stool filtrate to 12 volunteers [12]. The differentiation between infectious hepatitis and serum jaundice was provided by a series of experiments carried out among mentally disabled residents at the Willowbrook State School, Staten Island [13]. While, it was MacCallum who proposed the terms hepatitis A and hepatitis B in the year 1947 [14]. The virus was first cultured in the year 1979 [15]. The viral genome was identified by reversetranscriptase polymerase chain reaction. The cDNA copy was molecularly cloned. The RNA transcripts derived from cDNA clone proved infectious in cell cultures [16]. Figure 1 depicts the timeline of Hepatitis A virus.

Structure
HAV is classified in the family Picornaviridae and genus Hepatovirus. HAV is a non-enveloped, 27-to 28-nm spherical virus with icosahedral symmetry. The virus contains a positive-sense, single stranded linear RNA. The 5′ end of the viral genome consists of a covalently bound protein termed VPg typical of picornaviridae. The viral genome consists of 60 copies each of its 3 major structural proteins, namely, VP1, VP2, and VP3 (1D, 1B, and 1C). Although a variety of genotypes  (genogroups I-VII) have been identified by analysis of genome sequences, the virus has a single serotype. Individual strains of HAV have differences at the molecular level that may be useful for epidemiologic studies; however, a high degree of identity in nucleic acid (as high as 90%) and amino acid sequence (as high as 98%) is generally seen between strains [17,18].

Feco-oral
HAV is a common infectious etiology of acute hepatitis worldwide. It is most commonly transmitted through the feco-oral route. Although, HAV contamination of food material can occur anytime during cultivation/preparation/distribution, it occurs most commonly during food distribution due to infectious food handlers [19]. Virtually any food may be contaminated with the virus. HAV is relatively resistant to extremes of temperature and pH. Hepatitis A virus is omnipresent; it can perpetuate on environmental surfaces, hands of food handlers, sewage as well as in a variety of food products [20].

Parenteral
Rare reports of transfusion related hepatitis A have been published over the years. Transmission is via blood/blood products (Factor VIII and IX) collected from an infected donor during the phase of viremia [21-23].

Sexual transmission
Studies have found that people who engage in sex with casual partners, sex in gay saunas, oral-anal intercourse and household or sexual contact with acute hepatitis A (AHA) patients are at increased risk of HAV infection. Several reports of HAV infections have been reported among men who have sex with men (MSM) [24-28].

HAV vaccine -the holy grail
The discovery of hepatitis A virus, its propagation in cell culture and cloning of its genome culminated almost two decades later in the development and licensing of an effective vaccine [29,30]. According to the WHO, the most effective way to prevent HAV infection is to improve sanitation and immunization. Gamma globulin was found to be effective in prevention of measles in susceptible household contacts in the  [37][38][39].
The Food and Drug Administration (FDA) licensed HAVRIX in February 1995 for children (≥2 years), adults and travelers [34]. Centers for Disease Control and Prevention recommends vaccination for children 12 months or older, travelers to endemic countries, gays, illegal drug users, individuals with occupational risk exposure and chronic liver disease patients. The American College of Physicians too also recommends vaccination of high-risk groups [40].
In the United States, vaccination against hepatitis A is available as inactivated, monovalent vaccines (HAVRIX and VAQTA) or in combination with hepatitis B (TWINRIX). These vaccines are highly efficacious with seroconversion rates approaching 100% [41]. With the implementation of vaccination, the incidence of HAV in the United States has shown a drastic decline of 92% (12 cases per 100,000 in 1995 to 1 case per 100,000 in 2007) [42].
Among the developing nations, Indian Academy of Pediatrics (IAP) recommends two doses of vaccine for children (≥1 year). The recommended dose is 720 ELISA Units (ELU) for <19 years and 1440 ELU for ≥19 years. Protective antibody titers are seen in almost 100% vaccinees following the second dose [43]. No major adverse reactions have been associated with vaccine use.
CDC recommends vaccine instead of immunoglobulin for exposure to HAV in healthy individuals aged 1 to 40 years. Standard adult dosing recommends administration of two doses of the vaccine 6-12 months apart. For individuals 41 years and older, immunoglobulin administration is preferred due to the risk of more severe clinical presentation and limited evidence of vaccine efficacy in this age group. Immunoglobulins are also recommended for children less than 12 months, individuals with chronic liver disease, and immunocompromised patients [44][45][46].

The pre-vaccine era
In the pre-vaccine era, hepatitis A occurred in cycles, every 10-15 years, with majority of cases reported among children (≤15 years) [47,48]. Most cases (12-25%) of hepatitis A in the United States occurred as communitywide epidemics in which infection was transmitted from person to person among household or sexual contacts. International travel and foodborne outbreaks accounted for a small percentage of cases [49]. Asymptomatic infections among children played an important role in sustaining transmission. According to a survey conducted in the United States of America (1988-1994), a third of the population were sero-positive for anti-HAV IgG antibodies [50]. In the developing part of the world, majority of the population acquires asymptomatic hepatitis A infection early in life, such that large proportion of population is immune to HAV [51,52].
HAV infection resulted in devastating consequences in susceptible populations. An outbreak in Shanghai, China in 1988 affecting over 300,000 people due to consumption raw clams represents an example of the magnitude problem in the pre-vaccine era [53].
Virology of Hepatitis A 6

The world scenario -HAV sero-prevalence
WHO estimates that approximately 1.5 million people are infected with HAV each year [54]. The incidence of HAV in a given population correlates with socioeconomic properties such as income, density of housing, sanitation, and water quality. Endemic rates are high in developing countries with poor sanitation and hygiene practices. HAV endemicity is classified into low, intermediate, and high based on the seroprevalence of anti-HAV IgG (<15%, 15-50% and >50%) [37]. High sero-prevalence reflects that majority of the population is immune to HAV [55]. HAV in children is usually asymptomatic, while frank hepatitis is seen when HAV infection occurs in adults. Since 1999 several countries including, southern Asia, Latin America, and Europe, have experienced a decline in the incidence of HAV infection due to improved sanitation and routine vaccination. This has resulted in a higher incidence of HAV infection among adult population [56][57][58][59][60][61]. The shift in age group, which acquires hepatitis A, towards adolescents and adults has amplified the incidence of symptomatic disease, since childhood HAV infection is usually asymptomatic [51,52].
Since the availability of HAV vaccine, an overall increase in the incidence of reported HAV cases has been observed from European Union countries [62]. This points to new risks associated with globalization and population migration [62,63]. According to a health survey conducted in the USA, a significant decrease in HAV immunity among adult population was noted between 1988-1994 and 1999-2006 [64]. The survey also demonstrated rise in the rate of hospitalization among HAV infected individuals, consequent to a higher percentage of symptomatic infection among adult population over the last decade [65]. This is known as the "paradox of hepatitis A risk" [55].
Prognosis of HAV is usually good among younger population, with low mortality rates (0.1%). The mortality rate increases proportionately with age, to as high as 2.1% among ≥40 years old [66]. In developing world, including Asia, Africa and South America, evidence of past infection is nearly universal. Juxtapose to this, infection rates are low in developed countries such as the United States, Canada, and Europe. High-risk groups in these regions comprise of injection drug users, homosexuals, people traveling to endemic regions, and among isolated communities such as nursing homes etc. [67].
In the USA, HAV outbreaks were common among illicit drug users in the prevaccine era. Drug users accounted for over 20% of all HAV cases as reported by the CDC during mid-1980s [68,69]. Since 1999, with the implementation of routine HAV vaccination program, hepatitis A incidence has shown a steady decline until 2011 [70,71]. The incidence has stabilized at an annual average of over a 1000 cases per year. Most cases were reported among international travelers returning from countries endemic for HAV [72].
In a sero-prevalence study conducted among military personals in France, Lagarde found the prevalence of HAV antibodies as 16.3% [73]. Another study conducted in Korea found the overall HAV sero-prevalence of 63.8% [74]. Japan has been conducting sero-prevalence studies over the years. The overall HAV sero-prevalence has dramatically decreased from 96.9% in 1973 to 96.9% in 1984 and 12.2% in 2003. Notably, the population susceptibility increased annually [75]. A sero-prevalence survey in Taiwan during 2009-2010 showed that only 10% of MSM aged 18-40 years in Taiwan had anti-HAV antibodies [76]. HAV vaccination program was implemented in Taiwan in 2016. Although this lead to decline in the frequencies of both human cases and positive sewage samples, no substantial increase in vaccination coverage was seen among high risk groups like MSM and HIV-infected patients. [77]. Exposure to HAV is virtually universal before the age of 10 years in most developing countries [78]. In a study conducted in rural Liberia, an annual incidence of HAV was reported to be 45% among children aged 1-5 years [79]. In Indonesia, 95% of children, under the age of 10 years, were naturally immune to HAV infection [80]. Above-mentioned studies point towards the fact that, mass HAV vaccination might not be necessary in highly endemic regions.
In India, the sero-prevalence of anti-HAV antibodies exceeds 90% among adults [81]. However, there have been recent reports of a decreasing sero-prevalence across the country, paralleling with the industrialized world [82,83]. Accordingly, HAV vaccination has been recommended for school children as well as adults [84]. Another study conducted among children found the age-related sero-prevalence of HAV to be 50.3% in the age group of 6-10 years and 30.3% among 18 months to 6 years of age. The HAV prevalence correlated strongly with the child's education and socioeconomic status [85]. In another Indian study, the HAV prevalence was found to be 97.2% [78]. These findings were in agreement with the expected pattern of HAV sero-prevalence in an area of high endemicity. Similar findings have been reported from other parts of the country as well [86][87][88].
About 90% of Indian children acquire protective antibodies against HAV by the age of 10 years. Similar patterns of endemicity have been found in other developing countries, with high sero-prevalence of anti-HAV antibodies [89]. Surveys conducted among children in Egypt have also reported almost 100% sero-prevalence rates [90].
Several studies from India have recently reported a significant sero-epidemiological shift, with increasing incidence of infection among adults and adolescents. Recently in New Delhi, anti-HAV antibody prevalence among adults was reported to be as low as 36.7% [82].
Chile and Jordan have reported a decrease in anti-HAV sero-prevalence over the years [89,91]. The study conducted in Jordan showed a continual rise of the seroprevalence rates with rise in age. While, sero-prevalence was 26% among <2 years old, the rate increased to a whooping 94% for >20 years old [91]. A study conducted in Western Brazil revealed overall sero-prevalence among children as 16.7% in the year 2011, which significantly increased to 70.45% in a recently conducted survey [52,91]. This high prevalence might be attributed to disease outbreaks in few parts of the district of Gampaha.

HAV outbreaks over the last decade
Over the last 10 years, several outbreaks have been reported throughout the world Table 2 and Figure 2 [92-107].
Although feco-oral route has been implicated in most of the cases, sexual mode of transmission among high risk groups is the second most prevalent route of transmission [104,105].
In 2016, about 2000 cases of HAV were reported in the United State [92]. CDC and FDA investigated two major HAV outbreaks due to consumption of contaminated foods (strawberries imported from Egypt and scallops from Philippines). The first outbreak affected 134 people, with two hospitalization while, the second outbreak affected 292 individuals with 94 hospitalizations [93,94]. An HAV outbreak in California in 2017 encompassed homelessness individuals and illicit drug users with poor sanitation practices. The outbreak spread to several other states as well. A total of 694 individuals were infected, with 45 hospitalizations and 21 deaths [95].
A sizeable hepatitis A outbreak was reported in Australia in 2009, resulting in a 2-fold increase in the number of cases reported to the state health departments. Surveillance data suggested infection due to contaminated semidried tomatoes [96].
A total of 32 outbreaks of water/food-borne disease outbreaks were reported from Kerala, India alone, in the same year, involving 2421 cases. All these outbreaks were attributable to feco-oral route [97]. Around 223 hepatitis A cases were identified in a HAV outbreak in Kerala. Attack rate was found to be highest among the age group of 16-30 years (1.44%). Food/water from a newly opened hotel in the area was the possible source of the outbreak [101]. In another study, authors reported  HAV outbreak in the medical college area in Kottayam [100]. Another outbreak of acute hepatitis was reported from Mylapore village, Kollam district, southern India during February to June 2013. A total of 45 cases were affected, pipe water contamination from a bore well was identified as the source [101].
In a study conducted among acute viral hepatitis patients in North India, hepatitis A virus was identified as the most common etiological agent (26.96%) followed by hepatitis E virus [99].
Gassowski et al. reported two hepatitis A outbreaks in Europe. One affecting travelers returning from Morocco and the other among European residents without travel history. The outbreaks lasted from January to June 2018, affecting 163 patients in eight European countries. The HAV was genotypically identified as belonging to subgenotype IA DK2018-231 and subgenotype IB V18-16428. Common risk factor among the cases was found to be unvaccinated travel due to lack of awareness [102].
In July 2010, five cases of HAV infection were reported among the Orthodox Jewish (OJ) community in London, United Kingdom. Two of the cases gave history of travel to Israel for the same event a few days back. A total of 900 contacts of the cases were traced and vaccinated [106].
Cyclic outbreaks of HAV among high-risk groups (MSM and/ HIV) have been described in several reports. Outbreak strains among MSM across countries were found to be genetically alike and circulated for over a decade [104,105]. In June 2015, a considerable increase in reports of AHA infection was noted in Taiwan mostly affected MSM and patients with HIV or other STI. The strain was later identified as TA-15 strain. In 2016, multi-country HAV outbreaks predominately affecting MSM were observed in Europe. The EuroPride strain (RIVM-HAV16-090) detected was genetically quite similar to the TA-15 strain identified earlier [87,108]. A similar outbreak strain was also reported in the United States in 2017 [103], which suggests a global pattern of increased risk among susceptible male adults, with possible transmission through sexual contacts at MSM events.

Conclusion
HAV adversely affects the economy of a country by decreasing productivity of its citizens due to absenteeism from work, adding to medical costs and the effect on tourism. Improving sanitary conditions and providing clean drinking water are imperative pillars in curtailing spread of HAV. Simple method like hand hygiene is an effective way to prevent virus transmission. Vaccination forms the foundation in prevention of HAV. Both inactivated and live attenuated vaccines are licensed and available for use. Improved sanitation and vaccination although prevents Hepatitis A infection, it paradoxically increases the susceptibility of adult population towards a more symptomatic disease. This vicious cycle is the dilemma of HAV control and prevention program.