Preface

Although the subject of acute viral hepatitis A may be exhausted, this book aims to prove otherwise. The addition of a selection of three of the most important topics in hepatobiliary diseases adds weight to the current scientific endeavors, making this volume even more appealing to the specialist community interested in the joint infectious and non-infectious pathologies of the liver.

With large-scale vaccination programs for hepatitis A, its global incidence has steadily decreased. However, it remains a threat in several areas of the world, and in the context of globalization and frequent travelling it may emerge as a reputable threat to some medical systems on the globe. This book begins by tackling interesting epidemiological aspects and debating implications for at-risk populations while placing the pathology in a historical context and exploring possible future trends.

The second part of the book examines animal models used in medical research of viral hepatitis A. It explores aspects of molecular biology and introduces the reader to fringe aspects such as the complex chemical interactions of natural products and mechanisms of viral infection. This section is anchored in current realities with an up-to-date report on the demographic shifts and paradigm changes that came with large-scale vaccination efforts.

Finally, the third section of the book presents novel insight into three of the most important biliary diseases: cholestasis, primary sclerosing cholangitis, and hemophagocytic lymphohistiocytosis.

This book will appeal to medical professionals in different areas of expertise as well as the broader medical community. We hope the information contained herein will spark interest and research in viral hepatitis A.

**Streba Costin Teodor, MD, PhD, Msc, Vere Cristin Constantin, MD, PhD, Msc and Rogoveanu Ion, MD, PhD, Msc** University of Medicine and Pharmacy of Craiova, Romania

**II**

**Chapter 8 113**

**Chapter 9 123**

Primary Sclerosing Cholangitis (PSC) in Children

Cholestasis: The Close Relationship between Bile Acids

*by Manuela R. Martinefski, Silvia E. Lucangioli, Liliana G. Bianciotti* 

*by Sabina Wiecek*

and Coenzyme Q10

*and Valeria P. Tripodi*

**Prof. Dr. Valeria Tripodi and Dr. Silvia Lucangioli** University of Buenos Aires, Argentina

**1**

Section 1

Epidemiology of

Hepatitis A

Section 1

Epidemiology of Hepatitis A

**3**

**Chapter 1**

**Abstract**

Epidemiology of Hepatitis A: Past

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

**Keywords:** acute hepatitis, vaccine, feco-oral route, men who have sex with men,

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

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

and Current Trends

paradox of Hepatitis A epidemiology.

**1. Introduction**

around the world.

**2. The breakthrough**

outbreak, sero-prevalence, paradox of hepatitis A

*Anita Chakravarti and Tanisha Bharara*

#### **Chapter 1**

## Epidemiology of Hepatitis A: Past and Current Trends

*Anita Chakravarti and Tanisha Bharara*

#### **Abstract**

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.

**Keywords:** acute hepatitis, vaccine, feco-oral route, men who have sex with men, outbreak, sero-prevalence, paradox of hepatitis A

#### **1. 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.

#### **2. 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

**Figure 1.** *The timeline of Hepatitis A virus.*

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.

#### **3. Hepatitis A virus – structure and mode of transmission**

#### **3.1 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

**5**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

is generally seen between strains [17, 18].

as in a variety of food products [20].

**4. HAV vaccine – the holy grail**

an infected donor during the phase of viremia [21–23].

**3.2 Mode of transmission**

*3.2.1 Feco-oral*

*3.2.2 Parenteral*

*3.2.3 Sexual transmission*

(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%)

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

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

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].

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 year 1944 [31]. Joseph Stokes, a pediatrician working at the University of Pennsylvania School of Medicine, used the knowledge in curtailing hepatitis A

First HAV vaccine was developed in early 1900 [33, 34]. In 1991, a preliminary study was published among vaccinees, demonstrating neutralizing antibodies following the administration of formalin-inactivated vaccines [35]. Live attenuated

By 1992, the clinical efficacy of two formalin-inactivated hepatitis A vaccines HAVRIX (Smith-Kline Beecham) and VAQTA (Merck, Sharpe and Dohme) became obvious [30, 33]. Two laboratory-attenuated strains HM175 and CR326F respectively were used for vaccine production. The adverse reactions following vaccination were minimal, and seroconversion after two doses was found to be quite high (99.8%) [30]. Other monovalent formalin inactivated HAV vaccines available in market today

outbreak among children by administering gamma globulins [32].

hepatitis A vaccine was developed subsequently [36].

(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].

#### **3.2 Mode of transmission**

#### *3.2.1 Feco-oral*

*Hepatitis A and Other Associated Hepatobiliary Diseases*

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.

**3. Hepatitis A virus – structure and mode of transmission**

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

**4**

**3.1 Structure**

**Figure 1.**

*The timeline of Hepatitis A virus.*

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].

#### *3.2.2 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].

#### *3.2.3 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].

#### **4. 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 year 1944 [31]. Joseph Stokes, a pediatrician working at the University of Pennsylvania School of Medicine, used the knowledge in curtailing hepatitis A outbreak among children by administering gamma globulins [32].

First HAV vaccine was developed in early 1900 [33, 34]. In 1991, a preliminary study was published among vaccinees, demonstrating neutralizing antibodies following the administration of formalin-inactivated vaccines [35]. Live attenuated hepatitis A vaccine was developed subsequently [36].

By 1992, the clinical efficacy of two formalin-inactivated hepatitis A vaccines HAVRIX (Smith-Kline Beecham) and VAQTA (Merck, Sharpe and Dohme) became obvious [30, 33]. Two laboratory-attenuated strains HM175 and CR326F respectively were used for vaccine production. The adverse reactions following vaccination were minimal, and seroconversion after two doses was found to be quite high (99.8%) [30]. Other monovalent formalin inactivated HAV vaccines available in market today


**7**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

in the form of TWINRIX (GlaxoSmithKline) **Table 1** [37–39].

also recommends vaccination of high-risk groups [40].

100,000 in 1995 to 1 case per 100,000 in 2007) [42].

adverse reactions have been associated with vaccine use.

large proportion of population is immune to HAV [51, 52].

**5.1 The pre-vaccine era**

pre-vaccine era [53].

include AVAXIM (Aventis Pasteur), HEALIVE (Sinovac Biotech Co Ltd), Weisairuian (Institute of Medical Biology of the Chinese Academy of Medical Sciences; Kunming), Veraxim (Shanghai Wison Bioengineering Inc) and EPAXAL (Crucell/Berna Biotech). Hepatitis A vaccine is also available as a combined preparation with Hepatitis B vaccine

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

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

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

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, individu-

als with chronic liver disease, and immunocompromised patients [44–46].

**5. HAV epidemiology – pre-vaccine era and the paradox of 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

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

#### **Table 1.**

*List of HAV vaccines available in market.*

*Hepatitis A and Other Associated Hepatobiliary Diseases*

**6**

**Table 1.**

*List of HAV vaccines available in market.*

include AVAXIM (Aventis Pasteur), HEALIVE (Sinovac Biotech Co Ltd), Weisairuian (Institute of Medical Biology of the Chinese Academy of Medical Sciences; Kunming), Veraxim (Shanghai Wison Bioengineering Inc) and EPAXAL (Crucell/Berna Biotech). Hepatitis A vaccine is also available as a combined preparation with Hepatitis B vaccine in the form of TWINRIX (GlaxoSmithKline) **Table 1** [37–39].

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 [44–46].

#### **5. HAV epidemiology – pre-vaccine era and the paradox of vaccine era**

#### **5.1 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].

#### **5.2 The vaccine era**

#### *5.2.1 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 [56–61]. 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].

**9**

rates [90].

to be as low as 36.7% [82].

of the district of Gampaha.

transmission [104, 105].

*5.2.2 HAV outbreaks over the last decade*

world **Table 2** and **Figure 2** [92–107].

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

might not be necessary in highly endemic regions.

reported from other parts of the country as well [86–88].

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

In India, the sero-prevalence of anti-HAV antibodies exceeds 90% among adults

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

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

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

Over the last 10 years, several outbreaks have been reported throughout the

of transmission among high risk groups is the second most prevalent route of

Although feco-oral route has been implicated in most of the cases, sexual mode

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].

[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

#### *Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

*Hepatitis A and Other Associated Hepatobiliary Diseases*

*5.2.1 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 [56–61]. 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

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

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

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].

**5.2 The vaccine era**

hepatitis A risk" [55].

as nursing homes etc. [67].

countries endemic for HAV [72].

**8**

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 [86–88].

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.

#### *5.2.2 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].


**Table 2.** *Hepatitis A outbreaks around the world over the last decade.*

#### **Figure 2.** *Hepatitis A outbreaks throughout the world over the last decade.*

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

**11**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

by hepatitis E virus [99].

lack of awareness [102].

**6. Conclusion**

prevention program.

**Conflict of interest**

The authors declare no conflict of interest.

cases were traced and vaccinated [106].

nation from a bore well was identified as the source [101].

possible transmission through sexual contacts at MSM events.

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 contami-

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

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

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

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

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

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

*Hepatitis A and Other Associated Hepatobiliary Diseases*

*Hepatitis A outbreaks around the world over the last decade.*

**10**

**Figure 2.**

**Table 2.**

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

*Hepatitis A outbreaks throughout the world over the last decade.*

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.

#### **6. 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.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Hepatitis A and Other Associated Hepatobiliary Diseases*

#### **Author details**

Anita Chakravarti\* and Tanisha Bharara Department of Microbiology, Shree Gurugobind Singh Tricentenary University, Gurugram, Haryana, India

\*Address all correspondence to: anitachakravarti@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**13**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

> [12] Havens WP, Ward R, Drill VA, Paul JR. Experimental production of hepatitis by feeding icterogenic materials. Proceedings of the Society for Experimental Biology and Medicine.

[13] Krugman S, Ward R, Giles JP. The natural history of infectious hepatitis. The American Journal of Medicine.

[14] Anonymous.Homologous serum hepatitis. Lancet. 1947;**ii**:691-692

[15] Provost PJ, Hilleman MR. Propagation of human hepatitis A virus in cell culture *in vitro*. Proceedings of the Society for Experimental Biology and Medicine.

[16] Cohen JI, Ticehurst JR, Feinstone SM, Rosenblum B, Purcell RH. Hepatitis A virus cDNA and its RNA transcripts are infectious in cell culture. Journal of Virology.

1944;**57**:206-208

1962;**32**:717-728

1979;**160**:213-221

1987;**61**:3035-3039

2006;**19**:63-79

1992;**10**(1):40-44

2000;**11**:159-163

[17] Nainan OV, Xia G,

[18] Lemon SM, Jansen RW, Brown EA. Genetic, antigenic and bio- logical differences between strains of hepatitis A virus. Vaccine.

Diseases. 2004;**38**(5):705-715

[20] Sattar SA, Jason T, Bidawid S, Farber J. Foodborne spread of hepatitis A: Recent studies on virus survival, transfer and inactivation. Canadian Journal of Infectious Diseases.

Vaughan G. Diagnosis of hepatitis A virus infection: A molecular approach. Clinical Microbiology Reviews.

[19] Acheson D, Fiore AE. Hepatitis A transmitted by food. Clinical Infectious

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*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

#### **References**

*Hepatitis A and Other Associated Hepatobiliary Diseases*

**12**

**Author details**

Gurugram, Haryana, India

Anita Chakravarti\* and Tanisha Bharara

provided the original work is properly cited.

Department of Microbiology, Shree Gurugobind Singh Tricentenary University,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: anitachakravarti@gmail.com

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[27] Beebeejaun K, Degala S, Balogun K, Simms I, Woodhall SC, Heinsbroek E, et al. Outbreak of hepatitis A associated with men who have sex with men (MSM), England, July 2016 to January 2017. Euro Surveillance. 2017;**22**(5):304-354

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[30] Andre FE, D'Hondt E, Delem A. Clinical assessment of the safety and efficacy of an inactivated hepatitis A vaccine: Rationale and summary of findings. Vaccine. 1992;**10**(1):160-168

[31] Ordman CW, Jennings CG, Janeway CA. Chemical, clinical, and immunological studies on the products of human plasma fractionation. XII. Use of concentrated normal human serum gamma globulin (human immune serum globulin) in the prevention and attenuation of measles. Journal of Clinical Investigation. 1944;**23**:541-549

[32] Stokes J, Neefe JR. The prevention and attenuation of infectious hepatitis with gamma globulin (preliminary note). JAMA. 1945;**127**:144-145

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[34] Innis BL, Snitbhan R, Kunasol P, Laorakpongse T, Poopatanakool W, Kozik CA, et al. Protection against hepatitis A by an inactivated vaccine. JAMA. 1994;**271**:1328-1334

[35] Sjogren MH, Hoke CH, Binn LN, Eckels KH, Dubois DR, Lyde L, et al. Immunogenicity of an inactivated hepatitis A vaccine. Annals of Internal Medicine. 1991;**114**:470-471

[36] Midthun K, Ellerbeck E, Gershman K, Calandra G, Krah D,

**15**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

> patients with inflammatory bowel disease against infections patient attitude and personal immunization knowledge. Acta Gastroenterologica

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[46] Singh V, Crosby RA, Gratzer B, Gorbach PM, Markowitz LE,

is significantly associated with

Meites E. Disclosure of sexual behavior

receiving a panel of health care services recommended for men who have sex with men. Sexually Transmitted Diseases. 2018;**45**(12):803-807

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Report No. 58. Atlanta; 2003

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2008;**128**(6):699-704

Belgica. 2018;**81**(2):257-261

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2002;**49**:1-102

Mc-Caughtry M, et al. Safety and immunogenicity of a live attenuated hepatitis A virus vaccine in seronegative volunteers. The Journal of Infectious

[37] Shouval D. The immunological basis for immunization series. In: Immunization Vaccines and Biologicals. Switzerland: World Health Organization Department of Immunization; 2010. p. 39

Diseases. 1991;**163**:735-739

[38] Cui F, Liang X, Wang F,

[39] Sabanin IV, Rikhter VV,

2014;**24**:169-177

2010;**1**:35-39

Publishing; 2019

production, and postmarketing surveillance of hepatitis A vaccines in China. Journal of Epidemiology.

Zheng H, Hutin YJ, Yang W. Development,

Kuzin SN. Assessment of effectiveness and immunogenicity of hepatitis A vaccination in servicemen of internal forces of Ministry of Internal Affairs of Russia. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii.

[40] Gardner P, Eickhoff T, Poland GA, Gross P, Griffin M, LaForce FM, et al. Adult immunizations. Annals of Internal Medicine. 1996;**124**:35-40

[41] Iorio N, John S. Hepatitis A NCBI Bookshelf. A Service of the National Library of Medicine, National Institutes

Elder HA. Serologic investigation of an outbreak of hepatitis A in a rural daycare cente. American Journal of Public

of Health. StatPearls [Internet]. Treasure Island (FL): StatPearls

[42] Gingrich GA, Hadler SC,

Health. 1983;**73**:1190-1193

2012;**8**(8):1132-1134

[43] Verma R, Khanna P. Hepatitis A vaccine should receive priority in National Immunization Schedule in India. Human Vaccines & Immunotherapeutics.

[44] Waszczuk K, Waszczuk E, Szenborn L. Can we better protect *Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

Mc-Caughtry M, et al. Safety and immunogenicity of a live attenuated hepatitis A virus vaccine in seronegative volunteers. The Journal of Infectious Diseases. 1991;**163**:735-739

*Hepatitis A and Other Associated Hepatobiliary Diseases*

MSM linked to casual sex and gay saunas in Copenhagen, Denmark. Eurosurveillance. 2005;**10**(5):536

[30] Andre FE, D'Hondt E, Delem A. Clinical assessment of the safety and efficacy of an inactivated hepatitis A vaccine: Rationale and summary of findings. Vaccine. 1992;**10**(1):160-168

[31] Ordman CW, Jennings CG, Janeway CA. Chemical, clinical, and immunological studies on the products of human plasma fractionation. XII. Use of concentrated normal human serum gamma globulin (human immune serum globulin) in the prevention and attenuation of measles. Journal of Clinical Investigation. 1944;**23**:541-549

[32] Stokes J, Neefe JR. The prevention and attenuation of infectious hepatitis with gamma globulin (preliminary note). JAMA. 1945;**127**:144-145

[33] Werzberger A, Mensch B, Kuter B, Brown L, Lewis J, Sitrin R, et al. A controlled trial of a formalininactivated hepatitis a vaccine in healthy children. The New England Journal of

Medicine. 1992;**327**:453-457

JAMA. 1994;**271**:1328-1334

Medicine. 1991;**114**:470-471

[36] Midthun K, Ellerbeck E, Gershman K, Calandra G, Krah D,

[34] Innis BL, Snitbhan R, Kunasol P, Laorakpongse T, Poopatanakool W, Kozik CA, et al. Protection against hepatitis A by an inactivated vaccine.

[35] Sjogren MH, Hoke CH, Binn LN, Eckels KH, Dubois DR, Lyde L, et al. Immunogenicity of an inactivated hepatitis A vaccine. Annals of Internal

[29] Maynard JE, Lorenz D, Bradley DW. Review of infectivity studies in nonhuman primates with virus-like particles associated with MS-1 hepatitis. The American Journal of the Medical Sciences. 1975;**270**:81-85

[21] Mannucci PM, Gdovin S,

1994;**120**:1-7

1994;**67**(4):19-23

1995;**99**(2):132-136

Gringeri A. Transmission of hepatitis A to patients with hemophilia by factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. The Italian collaborative group. Annals of Internal Medicine.

[22] Lemon SM. The natural history of hepatitis A: The potential for transmission by transfusion of blood or blood products. Vox Sanguinis.

[23] Soucie JM, Robertson BH, Bell BP. Hepatitis A virus infections associated with clotting factor concentrate in the United States. Transfusion. 1998;**38**:573-579

[24] Henning KJ, Bell E, Braun J,

Barker ND. A community-wide outbreak of hepatitis A: Risk factors for infection among homosexual and bisexual men. The American Journal of Medicine.

[25] Kuijpers LA, Kool JL, Veugelers PJ, Coutinho RA, Griensven GJ. An outbreak of hepatitis A among homosexual men in Amsterdam, 1991- 1993. International Journal of Epidemiology. 1995;**24**(1):218-222

[26] Bell A, Ncube F, Hansell A,

Davison KL, Young Y, Gilson R, et al. An outbreak of hepatitis A among young men associated with having sex in public venues. Communicable Disease and Public Health. 2001;**4**(3):163-170

[27] Beebeejaun K, Degala S, Balogun K, Simms I, Woodhall SC, Heinsbroek E, et al. Outbreak of hepatitis A associated with men who have sex with men (MSM), England, July 2016 to January 2017. Euro Surveillance.

**14**

2017;**22**(5):304-354

[28] Mazick A, Howitz M, Rex S, Jensen IP, Weis N, Katzenstein TL, et al. Hepatitis A outbreak among

[37] Shouval D. The immunological basis for immunization series. In: Immunization Vaccines and Biologicals. Switzerland: World Health Organization Department of Immunization; 2010. p. 39

[38] Cui F, Liang X, Wang F, Zheng H, Hutin YJ, Yang W. Development, production, and postmarketing surveillance of hepatitis A vaccines in China. Journal of Epidemiology. 2014;**24**:169-177

[39] Sabanin IV, Rikhter VV, Kuzin SN. Assessment of effectiveness and immunogenicity of hepatitis A vaccination in servicemen of internal forces of Ministry of Internal Affairs of Russia. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii. 2010;**1**:35-39

[40] Gardner P, Eickhoff T, Poland GA, Gross P, Griffin M, LaForce FM, et al. Adult immunizations. Annals of Internal Medicine. 1996;**124**:35-40

[41] Iorio N, John S. Hepatitis A NCBI Bookshelf. A Service of the National Library of Medicine, National Institutes of Health. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019

[42] Gingrich GA, Hadler SC, Elder HA. Serologic investigation of an outbreak of hepatitis A in a rural daycare cente. American Journal of Public Health. 1983;**73**:1190-1193

[43] Verma R, Khanna P. Hepatitis A vaccine should receive priority in National Immunization Schedule in India. Human Vaccines & Immunotherapeutics. 2012;**8**(8):1132-1134

[44] Waszczuk K, Waszczuk E, Szenborn L. Can we better protect patients with inflammatory bowel disease against infections patient attitude and personal immunization knowledge. Acta Gastroenterologica Belgica. 2018;**81**(2):257-261

[45] O'Leary ST, Kimberlin DW. Update from the advisory committee on immunization practices. Journal of the Pediatric Infectious Diseases Society. 2018;**7**(3):181-187

[46] Singh V, Crosby RA, Gratzer B, Gorbach PM, Markowitz LE, Meites E. Disclosure of sexual behavior is significantly associated with receiving a panel of health care services recommended for men who have sex with men. Sexually Transmitted Diseases. 2018;**45**(12):803-807

[47] Groseclose SL, Brathwaite WS, Hall PA, Adams DA, Connor FJ, Sharp P, et al. Centers for Disease Control and Prevention. Summary of notifiable diseases, United States, 2000. MMWR Morbidity and Mortality Weekly Report. 2002;**49**:1-102

[48] Centers for Disease Control and Prevention. Hepatitis Surveil- lance Report No. 58. Atlanta; 2003

[49] Wasley A, Feinstone SM, Bell BP. Hepatitis A. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Churchill Livingstone; 2011. pp. 2367-2387

[50] Bell BP, Kruszon-Moran D, Shapiro CN. Hepatitis a virus infection in the United States: Serologic results from the third National Health and nutrition examination survey. Vaccine. 2005;**23**:5793-5806

[51] Mathur P, Arora N. Epidemiological transition of hepatitis A in India: Issues for vaccination in developing countries. Indian Journal of Medical Research. 2008;**128**(6):699-704

[52] Mantovani SAS, Delfino BM, Martins AC, Oliart-Guzmán H, Pereira TM, Branco FLCC, et al. Socioeconomic inequities and hepatitis A virus infection in Western Brazilian Amazonian children: Spatial distribution and associated factors. BMC Infectious Diseases. 2015;**15**(1):428

[53] Cooksley WG. What did we learn from the Shanghai hepatitis A epidemic? Journal of Viral Hepatitis. 2000;**7**(1):1-3

[54] World Health Organization. Hepatitis A Fact sheet No. 328. Available from: http://www.searo.who. int/thailand/factsheets/fs0030/en/ [Accessed: 31 July 2019]

[55] Mohd Hanafiah K, Jacobsen KH, Wiersma ST. Challenges to mapping the health risk of hepatitis A virus infection. International Journal of Health Geographics. 2011;**10**:57

[56] Barzaga BN. Hepatitis a, shifting epidemiology in South-East Asia and in China. Vaccine. 2000;**18**(1):61-64

[57] Poovorawan Y, Theamboonlers A, Sinalaparatsamee S, Chaiear K, Siraprapasiri T, Khwanjaipanich S, et al. Increasing susceptibility to HAV among members of the young generation in Thailand. Asian Pacific Journal of Allergy and Immunology. 2000;**18**:249-253

[58] Tanaka J. Hepatitis a shifting epidemiology in Latin America. Vaccine. 2000;**18**(1):57-60

[59] Sohn YM, Rho HO, Park MS. The changing epidemiology of hepatitis A in children and the consideration of active immunisation in Korea. Yonsei Medical Journal. 2000;**41**:34-39

[60] Dal-Re R, Garcia-Corberia P, Garcia-de-Lomas J. A large percentage of the Spanish population under 30 years of age is not protected against

hepatitis A. Journal of Medical Virology. 2000;**60**:363-366

[61] Gdalvich M, Grotto I, Mandel Y, Mimouni D, Sherman J, Ashkenezi I. Hepatitis A antibody prevalence among young adults in Israel, the decline continues. Epidemiology and Infection. 1998;**1221**:477-479

[62] European Centre for Disease Prevention and Control. Annual Epidemiological Report Hepatitis A. Available from: https:// ecdc.europa.eu/en/publications-data/ hepatitis-annual-epidemiologicalreport-2016 [Accessed: 31 July 2019]

[63] Gozlan Y, Bar-Or I, Rakovsky A. Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016–June 2017. Euro Surveillance. 2017;**22**:30575

[64] Klevens RM, Kruszon-Moran D, Wasley A. Seroprevalence of hepatitis A virus antibodies in the U.S.: Results from the National Health and nutrition examination survey. Public Health Reports. 2011;**126**:522-532

[65] Ly KN, Klevens RM. Trends in disease and complications of hepatitis A virus infection in the United States, 1999-2011: A new concern for adults. The Journal of Infectious Diseases. 2015;**212**:176-182

[66] Ariyarathna N, Abeysena C. Seroprevalence of viral hepatitis A in a district of Sri Lanka: A community based cross-sectional study. BMC Infectious Diseases. 2019;**19**:443

[67] Tan EM, Marcelin JR, Virk A. Pretravel counseling for immunocompromised travelers: A 12year singlecenter retrospective review. Infection, Disease & Health. 2019;**24**(1):13-22

[68] CDC. Viral hepatitis surveillance Atlanta, GA: US Department of

**17**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

> Seroepidemiology of hepatitis A in Japan, 1973-2003. Microbiology and Immunology. 2007;**51**(2):185-191

[76] Tseng YT, Sun HY, Chang SY, Wu CH, Liu WC, Wu PY, et al. Seroprevalence of hepatitis virus infection in men who have sex with men aged 18-40 years in Taiwan. Journal of the Formosan Medical Association.

[77] Lee YL, Lin KY, Cheng CY, Li CW, Yang CJ, Tsai MS, et al. Taiwan HIV study group. Evolution of hepatitis A virus seroprevalence among HIVpositive adults in Taiwan. PLoS One. 2017;**12**(10):e0186338. DOI: 10.1371/

[78] Battegay M, Gust ID, Feinstone SM. Hepatitis A virus. In: Mandel JL, Bennett JE, editors. Principles and Practices of Infectious Diseases.

New York: Churchill Livingstone; 1995.

[80] Brown P, Greguer G, Smallwood L, Ney R, Moerdowo RM, Gerety RJ. Serological markers of hepatitis A and B in the population of Bali, Indonesia. American Journal of Tropical Medicine

Joshi YK. Etiological spectrum of viral hepatitis and prevalence of markers of hepatitis A and B virus in northern India. Bulletin of the World Health Organization. 1984;**62**:67-73

[82] Das K, Jain A, Gupta S, Kapoor S, Gupta RK, Chakravorty A, et al. The changing epidemiological pattern of hepatitis A virus in an urban population in India: Emergence of a trend similar to

and Hygiene. 1985;**34**:616-619

[81] Tandon BN, Gandhi BM,

[79] Prince AM, Brotman B, Richardson L, White T, Pollock N, Riddle J. Incidence of hepatitis A virus (HAV) infection in rural Liberia. Journal of Medical Virology.

2012;**111**(8):431-438

journal.pone.0186338

pp. 1636-1656

1985;**15**:421-428

Health and Human Service. Available

hepatitis/statistics/2016surveillance/ pdfs/2016HepSurveillanceRpt.pdf

from: https://www.cdc.gov/

[Accessed: 01 August 2019]

August]

[69] CDC. Hepatitis surveillance: Report no. 55. Atlanta, GA: US Department of Health and Human. Available from: Service https://babel. hathitrust.org/cgi/pt?id=mdp.39015026 224173;view=1up;seq=24 [Accessed: 01

[70] Groseclose SL, Brathwaite WS, Hall PA, Adams DA, Connor FJ, Sharp P, et al. Centers for Disease Control Prevention. Summary of notifiable diseases, United States. MMWR Morbidity and Mortality Weekly Report. 2002;**49**:1-102

[71] Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitis—

Surveillance Summaries. 2008;**57**:1-24

Prevention. Viral hepatitis surveillance, United States 2016. Atlanta, GA: US Department of Health and Human Services, CDC. Available from: https://www.cdc.gov/hepatitis/ statistics/2016surveillance/

United States, 2006. MMWR

[72] Centers for Disease Control

pdfs/2016HepSurveillanceRpt.pdf

Lataillade J, Fabre G. Risk factors for hepatitis A infection in France: Drinking

tap water may be of importance. European Journal of Epidemiology.

[74] Yun H, Lee HJ, Yoon Y, Kim K, Kim S, Shin MH, et al. Seroprevalence of hepatitis-antibodies in relation to social factors, a preliminary study. Osong Public Health and Research Perspectives. 2012;**3**(1):31-35

[75] Kiyohara T, Sato T, Totsuka A, Miyamura T, Ito T, Yoneyama T. Shifting

[Accessed: 01 August 2019]

[73] Lagarde E, Joussemet M,

1995;**11**(2):145-148

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

Health and Human Service. Available from: https://www.cdc.gov/ hepatitis/statistics/2016surveillance/ pdfs/2016HepSurveillanceRpt.pdf [Accessed: 01 August 2019]

*Hepatitis A and Other Associated Hepatobiliary Diseases*

hepatitis A. Journal of Medical Virology.

[61] Gdalvich M, Grotto I, Mandel Y, Mimouni D, Sherman J, Ashkenezi I. Hepatitis A antibody prevalence among young adults in Israel, the decline continues. Epidemiology and Infection.

2000;**60**:363-366

1998;**1221**:477-479

[62] European Centre for

Disease Prevention and Control. Annual Epidemiological Report Hepatitis A. Available from: https:// ecdc.europa.eu/en/publications-data/ hepatitis-annual-epidemiologicalreport-2016 [Accessed: 31 July 2019]

[63] Gozlan Y, Bar-Or I, Rakovsky A. Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016–June 2017. Euro

[64] Klevens RM, Kruszon-Moran D, Wasley A. Seroprevalence of hepatitis A virus antibodies in the U.S.: Results from the National Health and nutrition examination survey. Public Health

[65] Ly KN, Klevens RM. Trends in disease and complications of hepatitis A virus infection in the United States, 1999-2011: A new concern for adults. The Journal of Infectious Diseases.

[66] Ariyarathna N, Abeysena C. Seroprevalence of viral hepatitis A in a district of Sri Lanka: A community based cross-sectional study. BMC Infectious Diseases. 2019;**19**:443

[68] CDC. Viral hepatitis surveillance Atlanta, GA: US Department of

Surveillance. 2017;**22**:30575

Reports. 2011;**126**:522-532

[67] Tan EM, Marcelin JR, Virk A. Pretravel counseling for immunocompromised travelers: A 12year singlecenter retrospective review. Infection, Disease & Health.

2015;**212**:176-182

2019;**24**(1):13-22

[52] Mantovani SAS, Delfino BM, Martins AC, Oliart-Guzmán H, Pereira TM, Branco FLCC, et al. Socioeconomic inequities and

hepatitis A virus infection in Western Brazilian Amazonian children: Spatial distribution and associated factors. BMC Infectious Diseases.

[53] Cooksley WG. What did we learn from the Shanghai hepatitis A epidemic? Journal of Viral Hepatitis. 2000;**7**(1):1-3

Available from: http://www.searo.who. int/thailand/factsheets/fs0030/en/

[55] Mohd Hanafiah K, Jacobsen KH, Wiersma ST. Challenges to mapping the health risk of hepatitis A virus infection.

[56] Barzaga BN. Hepatitis a, shifting epidemiology in South-East Asia and in China. Vaccine. 2000;**18**(1):61-64

[57] Poovorawan Y, Theamboonlers A, Sinalaparatsamee S, Chaiear K, Siraprapasiri T, Khwanjaipanich S, et al. Increasing susceptibility to HAV among members of the young generation in Thailand. Asian Pacific Journal of Allergy and Immunology.

[58] Tanaka J. Hepatitis a shifting

epidemiology in Latin America. Vaccine.

[59] Sohn YM, Rho HO, Park MS. The changing epidemiology of hepatitis A in children and the consideration of active immunisation in Korea. Yonsei Medical

[60] Dal-Re R, Garcia-Corberia P, Garcia-de-Lomas J. A large percentage of the Spanish population under 30 years of age is not protected against

International Journal of Health Geographics. 2011;**10**:57

[54] World Health Organization. Hepatitis A Fact sheet No. 328.

[Accessed: 31 July 2019]

2000;**18**:249-253

2000;**18**(1):57-60

Journal. 2000;**41**:34-39

2015;**15**(1):428

**16**

[69] CDC. Hepatitis surveillance: Report no. 55. Atlanta, GA: US Department of Health and Human. Available from: Service https://babel. hathitrust.org/cgi/pt?id=mdp.39015026 224173;view=1up;seq=24 [Accessed: 01 August]

[70] Groseclose SL, Brathwaite WS, Hall PA, Adams DA, Connor FJ, Sharp P, et al. Centers for Disease Control Prevention. Summary of notifiable diseases, United States. MMWR Morbidity and Mortality Weekly Report. 2002;**49**:1-102

[71] Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitis— United States, 2006. MMWR Surveillance Summaries. 2008;**57**:1-24

[72] Centers for Disease Control Prevention. Viral hepatitis surveillance, United States 2016. Atlanta, GA: US Department of Health and Human Services, CDC. Available from: https://www.cdc.gov/hepatitis/ statistics/2016surveillance/ pdfs/2016HepSurveillanceRpt.pdf [Accessed: 01 August 2019]

[73] Lagarde E, Joussemet M, Lataillade J, Fabre G. Risk factors for hepatitis A infection in France: Drinking tap water may be of importance. European Journal of Epidemiology. 1995;**11**(2):145-148

[74] Yun H, Lee HJ, Yoon Y, Kim K, Kim S, Shin MH, et al. Seroprevalence of hepatitis-antibodies in relation to social factors, a preliminary study. Osong Public Health and Research Perspectives. 2012;**3**(1):31-35

[75] Kiyohara T, Sato T, Totsuka A, Miyamura T, Ito T, Yoneyama T. Shifting Seroepidemiology of hepatitis A in Japan, 1973-2003. Microbiology and Immunology. 2007;**51**(2):185-191

[76] Tseng YT, Sun HY, Chang SY, Wu CH, Liu WC, Wu PY, et al. Seroprevalence of hepatitis virus infection in men who have sex with men aged 18-40 years in Taiwan. Journal of the Formosan Medical Association. 2012;**111**(8):431-438

[77] Lee YL, Lin KY, Cheng CY, Li CW, Yang CJ, Tsai MS, et al. Taiwan HIV study group. Evolution of hepatitis A virus seroprevalence among HIVpositive adults in Taiwan. PLoS One. 2017;**12**(10):e0186338. DOI: 10.1371/ journal.pone.0186338

[78] Battegay M, Gust ID, Feinstone SM. Hepatitis A virus. In: Mandel JL, Bennett JE, editors. Principles and Practices of Infectious Diseases. New York: Churchill Livingstone; 1995. pp. 1636-1656

[79] Prince AM, Brotman B, Richardson L, White T, Pollock N, Riddle J. Incidence of hepatitis A virus (HAV) infection in rural Liberia. Journal of Medical Virology. 1985;**15**:421-428

[80] Brown P, Greguer G, Smallwood L, Ney R, Moerdowo RM, Gerety RJ. Serological markers of hepatitis A and B in the population of Bali, Indonesia. American Journal of Tropical Medicine and Hygiene. 1985;**34**:616-619

[81] Tandon BN, Gandhi BM, Joshi YK. Etiological spectrum of viral hepatitis and prevalence of markers of hepatitis A and B virus in northern India. Bulletin of the World Health Organization. 1984;**62**:67-73

[82] Das K, Jain A, Gupta S, Kapoor S, Gupta RK, Chakravorty A, et al. The changing epidemiological pattern of hepatitis A virus in an urban population in India: Emergence of a trend similar to European countries. European Journal of Epidemiology. 2000;**16**:507-510

[83] Dhawan PS, Shah SS, Alvares JF, Kher A, Shankaran KPW, et al. Seroprevalence of hepatitis A virus in Mumbai and immunogenicity and safety of hepatitis A vaccine. Indian Journal of Gastroenterology. 1998;**17**:16-18

[84] Das K, Kar P, Chakarborty A, Gupta S, Das BC. Is a vaccination programme against hepatitis A needed in India? Indian Journal of Gastroenterology. 1998;**17**:158

[85] Arankalle V, Mitra M, Bhave S. Changing epidemiology of hepatitis A virus in Indian children. Dovepress. 2014;**4**:7-13

[86] Aggarwal R, Naik S, Yachha SK, Naik SR. Seroprevalence of antibodies to the hepatitis A virus among children in northern India. Indian Paediatrics. 1999;**36**:1248-1250

[87] Freidl GS, Sonder GJ, Bovée LP, Friesema IH, van Rijckevorsel GG, Ruijs WL, et al. Hepatitis A outbreak among men who have sex with men (MSM) predominantly linked with the EuroPride, the Netherlands, July 2016 to February 2017. Euro Surveillance. 2017;**22**(8):30468

[88] Acharya SK, Batra Y, Bhatkal B. Seroepidemiology of hepatitis A virus infection among school children in Delhi and north Indian patients with chronic liver disease: Implications for HAV vaccination. Journal of Gastroenterology and Hepatology. 2003;**18**(7):822-827

[89] Fix AD, Martin OS, Gallicchio L, Vial PA, Lagos R. Age-specific prevalence of antibodies to hepatitis A in Santiago, Chile: Risk factors and shift in age of infection among children and young adults. The American Journal

of Tropical Medicine and Hygiene. 2002;**66**(5):628-632

[90] Acharya SK, Madan K, Dattagupta S, Panda SK. Viral hepatitis in India. National Medical Journal of India. 2006;**19**(4):203-217

[91] Hayajneh WA, Balbeesi A, Faouri S. Hepatitis A virus age-specific sero- prevalence and risk factors among Jordanian children. Journal of Medical Virology. 2015;**87**(4):569-574

[92] Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report (MMWR). Provisional cases of selected notifiable diseases, and selected low frequency diseases, United States and U.S. territories, weeks ending November 11, 2017, and November 12, 2016. Available from: www.cdc.gov/ mmwr/volumes/66/wr/mm6645md.htm [Accessed: 01 August 2019]

[93] Centers for Disease Control and Prevention. Viral hepatitis: 2016– Multistate outbreak of hepatitis A linked to frozen strawberries (final update). Available from: www.cdc. gov/hepatitis/outbreaks/2016/havstrawberries.htm [Accessed: 28 July 2019]

[94] State of Hawaii, Department of Health: Disease Outbreak Control Division. Hepatitis A outbreak 2016. Available from: http://health.hawaii. gov/docd/hepatitis-a-outbreak-2016 [Accessed: 28 July 2019]

[95] California Department of Public Health. Hepatitis A outbreak in California. 2018. Available from: www. cdph.ca.gov/Programs/CID/DCDC/ Pages/Immunization/Hepatitis-A-Outbreak.aspx [Accessed: 28 July 2019]

[96] Donnan EJ, Fielding JE, Gregory JE, Lalor K, Rowe S, Goldsmith P, et al. A multistate outbreak of hepatitis A associated with semidried tomatoes in

**19**

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

> reported hepatitis a infections among men who have sex with men - New York City, January-August 2017. MMWR Morbidity and Mortality Weekly Report. 2017;**66**(37):999-1000. DOI: 10.15585/

[104] Urbanus AT, van Houdt R, van de Laar TJ, Coutinho RA. Viral hepatitis among men who have sex with men, epidemiology and public health consequences. Euro Surveillance.

[105] Stene-Johansen K, Tjon G, Schreier E, Bremer V, Bruisten S,

Turbitt D, Balogun K, Figueroa J, Nixon G. Hepatitis A outbreak in an orthodox Jewish community in London,

July 2010. Eurosurveillance.

[107] Lim HS, Choi K, Lee S.

Epidemiological investigation of an outbreak of hepatitis A at a residential facility for the disabled. Journal of Preventive Medicine and Public Health.

[108] European Centre for Disease Prevention and Control (ECDC). Rapid risk assessment: Hepatitis A outbreak in the EU/EEA mostly affecting men who have sex with men. Available from: https://ecdc.europa. eu/en/publications-data/rapid-riskassessment-hepatitis-outbreak-eueeamostly-affecting-men-who-have-sex

Ngui SL, et al. Molecular epidemiological studies show that hepatitis A virus is endemic among active homosexual men in Europe. Journal of Medical Virology.

mmwr.mm6637a7

2009;**14**(47):19-21

2007;**79**(4):356-365

[106] Edelstein M,

2010;**15**(37):19662

2013;**46**(2):62-73

[Accessed: 28 July 2019]

Australia. Clinical Infectious Diseases.

[97] Integrated Disease Surveillance Project. Recent Weekly Outbreak. Available from: http://www.idsp.nic.in/ index4.php?lang=1&level=0&linkid=4 06&lid=3689 [Last Accessed: 01 August

[98] Rakesh PS, Mainu TT, Raj A, Babu D, Rajiv M, Sreelakshmi K, et al. Investigating a community wide

Care. 2018;**7**:1537-1541

2013;**31**(3):261-265

2014;**6**(2):59-64

[100] Arankalle VA, Sarada Devi KL, Lole KS, Shenoy KT, Verma V, Haneephabi M. Molecular characterization of hepatitis A virus from a large outbreak from Kerala, India. Indian Journal of Medical Research. 2006;**123**(6):760-769

[101] Rakesh PS, Sherin D, Sankar H, Shaji M, Subhagan S, Salila S. Investigating a community-wide outbreak of hepatitis A in India. Journal of Global Infectious Diseases.

[102] Gassowski M, Michaelis K, Wenzel JJ, Faber M, Figoni J, Mouna L, et al. Two concurrent outbreaks of hepatitis A highlight the risk of infection for non-immune travellers to Morocco, January to June 2018. Euro

Surveillance. 2018;**5**(27):1-5

[103] Latash J, Dorsinville M, Del

Rosso P, Antwi M, Reddy V, Waechter H, et al. Notes from the eld: increase in

[99] Jain P, Prakash S, Gupta S.

outbreak of hepatitis A in Kerala, India. Journal of Family Medicine and Primary

Prevalence of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus and hepatitis E virus as causes of acute viral hepatitis in North India: A hospital based study. Indian Journal of Medical Microbiology.

2012;**54**:775-781

2019]

*Epidemiology of Hepatitis A: Past and Current Trends DOI: http://dx.doi.org/10.5772/intechopen.89248*

Australia. Clinical Infectious Diseases. 2012;**54**:775-781

*Hepatitis A and Other Associated Hepatobiliary Diseases*

of Tropical Medicine and Hygiene.

Dattagupta S, Panda SK. Viral hepatitis in India. National Medical Journal of

Faouri S. Hepatitis A virus age-specific sero- prevalence and risk factors among Jordanian children. Journal of Medical

[92] Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report (MMWR). Provisional cases of selected notifiable diseases, and selected low frequency diseases, United States and U.S. territories, weeks ending November 11, 2017, and November 12, 2016. Available from: www.cdc.gov/ mmwr/volumes/66/wr/mm6645md.htm

2002;**66**(5):628-632

[90] Acharya SK, Madan K,

India. 2006;**19**(4):203-217

[91] Hayajneh WA, Balbeesi A,

Virology. 2015;**87**(4):569-574

[Accessed: 01 August 2019]

2019]

[93] Centers for Disease Control and Prevention. Viral hepatitis: 2016– Multistate outbreak of hepatitis A linked to frozen strawberries (final update). Available from: www.cdc. gov/hepatitis/outbreaks/2016/havstrawberries.htm [Accessed: 28 July

[94] State of Hawaii, Department of Health: Disease Outbreak Control Division. Hepatitis A outbreak 2016. Available from: http://health.hawaii. gov/docd/hepatitis-a-outbreak-2016

[95] California Department of Public Health. Hepatitis A outbreak in California. 2018. Available from: www. cdph.ca.gov/Programs/CID/DCDC/ Pages/Immunization/Hepatitis-A-Outbreak.aspx [Accessed: 28 July 2019]

[96] Donnan EJ, Fielding JE, Gregory JE, Lalor K, Rowe S, Goldsmith P, et al. A multistate outbreak of hepatitis A associated with semidried tomatoes in

[Accessed: 28 July 2019]

European countries. European Journal of Epidemiology. 2000;**16**:507-510

[83] Dhawan PS, Shah SS, Alvares JF, Kher A, Shankaran KPW, et al. Seroprevalence of hepatitis A virus in Mumbai and immunogenicity and safety of hepatitis A vaccine. Indian Journal of Gastroenterology.

[84] Das K, Kar P, Chakarborty A, Gupta S, Das BC. Is a vaccination programme against hepatitis A needed in India? Indian Journal of Gastroenterology. 1998;**17**:158

[85] Arankalle V, Mitra M, Bhave S. Changing epidemiology of hepatitis A virus in Indian children. Dovepress.

[86] Aggarwal R, Naik S, Yachha SK, Naik SR. Seroprevalence of antibodies to the hepatitis A virus among children in northern India. Indian Paediatrics.

[87] Freidl GS, Sonder GJ, Bovée LP, Friesema IH, van Rijckevorsel GG, Ruijs WL, et al. Hepatitis A outbreak among men who have sex with men (MSM) predominantly linked with the EuroPride, the Netherlands, July 2016 to February 2017. Euro Surveillance.

[88] Acharya SK, Batra Y, Bhatkal B. Seroepidemiology of hepatitis A virus infection among school children in Delhi and north Indian patients with chronic liver disease: Implications for HAV vaccination. Journal of Gastroenterology and Hepatology.

[89] Fix AD, Martin OS, Gallicchio L, Vial PA, Lagos R. Age-specific

prevalence of antibodies to hepatitis A in Santiago, Chile: Risk factors and shift in age of infection among children and young adults. The American Journal

1998;**17**:16-18

2014;**4**:7-13

1999;**36**:1248-1250

2017;**22**(8):30468

2003;**18**(7):822-827

**18**

[97] Integrated Disease Surveillance Project. Recent Weekly Outbreak. Available from: http://www.idsp.nic.in/ index4.php?lang=1&level=0&linkid=4 06&lid=3689 [Last Accessed: 01 August 2019]

[98] Rakesh PS, Mainu TT, Raj A, Babu D, Rajiv M, Sreelakshmi K, et al. Investigating a community wide outbreak of hepatitis A in Kerala, India. Journal of Family Medicine and Primary Care. 2018;**7**:1537-1541

[99] Jain P, Prakash S, Gupta S. Prevalence of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus and hepatitis E virus as causes of acute viral hepatitis in North India: A hospital based study. Indian Journal of Medical Microbiology. 2013;**31**(3):261-265

[100] Arankalle VA, Sarada Devi KL, Lole KS, Shenoy KT, Verma V, Haneephabi M. Molecular characterization of hepatitis A virus from a large outbreak from Kerala, India. Indian Journal of Medical Research. 2006;**123**(6):760-769

[101] Rakesh PS, Sherin D, Sankar H, Shaji M, Subhagan S, Salila S. Investigating a community-wide outbreak of hepatitis A in India. Journal of Global Infectious Diseases. 2014;**6**(2):59-64

[102] Gassowski M, Michaelis K, Wenzel JJ, Faber M, Figoni J, Mouna L, et al. Two concurrent outbreaks of hepatitis A highlight the risk of infection for non-immune travellers to Morocco, January to June 2018. Euro Surveillance. 2018;**5**(27):1-5

[103] Latash J, Dorsinville M, Del Rosso P, Antwi M, Reddy V, Waechter H, et al. Notes from the eld: increase in

reported hepatitis a infections among men who have sex with men - New York City, January-August 2017. MMWR Morbidity and Mortality Weekly Report. 2017;**66**(37):999-1000. DOI: 10.15585/ mmwr.mm6637a7

[104] Urbanus AT, van Houdt R, van de Laar TJ, Coutinho RA. Viral hepatitis among men who have sex with men, epidemiology and public health consequences. Euro Surveillance. 2009;**14**(47):19-21

[105] Stene-Johansen K, Tjon G, Schreier E, Bremer V, Bruisten S, Ngui SL, et al. Molecular epidemiological studies show that hepatitis A virus is endemic among active homosexual men in Europe. Journal of Medical Virology. 2007;**79**(4):356-365

[106] Edelstein M,

Turbitt D, Balogun K, Figueroa J, Nixon G. Hepatitis A outbreak in an orthodox Jewish community in London, July 2010. Eurosurveillance. 2010;**15**(37):19662

[107] Lim HS, Choi K, Lee S. Epidemiological investigation of an outbreak of hepatitis A at a residential facility for the disabled. Journal of Preventive Medicine and Public Health. 2013;**46**(2):62-73

[108] European Centre for Disease Prevention and Control (ECDC). Rapid risk assessment: Hepatitis A outbreak in the EU/EEA mostly affecting men who have sex with men. Available from: https://ecdc.europa. eu/en/publications-data/rapid-riskassessment-hepatitis-outbreak-eueeamostly-affecting-men-who-have-sex [Accessed: 28 July 2019]

**21**

**Chapter 2**

**Abstract**

**1. Introduction**

mortality from viral hepatitis) [1].

**2. Mode of transmission**

contaminated food or water [4].

Hepatitis A: At-Risk Populations

Hepatitis A virus (HAV) is transmitted mostly through exposure to contaminated food or water, or through exposure to infected persons. This infection can occur sporadically or in an epidemic form, confers lifelong immunity and it is preventable by a safe and effective vaccine. Therefore, prevention strategies are crucial and could eradicate the infection if they were successfully employed. In this chapter, authors summarize mode of transmission and preventive measures for HAV among the following population groups: travellers, health care workers, men who have sex with men, individuals who use illicit drugs, sewage workers, food handlers, military personnel, prisoners, blood transfusions recipients, haemophiliacs and patients with HIV and chronic liver disease. Moreover, authors describe which of these groups are eligible for HAV vaccination according to available data.

**Keywords:** hepatitis A, MSM, men who have sex with men, outbreak, sexually

approximately 11 000 deaths in 2015 worldwide (accounting for 0.8% of the

widespread prevention strategies could eradicate the infection.

nel, prisoners, blood transfusions recipients and haemophiliacs [3].

Hepatitis A virus (HAV) is a common cause of acute viral hepatitis and caused

HAV infection can occur sporadically or in an epidemic form, confers lifelong immunity [2] and is preventable by a safe and effective vaccine. As a matter of fact, humans are the only known reservoir for HAV, so the successful employment of

In the literature, some risk groups for HAV infection were identified, such as travellers, healthcare workers (HCWs), men who have sex with men (MSM), individuals who use illicit drugs, sewage workers, food handlers, military person-

HAV is usually transmitted by the faecal-oral route: primarily through close personal contact or by oral intake after faecal contamination of skin or mucous membranes. Less commonly, the transmission occurs due to consumption of

Regarding person to person contact, the transmission can occur within households, residential institutions and daycare centres, among military personnel and during sexual intercourse. HAV infection due to consumption of contaminated

transmitted infections, viral infections, viral infections

*Rosa Coelho and Guilherme Macedo*

#### **Chapter 2**

## Hepatitis A: At-Risk Populations

*Rosa Coelho and Guilherme Macedo*

#### **Abstract**

Hepatitis A virus (HAV) is transmitted mostly through exposure to contaminated food or water, or through exposure to infected persons. This infection can occur sporadically or in an epidemic form, confers lifelong immunity and it is preventable by a safe and effective vaccine. Therefore, prevention strategies are crucial and could eradicate the infection if they were successfully employed. In this chapter, authors summarize mode of transmission and preventive measures for HAV among the following population groups: travellers, health care workers, men who have sex with men, individuals who use illicit drugs, sewage workers, food handlers, military personnel, prisoners, blood transfusions recipients, haemophiliacs and patients with HIV and chronic liver disease. Moreover, authors describe which of these groups are eligible for HAV vaccination according to available data.

**Keywords:** hepatitis A, MSM, men who have sex with men, outbreak, sexually transmitted infections, viral infections, viral infections

#### **1. Introduction**

Hepatitis A virus (HAV) is a common cause of acute viral hepatitis and caused approximately 11 000 deaths in 2015 worldwide (accounting for 0.8% of the mortality from viral hepatitis) [1].

HAV infection can occur sporadically or in an epidemic form, confers lifelong immunity [2] and is preventable by a safe and effective vaccine. As a matter of fact, humans are the only known reservoir for HAV, so the successful employment of widespread prevention strategies could eradicate the infection.

In the literature, some risk groups for HAV infection were identified, such as travellers, healthcare workers (HCWs), men who have sex with men (MSM), individuals who use illicit drugs, sewage workers, food handlers, military personnel, prisoners, blood transfusions recipients and haemophiliacs [3].

#### **2. Mode of transmission**

HAV is usually transmitted by the faecal-oral route: primarily through close personal contact or by oral intake after faecal contamination of skin or mucous membranes. Less commonly, the transmission occurs due to consumption of contaminated food or water [4].

Regarding person to person contact, the transmission can occur within households, residential institutions and daycare centres, among military personnel and during sexual intercourse. HAV infection due to consumption of contaminated

food or water includes ingesting raw or undercooked foods, namely, shellfish and vegetables, or consumption of meals contaminated by infected food handlers.

Other modes of HAV transmission are due to blood transfusion and use of illicit drugs. Maternal-foetal transmission has not been described.

According to endemicity of hepatitis A (HA) disease, it can occur in three distinct ways [5]. In developing countries, with poor sanitary infrastructure, there are high infection rates occurring in childhood, and HA is endemic. Therefore, in these areas outbreaks are not frequent, and children develop immunity without ever being symptomatic [5]. In contrast, in developed countries with adequate sanitation and infrastructure, infection rates are low, and outbreaks are infrequent as long as the disease is not introduced into the population from an external source [5, 6]. Countries with intermediate levels of HA present increased numbers of susceptible adults and, occasionally, large outbreaks [5, 7]. In terms of HA endemicity, it is important to point out that exportation of food that cannot be sterilised, from countries of high endemicity to areas with low rates of infection, is a potentially important source of infection [5–7].

#### **3. At-risk populations**

#### **3.1 Travellers to endemic countries**

Travel is still one of the most important risk factors for HAV infection despite the improvement of socio-economic level considering the last decades [8]. The risk is varied and depends on the endemicity of visited countries and on the adherence of hygienic practices [3, 8].

Although the risk of infection may have slightly decreased in recent years, the incidence rate for non-protected travellers is estimated to be 3 cases per 1000 travellers per month of stay in developing countries [3].

A population-based study performed showed that the highest risk was associated with travel to East Africa followed by the Middle East, India and neighbouring countries [9]. The risk increases among young children visiting friends and relatives that accounted for a large proportion of cases and should be prioritised for vaccination [8, 10].

Few prevalence studies with contrasting and inconclusive data have been published regarding anti-HAV positivity and history of travel [3].

Considering prophylaxis for travellers in several countries, many recommendations and guidelines have been issued emphasising the importance of a correct information and prophylaxis for this at-risk group. Bearing in mind that vaccinated travellers still represent a small amount, it is crucial to promote this prophylaxis measure among physicians and this at-risk population [3].

#### **3.2 Men who have sex with men**

Since the 1980s, when an important decrease in HA incidence due to socioeconomic improvements was evident, a peak in the incidence of HAV was noticed in males from 20 to 39 years old. These cases were attributed to sexually transmitted HAV and justified some outbreaks among MSM that have been described in Denmark, Sweden, the United Kingdom and the United States [3, 11, 12]. The predominant circulating HAV strains among MSM belonged to genotype IA [13].

Among MSM population, some risk factors for HAV infection were identified, such as oro-anal sexual practices and digital-rectal intercourse, history of sexual contacts with anonymous sex partners, group sex and sexual promiscuity [3].

**23**

*Hepatitis A: At-Risk Populations*

who use illicit drugs) [3].

**3.3 Persons who use illicit drugs**

Kingdom, Norway and Italy [13].

ing those among food handlers [19].

**3.4 Food handlers**

*DOI: http://dx.doi.org/10.5772/intechopen.89172*

As a matter of fact, in this at-risk group, the widespread availability and use of mobile-accessible, especially geosocial networking apps for MSM facilitate anonymous sexual activities being potential drivers of recent outbreaks of HAV [13–16]. On the other hand, dating apps and websites can be an important and effective tool to promote HAV infection prevention campaigns in outbreaks, with the advantage

Although MSM with sexual behaviour risks are responsible for HAV infection outbreaks, several prevalence studies do not demonstrate significant differences in anti-HAV positivity between MSM and control groups (general population/persons

Since the mid-1990s, HAV vaccine has been licenced and recommended for MSM. However, the emergence of HAV infection has continued to constitute a

Since the 1970s, as the numbers of injecting drug users (IDUs) increased, several outbreaks of acute HAV infection among IDUs' communities have been reported in

HAV acute infection in this at-risk group is strongly associated with the changing prevalence of this viral infection in the general population, usually in whom

Most of the outbreaks were described in Europe and the United States in the 1980s and 1990s but were seldom described after the early 2000s [13]. Some preva-

Transmission can occur via faecal-oral contact through poor personal hygiene and living conditions or percutaneously through contamination of illicit drugs or

In the literature the most important risk factors identified for HAV infection in this group are scarce personal hygiene, socio-economic factors, sexual promiscuity, syringe exchange and contamination of instruments used to prepare drug consumption [3]. Prevention of HAV is important, and vaccination programmes should be implemented as occurred already in some European countries, such as the United

In the HAV transmission chain, food handlers can be involved in two different ways: they can become infected via contaminated food (principally shellfish and raw seafood), and, once infected, they may be the source of outbreaks [3].

Despite numerous HAV epidemics having been described [3], since the introduction of the HAV vaccine, the incidence of HAV infection has decreased, includ-

However, due to their occupation, food handlers are not considered an at-risk group for HAV infection, as it can be easily avoidable if the most common hygienic precautions are taken. Some studies described a very slight increase in prevalence in food handlers under the age of 30 years versus the general population of the same age. Also higher anti-HAV antibody seroprevalence was detected in the personnel employed in the kitchen than in medical personnel, but socio-economic factors are not taken into account [3]. Nonetheless, this group may belong to demographic groups, such as young people and people with lower socio-economic status, who

have a higher incidence of HAV than the general population [20].

of a range of hard-to-reach MSM seeking anonymous sex [17].

health threat to MSM in several developed countries [13].

several developed countries of low endemicity for HAV infection [13].

lence studies described an increased antibody prevalence among IDUs [3].

natural immunity was reduced in countries with low incidence.

injecting equipment by faecal materials or blood [13, 18].

#### *Hepatitis A: At-Risk Populations DOI: http://dx.doi.org/10.5772/intechopen.89172*

*Hepatitis A and Other Associated Hepatobiliary Diseases*

**3. At-risk populations**

of hygienic practices [3, 8].

**3.2 Men who have sex with men**

tion [8, 10].

**3.1 Travellers to endemic countries**

lers per month of stay in developing countries [3].

drugs. Maternal-foetal transmission has not been described.

food or water includes ingesting raw or undercooked foods, namely, shellfish and vegetables, or consumption of meals contaminated by infected food handlers.

Other modes of HAV transmission are due to blood transfusion and use of illicit

According to endemicity of hepatitis A (HA) disease, it can occur in three distinct ways [5]. In developing countries, with poor sanitary infrastructure, there are high infection rates occurring in childhood, and HA is endemic. Therefore, in these areas outbreaks are not frequent, and children develop immunity without ever being symptomatic [5]. In contrast, in developed countries with adequate sanitation and infrastructure, infection rates are low, and outbreaks are infrequent as long as the disease is not introduced into the population from an external source [5, 6]. Countries with intermediate levels of HA present increased numbers of susceptible adults and, occasionally, large outbreaks [5, 7]. In terms of HA endemicity, it is important to point out that exportation of food that cannot be sterilised, from countries of high endemicity to areas with low rates of infection, is a potentially important source of infection [5–7].

Travel is still one of the most important risk factors for HAV infection despite the improvement of socio-economic level considering the last decades [8]. The risk is varied and depends on the endemicity of visited countries and on the adherence

Although the risk of infection may have slightly decreased in recent years, the incidence rate for non-protected travellers is estimated to be 3 cases per 1000 travel-

A population-based study performed showed that the highest risk was associated with travel to East Africa followed by the Middle East, India and neighbouring countries [9]. The risk increases among young children visiting friends and relatives that accounted for a large proportion of cases and should be prioritised for vaccina-

Few prevalence studies with contrasting and inconclusive data have been

Considering prophylaxis for travellers in several countries, many recommendations and guidelines have been issued emphasising the importance of a correct information and prophylaxis for this at-risk group. Bearing in mind that vaccinated travellers still represent a small amount, it is crucial to promote this prophylaxis

Since the 1980s, when an important decrease in HA incidence due to socioeconomic improvements was evident, a peak in the incidence of HAV was noticed in males from 20 to 39 years old. These cases were attributed to sexually transmitted HAV and justified some outbreaks among MSM that have been described in Denmark, Sweden, the United Kingdom and the United States [3, 11, 12]. The predominant circulating HAV strains among MSM belonged to genotype IA [13]. Among MSM population, some risk factors for HAV infection were identified, such as oro-anal sexual practices and digital-rectal intercourse, history of sexual contacts with anonymous sex partners, group sex and sexual promiscuity [3].

published regarding anti-HAV positivity and history of travel [3].

measure among physicians and this at-risk population [3].

**22**

As a matter of fact, in this at-risk group, the widespread availability and use of mobile-accessible, especially geosocial networking apps for MSM facilitate anonymous sexual activities being potential drivers of recent outbreaks of HAV [13–16]. On the other hand, dating apps and websites can be an important and effective tool to promote HAV infection prevention campaigns in outbreaks, with the advantage of a range of hard-to-reach MSM seeking anonymous sex [17].

Although MSM with sexual behaviour risks are responsible for HAV infection outbreaks, several prevalence studies do not demonstrate significant differences in anti-HAV positivity between MSM and control groups (general population/persons who use illicit drugs) [3].

Since the mid-1990s, HAV vaccine has been licenced and recommended for MSM. However, the emergence of HAV infection has continued to constitute a health threat to MSM in several developed countries [13].

#### **3.3 Persons who use illicit drugs**

Since the 1970s, as the numbers of injecting drug users (IDUs) increased, several outbreaks of acute HAV infection among IDUs' communities have been reported in several developed countries of low endemicity for HAV infection [13].

HAV acute infection in this at-risk group is strongly associated with the changing prevalence of this viral infection in the general population, usually in whom natural immunity was reduced in countries with low incidence.

Most of the outbreaks were described in Europe and the United States in the 1980s and 1990s but were seldom described after the early 2000s [13]. Some prevalence studies described an increased antibody prevalence among IDUs [3].

Transmission can occur via faecal-oral contact through poor personal hygiene and living conditions or percutaneously through contamination of illicit drugs or injecting equipment by faecal materials or blood [13, 18].

In the literature the most important risk factors identified for HAV infection in this group are scarce personal hygiene, socio-economic factors, sexual promiscuity, syringe exchange and contamination of instruments used to prepare drug consumption [3].

Prevention of HAV is important, and vaccination programmes should be implemented as occurred already in some European countries, such as the United Kingdom, Norway and Italy [13].

#### **3.4 Food handlers**

In the HAV transmission chain, food handlers can be involved in two different ways: they can become infected via contaminated food (principally shellfish and raw seafood), and, once infected, they may be the source of outbreaks [3].

Despite numerous HAV epidemics having been described [3], since the introduction of the HAV vaccine, the incidence of HAV infection has decreased, including those among food handlers [19].

However, due to their occupation, food handlers are not considered an at-risk group for HAV infection, as it can be easily avoidable if the most common hygienic precautions are taken. Some studies described a very slight increase in prevalence in food handlers under the age of 30 years versus the general population of the same age. Also higher anti-HAV antibody seroprevalence was detected in the personnel employed in the kitchen than in medical personnel, but socio-economic factors are not taken into account [3]. Nonetheless, this group may belong to demographic groups, such as young people and people with lower socio-economic status, who have a higher incidence of HAV than the general population [20].

Mandatory food handler vaccination is unlikely to be cost-effective. However, based on local needs, health departments of each country should make decisions about requiring vaccination for this group [21].

#### **3.5 Healthcare workers**

Data regarding the mode of HAV transmission show that personal contact with an infected person is the most common risk factor for developing the infection. Thus, healthcare workers are at potential risk of exposure to contagious patients infected with HA, particularly in paediatric wards [22–24].

The analysis of several studies regarding outbreaks in hospital settings indicates the main risk factors are eating and drinking in hospital divisions and inadequate hand cleaning [3].

The seroprevalence studies did not show consistent findings, and there were wide variations in the proportion of seropositive HCWs, taking into account different countries and professional groups [24].

As a matter of fact, studies comparing anti-HAV antibody seroprevalence between paediatric divisions' nurses and nurses of other hospital departments did not show any difference [3].

It is interesting to point out that one study comparing the hospital laundry workers with nurses suggested that the former group was more exposed to HA occupational risk, probably due to contact with handling dirty linen prior to washing them [25].

However, considering that universal precautions should be implemented in healthcare centres, some authors might argue that HCWs do not constitute an atrisk group for HAV [3, 24].

Nonetheless, considering that HA vaccines provide a safe, immunogenic and efficacious prevention tool, some authors recommend vaccination considering that HCWs are exposed to a higher risk infection than the general population [24].

It is crucial to implement general precautionary measures at the workplace that could reduce the transmission of HAV. Moreover, it is crucial that hospitals have an effective infection control of HA outbreaks which means early recognition, including awareness of atypical presentations of HAV infection, and strict adherence to universal infection control measures [24].

#### **3.6 Sewage workers**

Wastewater plant workers may be exposed to various infectious agents. However, at the moment it is unclear whether sewage workers have an increased risk of contracting HA or not, especially if the disease is preventable by using a vaccine [26].

Actually, sewage workers can be exposed to aerosols and direct contact with potentially contaminated materials such as raw wastewater, which means that a plausible biological risk to acquire HA in this group of employees exists [3, 26]. However, studies regarding anti-HAV antibody seroprevalence and risk of acquiring the disease are conflicting [26]. A recent systematic review [27] concluded that the incidence of clinical HA does not show an increased risk in sewage workers. Nonetheless, it found a moderately increased risk of subclinical HA infection when seroprevalence studies are considered. Results of seroprevalence studies may be flawed by several methodological factors.

Considering these discrepant results, there is no consensus on the need to vaccinate sewage workers. On the one hand, some authors recommend a systematic vaccination because of the increased risk. On the other hand, some authors do not

**25**

HA [31].

*Hepatitis A: At-Risk Populations*

North America [27].

**3.7 Military personnel**

ing the military strategies [3].

of universal HAV vaccination.

promiscuity, drug abuse and poor sanitation.

for HA [3].

**3.8 Prisoners**

practices [31].

*DOI: http://dx.doi.org/10.5772/intechopen.89172*

specific epidemiological situation [27].

consider vaccination necessary, and some authors consider that vaccination programmes can be discussed for those workers heavily exposed to sewage [27].

Some specialists in occupational health just recommend immunisation in order to "maintain labour peace", to prevent litigation costs, or only after evaluating the

However, these conclusions may not be generalisable to populations with different natural immunity as they are based mostly on investigations from Europe and

Control of HA has been an important concern for US military forces in war and peace mostly in the past. However, nowadays due to the improvement of the sanitation level with better hygienic sanitary conditions, the risk of HA in this group is mainly attributed to activities in high endemic areas. As a matter of fact, this group usually works in difficult areas characterised by poor hygienic conditions and scarce control on food sources and drinking water supplies. Moreover, in remote areas, soldiers can be exposed to parenterally transmitted infections in case of injuries, hospitalisations and transfusions [3, 28]. In fact, most studies reporting HA epidemics among military personnel were published before 1990 showing numerous HA outbreaks that devastated whole army forces during the world wars, condition-

Almost all the studies published later analysed the vaccine effectiveness and suggest different vaccination programmes considering soldiers as an at-risk group

However, in several papers military personnel is considered just as a sample of the general population, and as it has been recently occurring in other groups, a decrease in seroprevalence is evident. Moreover, only a few studies analyse the correlation between HA infection with epidemiologic factors such as overcrowding and

A recent and large multicentric cross-sectional study (11 training centres) conducted within the Indian Armed Forces during 1 year (2010–2011) showed a high seroprevalence of HAV (93%) among healthy young adults [29]. In contrast, HA was found to be a cause of acute viral hepatitis in 30% of 102 cases seen in an Armed Forces hospital from southern India [30]. So, even in the same countries, data are not consistent, and therefore, it can be difficult to justify the economic cost

Prison is considered to be an environment where many risk factors for HA can be easily identified, such as overcrowding, frequent prison relocation, sexual

As a matter of fact, prison facilities in which inmates live in close proximity and engage in high-risk behaviours for HAV transmissions may diminish the effectiveness of strategies of infection control based on universal adoption of hygienic

Data regarding HAV prevalence among prisoners are few, conflicting and not conclusive [3]. Epidemiological investigations concluded that HA among prisoners have been introduced mainly by newly arrived prison entrants who were incarcerated during their incubation period who subsequently developed acute

consumption of contaminated food and water in military activities [3].

#### *Hepatitis A: At-Risk Populations DOI: http://dx.doi.org/10.5772/intechopen.89172*

consider vaccination necessary, and some authors consider that vaccination programmes can be discussed for those workers heavily exposed to sewage [27].

Some specialists in occupational health just recommend immunisation in order to "maintain labour peace", to prevent litigation costs, or only after evaluating the specific epidemiological situation [27].

However, these conclusions may not be generalisable to populations with different natural immunity as they are based mostly on investigations from Europe and North America [27].

#### **3.7 Military personnel**

*Hepatitis A and Other Associated Hepatobiliary Diseases*

about requiring vaccination for this group [21].

ent countries and professional groups [24].

universal infection control measures [24].

flawed by several methodological factors.

infected with HA, particularly in paediatric wards [22–24].

**3.5 Healthcare workers**

hand cleaning [3].

not show any difference [3].

risk group for HAV [3, 24].

**3.6 Sewage workers**

vaccine [26].

Mandatory food handler vaccination is unlikely to be cost-effective. However, based on local needs, health departments of each country should make decisions

Data regarding the mode of HAV transmission show that personal contact with an infected person is the most common risk factor for developing the infection. Thus, healthcare workers are at potential risk of exposure to contagious patients

The analysis of several studies regarding outbreaks in hospital settings indicates the main risk factors are eating and drinking in hospital divisions and inadequate

The seroprevalence studies did not show consistent findings, and there were wide variations in the proportion of seropositive HCWs, taking into account differ-

As a matter of fact, studies comparing anti-HAV antibody seroprevalence between paediatric divisions' nurses and nurses of other hospital departments did

It is interesting to point out that one study comparing the hospital laundry workers with nurses suggested that the former group was more exposed to HA occupational risk, probably due to contact with handling dirty linen prior to washing them [25]. However, considering that universal precautions should be implemented in healthcare centres, some authors might argue that HCWs do not constitute an at-

Nonetheless, considering that HA vaccines provide a safe, immunogenic and efficacious prevention tool, some authors recommend vaccination considering that HCWs are exposed to a higher risk infection than the general population [24].

It is crucial to implement general precautionary measures at the workplace that could reduce the transmission of HAV. Moreover, it is crucial that hospitals have an effective infection control of HA outbreaks which means early recognition, including awareness of atypical presentations of HAV infection, and strict adherence to

Wastewater plant workers may be exposed to various infectious agents. However, at the moment it is unclear whether sewage workers have an increased risk of contracting HA or not, especially if the disease is preventable by using a

Actually, sewage workers can be exposed to aerosols and direct contact with potentially contaminated materials such as raw wastewater, which means that a plausible biological risk to acquire HA in this group of employees exists [3, 26]. However, studies regarding anti-HAV antibody seroprevalence and risk of acquiring the disease are conflicting [26]. A recent systematic review [27] concluded that the incidence of clinical HA does not show an increased risk in sewage workers. Nonetheless, it found a moderately increased risk of subclinical HA infection when seroprevalence studies are considered. Results of seroprevalence studies may be

Considering these discrepant results, there is no consensus on the need to vaccinate sewage workers. On the one hand, some authors recommend a systematic vaccination because of the increased risk. On the other hand, some authors do not

**24**

Control of HA has been an important concern for US military forces in war and peace mostly in the past. However, nowadays due to the improvement of the sanitation level with better hygienic sanitary conditions, the risk of HA in this group is mainly attributed to activities in high endemic areas. As a matter of fact, this group usually works in difficult areas characterised by poor hygienic conditions and scarce control on food sources and drinking water supplies. Moreover, in remote areas, soldiers can be exposed to parenterally transmitted infections in case of injuries, hospitalisations and transfusions [3, 28]. In fact, most studies reporting HA epidemics among military personnel were published before 1990 showing numerous HA outbreaks that devastated whole army forces during the world wars, conditioning the military strategies [3].

Almost all the studies published later analysed the vaccine effectiveness and suggest different vaccination programmes considering soldiers as an at-risk group for HA [3].

However, in several papers military personnel is considered just as a sample of the general population, and as it has been recently occurring in other groups, a decrease in seroprevalence is evident. Moreover, only a few studies analyse the correlation between HA infection with epidemiologic factors such as overcrowding and consumption of contaminated food and water in military activities [3].

A recent and large multicentric cross-sectional study (11 training centres) conducted within the Indian Armed Forces during 1 year (2010–2011) showed a high seroprevalence of HAV (93%) among healthy young adults [29]. In contrast, HA was found to be a cause of acute viral hepatitis in 30% of 102 cases seen in an Armed Forces hospital from southern India [30]. So, even in the same countries, data are not consistent, and therefore, it can be difficult to justify the economic cost of universal HAV vaccination.

#### **3.8 Prisoners**

Prison is considered to be an environment where many risk factors for HA can be easily identified, such as overcrowding, frequent prison relocation, sexual promiscuity, drug abuse and poor sanitation.

As a matter of fact, prison facilities in which inmates live in close proximity and engage in high-risk behaviours for HAV transmissions may diminish the effectiveness of strategies of infection control based on universal adoption of hygienic practices [31].

Data regarding HAV prevalence among prisoners are few, conflicting and not conclusive [3]. Epidemiological investigations concluded that HA among prisoners have been introduced mainly by newly arrived prison entrants who were incarcerated during their incubation period who subsequently developed acute HA [31].

A recent cross-sectional survey undertaken after a multicentre outbreak of HAV infection in the Queensland prison system, following a community-based HAV epidemic among users of illicit drugs, identifies the determinants for recent and past HAV infection [31]. The authors concluded that the common factor among recently acquired and past infection of HA was due to the use of illicit drugs. In contrast, there was no evidence that IDUs were associated to higher rates of HAV-IgG seropositivity (past infection) [31].

In prison settings, routine vaccination of all susceptible inmates with inactivated HA vaccine may be considered as an important strategy in order to prevent transmission of HAV infection especially during periods of higher incidence among the incoming prisoner population [31].

#### **3.9 Blood transfusion recipients**

HAV infection is not a significant complication of blood transfusion due to the short-lasting viremic period [3]. As a matter of fact, considering the sporadic nature of the HAV acute infection among blood donors and the lack of HAV chronic carriers, antibody screening tests for HAV for serological screening of blood donors are not recommended in any country [32]. However, even if it is rare, HAV parenteral transmission is possible, and many countries recommend vaccination for polytransfused patients [33, 34].

In the past, some epidemic cases of HA were reportedly caused by children who received infected blood or plasma. However, none of the prospective studies, conducted in the 1970s and 1980s to establish incidence and agents of posttransfusion hepatitis, identified cases of HAV infection [3]. In fact, no data showing higher prevalence of HAV in subjects receiving blood transfusion are available, which means that there is no evidence to consider polytransfused patients as a risk group.

Nonetheless, recently two cases of HAV transmission to blood recipients from a healthy donor that later presented to the blood bank with jaundice were published [32]. Actually, one of the cases was fatal and the patient died from fulminant HA. It is important to highlight that the patient was immunocompromised due to bone marrow transplantation and had also hepatitis C [32]. This case report points out the importance of timely identification of post-donation symptoms and notification to blood banks and also that specific groups of immunocompromised patients may benefit from a HAV vaccination programme [32].

#### **3.10 Haemophiliacs**

Some outbreaks of HAV infection among haemophilia patients have been reported due to transfusions of factors VIII/IX concentrates treated with the solvent/detergent method used to inactivate blood-borne viruses [3]. In fact, in these studies a causal relationship was found between the injection of blood clotting factors and an outbreak of HA among haemophilia patients.

Clotting factor concentrates manufactured from large pool may be contaminated by HAV, which can be present even in a single highly viremic blood donor.

The solvent/detergent method used to inactivate HAV virus seemed to be not effective to ensure the safety of clotting factor concentrates [35]. Therefore, Guilaume TA et al. proposed a new method using a terminal 100°C dry-heat sterilisation in order to destroy also non-lipid-enveloped viruses [36].

However, case–control papers and studies regarding seroprevalence of HAV in this group did not show an increased risk of contracting HA among haemophiliacs [3], and therefore at present haemophiliacs are not included as an at-risk group to acquire HAV.

**27**

*Hepatitis A: At-Risk Populations*

**3.11 Other populations**

damage [41–43].

liver disease.

to others [44].

sexual behaviours [13].

*DOI: http://dx.doi.org/10.5772/intechopen.89172*

high risk of liver failure but also of death [37, 38].

chronic liver failure in cases of HAV infection [38, 39].

HA results in acute liver failure in less than 1%, age superior to 50 years old and those with underlying liver disease being important risk factors, especially with chronic hepatitis B and C virus infections [37, 38]. As a matter of fact, HAV superinfection in patients with underlying chronic liver disease is not also associated with a

Besides, patients with pre-existing liver disease (i.e. non-alcoholic fatty liver disease or alcoholic steatohepatitis) present a higher risk of developing an acute-on-

Therefore, it has been recommended to vaccinate against HAV in patients with chronic liver disease [40]. Nonetheless, studies show HAV testing and vaccination rates were low in clinical practice. Public health programmes are needed in order to increase awareness about HAV vaccination in patients with pre-existing liver

HAV infections among older individuals continue to pose public health and clinical challenges because HA illness severity increases with age, presence of liver disease and other comorbid medical conditions [42]. In fact, the increased number of HAV infection in hospitalised patients with hypertension, ischemic heart disease, disorders of lipid metabolism and chronic kidney disease may also reflect increasing age. Older age (over 65 years old) and any liver disease are independent risk factors to being hospitalised more than 5 days, suggesting that these factors increase the severity of HA illness [42]. Therefore, more studies are needed to guide recommendations for HA vaccination in adults with other chronic diseases other than chronic

Considering HIV-positive individuals, only very few studies with a limit number of patients address the risk of HA in these populations [3]. Even though the direct evidence on the correlation between contracting HIV and HAV was scarce, observational data suggested that HIV-positive individuals, especially MSM and IDUs, are at increased risk of acquiring HAV [3]. Moreover, Ida et al. published a study of 15 HIV-positive individuals that showed that the duration of HAV viremia in HIV-seropositive individuals with acute HA was prolonged compared to that in HIV-negative individuals, which may increase the probability of HAV transmission

Considering HIV-seropositive patients, two independent risk factors associated

Regarding prophylaxis in HIV-positive patients, HAV vaccination is not universally recommended but specifically for those with increased risks of exposure (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant

with seropositivity for HAV were recognised: older age and injecting drug use. However, HAV seroprevalence was lower in HIV-positive MSM despite the at-risk

disease (such as those with chronic hepatitis) [45, 46].

#### **3.11 Other populations**

*Hepatitis A and Other Associated Hepatobiliary Diseases*

seropositivity (past infection) [31].

incoming prisoner population [31].

**3.9 Blood transfusion recipients**

polytransfused patients [33, 34].

patients as a risk group.

**3.10 Haemophiliacs**

A recent cross-sectional survey undertaken after a multicentre outbreak of HAV

In prison settings, routine vaccination of all susceptible inmates with inactivated HA vaccine may be considered as an important strategy in order to prevent transmission of HAV infection especially during periods of higher incidence among the

HAV infection is not a significant complication of blood transfusion due to the short-lasting viremic period [3]. As a matter of fact, considering the sporadic nature of the HAV acute infection among blood donors and the lack of HAV chronic carriers, antibody screening tests for HAV for serological screening of blood donors are not recommended in any country [32]. However, even if it is rare, HAV parenteral transmission is possible, and many countries recommend vaccination for

In the past, some epidemic cases of HA were reportedly caused by children

Nonetheless, recently two cases of HAV transmission to blood recipients from a healthy donor that later presented to the blood bank with jaundice were published [32]. Actually, one of the cases was fatal and the patient died from fulminant HA. It is important to highlight that the patient was immunocompromised due to bone marrow transplantation and had also hepatitis C [32]. This case report points out the importance of timely identification of post-donation symptoms and notification to blood banks and also that specific groups of immunocompromised patients

Some outbreaks of HAV infection among haemophilia patients have been reported due to transfusions of factors VIII/IX concentrates treated with the solvent/detergent method used to inactivate blood-borne viruses [3]. In fact, in these studies a causal relationship was found between the injection of blood clotting

Clotting factor concentrates manufactured from large pool may be contaminated by HAV, which can be present even in a single highly viremic blood donor. The solvent/detergent method used to inactivate HAV virus seemed to be not effective to ensure the safety of clotting factor concentrates [35]. Therefore, Guilaume TA et al. proposed a new method using a terminal 100°C dry-heat sterili-

However, case–control papers and studies regarding seroprevalence of HAV in this group did not show an increased risk of contracting HA among haemophiliacs [3], and therefore at present haemophiliacs are not included as an at-risk group to acquire HAV.

who received infected blood or plasma. However, none of the prospective studies, conducted in the 1970s and 1980s to establish incidence and agents of posttransfusion hepatitis, identified cases of HAV infection [3]. In fact, no data showing higher prevalence of HAV in subjects receiving blood transfusion are available, which means that there is no evidence to consider polytransfused

may benefit from a HAV vaccination programme [32].

factors and an outbreak of HA among haemophilia patients.

sation in order to destroy also non-lipid-enveloped viruses [36].

infection in the Queensland prison system, following a community-based HAV epidemic among users of illicit drugs, identifies the determinants for recent and past HAV infection [31]. The authors concluded that the common factor among recently acquired and past infection of HA was due to the use of illicit drugs. In contrast, there was no evidence that IDUs were associated to higher rates of HAV-IgG

**26**

HA results in acute liver failure in less than 1%, age superior to 50 years old and those with underlying liver disease being important risk factors, especially with chronic hepatitis B and C virus infections [37, 38]. As a matter of fact, HAV superinfection in patients with underlying chronic liver disease is not also associated with a high risk of liver failure but also of death [37, 38].

Besides, patients with pre-existing liver disease (i.e. non-alcoholic fatty liver disease or alcoholic steatohepatitis) present a higher risk of developing an acute-onchronic liver failure in cases of HAV infection [38, 39].

Therefore, it has been recommended to vaccinate against HAV in patients with chronic liver disease [40]. Nonetheless, studies show HAV testing and vaccination rates were low in clinical practice. Public health programmes are needed in order to increase awareness about HAV vaccination in patients with pre-existing liver damage [41–43].

HAV infections among older individuals continue to pose public health and clinical challenges because HA illness severity increases with age, presence of liver disease and other comorbid medical conditions [42]. In fact, the increased number of HAV infection in hospitalised patients with hypertension, ischemic heart disease, disorders of lipid metabolism and chronic kidney disease may also reflect increasing age. Older age (over 65 years old) and any liver disease are independent risk factors to being hospitalised more than 5 days, suggesting that these factors increase the severity of HA illness [42]. Therefore, more studies are needed to guide recommendations for HA vaccination in adults with other chronic diseases other than chronic liver disease.

Considering HIV-positive individuals, only very few studies with a limit number of patients address the risk of HA in these populations [3]. Even though the direct evidence on the correlation between contracting HIV and HAV was scarce, observational data suggested that HIV-positive individuals, especially MSM and IDUs, are at increased risk of acquiring HAV [3]. Moreover, Ida et al. published a study of 15 HIV-positive individuals that showed that the duration of HAV viremia in HIV-seropositive individuals with acute HA was prolonged compared to that in HIV-negative individuals, which may increase the probability of HAV transmission to others [44].

Considering HIV-seropositive patients, two independent risk factors associated with seropositivity for HAV were recognised: older age and injecting drug use. However, HAV seroprevalence was lower in HIV-positive MSM despite the at-risk sexual behaviours [13].

Regarding prophylaxis in HIV-positive patients, HAV vaccination is not universally recommended but specifically for those with increased risks of exposure (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis) [45, 46].

*Hepatitis A and Other Associated Hepatobiliary Diseases*

#### **Author details**

Rosa Coelho and Guilherme Macedo\* Gastroenterology Department, Centro Hospitalar São João, Porto, Portugal

\*Address all correspondence to: guilhermemacedo59@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**29**

*Hepatitis A: At-Risk Populations*

**References**

2001;**14**(1):38-58

2009;**58**(3):1

6192-6198

*DOI: http://dx.doi.org/10.5772/intechopen.89172*

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[11] Mazick A, Howitz M, Rex S, et al. Hepatitis A outbreak among MSM linked to casual sex and gay saunas in Copenhagen, Denmark. Euro Surveillance. 2005;**10**(5):5-6

[12] Sfetcu O, Irvine N, Ngui SL, Emerson C, McCaughey C, Donaghy P. Hepatitis A outbreak predominantly affecting men who have sex with men in Northern Ireland, October 2008 to July 2009. Euro Surveillance. 2011;**16**(9):16

[13] Lin KY, Chen GJ, Lee YL, et al. Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive

[14] Thomas DR, Williams CJ, Andrady U, et al. Outbreak of syphilis in men who have sex with men living in rural North Wales (UK) associated with the use of social media. Sexually Transmitted Infections. 2016;**92**(5):359-364

[15] Beebeejaun K, Degala S, Balogun K, et al. Outbreak of hepatitis A associated with men who have sex with men (MSM), England, July 2016 to January

Jenkins C, et al. Sex, drugs and smart phone applications: Findings from semistructured interviews with men who have sex with men diagnosed with Shigella flexneri 3a in England and Wales. Sexually Transmitted Infections.

2017. Euro Surveillance. 2 Feb 2017;**22**(5). DOI: 10.2807/1560-7917.

ES.2017.22.5.30454

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[4] Daniels D, Grytdal S, Wasley A, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis—United States, 2007. MMWR Surveillance Summaries.

[5] Shapiro CN, Margolis HS. Worldwide epidemiology of hepatitis A virus infection. Journal of Hepatology.

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[6] Klevens RM, Denniston MM, Jiles-Chapman RB, Murphy TV.

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[8] Beauté J, Westrell T, Schmid D, et al. Travel-associated hepatitis A in Europe, 2009 to 2015. Euro Surveillance.

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2018;**23**(22):1700583

2009;**16**(4):233-238

### **References**

*Hepatitis A and Other Associated Hepatobiliary Diseases*

**28**

**Author details**

Rosa Coelho and Guilherme Macedo\*

provided the original work is properly cited.

Gastroenterology Department, Centro Hospitalar São João, Porto, Portugal

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: guilhermemacedo59@gmail.com

[1] Hepatitis A fact sheet. In: World Health Organization: Media centre. [website] http://www.who.int/ mediacentre/factsheets/fs328/en/

[2] Cuthbert JA. Hepatitis A: Old and new. Clinical Microbiology Reviews. 2001;**14**(1):38-58

[3] Franco E, Giambi C, Ialacci R, Coppola RC, Zanetti AR. Risk groups for hepatitis A virus infection. Vaccine. 2003;**21**(19-20):2224-2233

[4] Daniels D, Grytdal S, Wasley A, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis—United States, 2007. MMWR Surveillance Summaries. 2009;**58**(3):1

[5] Shapiro CN, Margolis HS. Worldwide epidemiology of hepatitis A virus infection. Journal of Hepatology. 1993;**18**(Suppl 2):S11-S14

[6] Klevens RM, Denniston MM, Jiles-Chapman RB, Murphy TV. Decreasing immunity to hepatitis A virus infection among US adults: Findings from the National Health and nutrition examination survey (NHANES), 1999-2012. Vaccine. 2015;**33**(46): 6192-6198

[7] Hofmeister MG, Foster MA, Teshale EH. Epidemiology and transmission of hepatitis A virus and hepatitis E virus infections in the United States. Cold Spring Harbor Perspectives in Medicine. 2019;**9**(4):pii: a033431

[8] Beauté J, Westrell T, Schmid D, et al. Travel-associated hepatitis A in Europe, 2009 to 2015. Euro Surveillance. 2018;**23**(22):1700583

[9] Askling HH, Rombo L, Andersson Y, Martin S, Ekdahl K. Hepatitis A risk in travelers. Journal of Travel Medicine. 2009;**16**(4):233-238

[10] Sane J, de Sousa R, van Pelt W, Petrignani M, Verhoef L, Koopmans M. Risk of hepatitis A decreased among Dutch travelers to endemic regions in 2003 to 2011. Journal of Travel Medicine. 2015;**22**(3):208-211

[11] Mazick A, Howitz M, Rex S, et al. Hepatitis A outbreak among MSM linked to casual sex and gay saunas in Copenhagen, Denmark. Euro Surveillance. 2005;**10**(5):5-6

[12] Sfetcu O, Irvine N, Ngui SL, Emerson C, McCaughey C, Donaghy P. Hepatitis A outbreak predominantly affecting men who have sex with men in Northern Ireland, October 2008 to July 2009. Euro Surveillance. 2011;**16**(9):16

[13] Lin KY, Chen GJ, Lee YL, et al. Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review. World Journal of Gastroenterology. 2017;**23**(20):3589-3606

[14] Thomas DR, Williams CJ, Andrady U, et al. Outbreak of syphilis in men who have sex with men living in rural North Wales (UK) associated with the use of social media. Sexually Transmitted Infections. 2016;**92**(5):359-364

[15] Beebeejaun K, Degala S, Balogun K, et al. Outbreak of hepatitis A associated with men who have sex with men (MSM), England, July 2016 to January 2017. Euro Surveillance. 2 Feb 2017;**22**(5). DOI: 10.2807/1560-7917. ES.2017.22.5.30454

[16] Gilbart VL, Simms I, Jenkins C, et al. Sex, drugs and smart phone applications: Findings from semistructured interviews with men who have sex with men diagnosed with Shigella flexneri 3a in England and Wales. Sexually Transmitted Infections. 2015;**91**(8):598-602

[17] Ruscher C, Werber D, Thoulass J, et al. Dating apps and websites as tools to reach anonymous sexual contacts during an outbreak of hepatitis A among men who have sex with men, Berlin, 2017. Euro Surveillance. 2019;**24**(21):1800460

[18] Spada E, Genovese D, Tosti ME, et al. An outbreak of hepatitis A virus infection with a high case-fatality rate among injecting drug users. Journal of Hepatology. 2005;**43**(6):958-964

[19] Sharapov UM, Kentenyants K, Groeger J, Roberts H, Holmberg SD, Collier MG. Hepatitis A infections among food handlers in the United States, 1993-2011. Public Health Reports. 2016;**131**(1):26-29

[20] Fiore AE. Hepatitis A transmitted by food. Clinical Infectious Diseases. 2004;**38**(5):705-715. Epub 2004 Feb 11

[21] Meltzer MI, Shapiro CN, Mast EE, Arcari C. The economics of vaccinating restaurant workers against hepatitis A. Vaccine. 2001;**19**:2138-2145

[22] Shapiro CN, Coleman PJ, McQuillan GM, et al. Epidemiology of hepatitis A: Seroepidemiology and risk groups in the USA. Vaccine. 1992;**10**(Suppl):S59-S62

[23] Smith S, Weber S, Wiblin T, et al. Cost-effectiveness of hepatitis A vaccination in healthcare workers. Infection Control and Hospital Epidemiology. 1997;**18**:688-691

[24] Chodick G, Ashkenazi S, Lerman Y. The risk of hepatitis A infection among healthcare workers: A review of reported outbreaks and seroepidemiologic studies. The Journal of Hospital Infection. 2006;**62**(4):414-420. Epub 2006 Feb 20

[25] Borg MA, Portelli A. Hospital laundry workers-an at-risk group for hepatitis A? Occupational Medicine (London). 1999;**49**(7):448-450

[26] Divizia M, Cencioni B, Palombi L, Panà A. Sewage workers: Risk of acquiring enteric virus infections including hepatitis A. The New Microbiologica. 2008;**31**(3):337-334

[27] Glas C, Hotz P, Steffen R. Hepatitis A in workers exposed to sewage: A systematic review. Occupational and Environmental Medicine. 2001;**58**(12):762-768

[28] Puri P, Sharma PK, Nagpal AK. Viral hepatitis in India: Armed forces perspective. Medical Journal, Armed Forces India. 2016;**72**(3):201-203

[29] Kotwal A, Singh H, Verma AK. A study of hepatitis A and E virus seropositivity profile amongst young healthy adults in India. Medical Journal, Armed Forces India. 2014;**70**:225-229

[30] Nandi B, Hadimani P, Srunachalam R, Ganjoo RK. Spectrum of acute viral hepatitis in southern India. Medical Journal, Armed Forces India. 2009;**65**:7-9

[31] Whiteman D, McCall B, Falconer A. Prevalence and determinants of hepatitis A virus exposure among prison entrants in Queensland, Australia: Implications for public health control. Journal of Viral Hepatitis. 1998;**5**(4):277-283

[32] Gonçalves S, Leon L, Alves G, et al. A rare case of transfusion transmission of hepatitis A virus to two patients with Haematological disease. Transfusion Medicine and Hemotherapy. 2016;**43**(2):137-141

[33] Anonymous. Workshop Consensus Conference, Roma, 1995. The Italian Journal of Gastroenterology. 1996;**28**:181-184

**31**

*Hepatitis A: At-Risk Populations*

1998;**5**:321-325

1996;**71**:126-128

*DOI: http://dx.doi.org/10.5772/intechopen.89172*

States, 2002-2011. Hepatology.

and Mortality Weekly Report.

Diseases. 2002;**34**:379-385

[45] Aberg JA, Gallant JE,

[43] CDC. Adult vaccination coverage— United States, 2010. MMWR. Morbidity

[44] Ida S, Tachikawa N, Nakajima A, Daikoku M, Yano M, Kikuchi Y, et al. Influence of human immunodeficiency virus type 1 infection on acute hepatitis A virus infection. Clinical Infectious

Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine Association of the Infectious Diseases Society of America. Clinical Infectious Diseases. 2014;**58**(1):e1-e34

[46] Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centres for Disease Control and Prevention, The National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

2015;**61**(2):481-485

2012;**61**:66-72

2018

[34] Lagarder B. Vaccination contre l'hepatite A. Archives de Pédiatrie.

[35] Lawlor E, Graham S, Davidson F, et al. Hepatitis A transmission by factor

IX concentrates. Vox Sanguinis.

[36] Guilaume TA. Outbreaks of hepatitis A and emergence of new AIDS-associated agents: The need to add terminal 100°C dry-heat sterilization to factor VIII and factor IX concentrates.

Vox Sanguinis. 1993;**65**:158

A in the era of vaccination.

111. Epub 2006 Jun 14

2016;**32**(2):80-85

[37] Wasley A, Fiore A, Bell BP. Hepatitis

Epidemiologic Reviews. 2006;**28**:101-

[38] Mank P, Verheyen J, Gerken G, Canbaya A. Liver failure due to acute viral hepatitis (A-E). Visceral Medicine.

[39] Canbay A, Chen SY, Gieseler RK, et al. Overweight patients are more susceptible for acute liver failure. Hepato-Gastroenterology. 2005-Oct;**52**(65):1516-1520

[40] Strikas RA, Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization

Practices (ACIP), ACIP Child/ Adolescent Immunization Work Group. Advisory Committee on immunization practices recommended immunization schedules for persons aged 0 through 18 years—United States. MMWR. Morbidity and Mortality Weekly Report. 2015;**64**(4):93

[41] Shim M, Khaykis I, Park J, Bini EJ. Susceptibility to hepatitis A in patients with chronic liver disease due to hepatitis C virus infection: Missed opportunities for vaccination. Hepatology. 2005;**42**(3):688-695

[42] Collier MG, Tong X, Xu F. Hepatitis

A hospitalizations in the United

#### *Hepatitis A: At-Risk Populations DOI: http://dx.doi.org/10.5772/intechopen.89172*

[34] Lagarder B. Vaccination contre l'hepatite A. Archives de Pédiatrie. 1998;**5**:321-325

*Hepatitis A and Other Associated Hepatobiliary Diseases*

hepatitis A? Occupational Medicine (London). 1999;**49**(7):448-450

Palombi L, Panà A. Sewage workers: Risk of acquiring enteric virus infections

[27] Glas C, Hotz P, Steffen R. Hepatitis A in workers exposed to sewage: A systematic review. Occupational and Environmental Medicine.

[28] Puri P, Sharma PK, Nagpal AK. Viral

[29] Kotwal A, Singh H, Verma AK. A study of hepatitis A and E virus seropositivity profile amongst young healthy adults in India. Medical Journal, Armed Forces India.

Srunachalam R, Ganjoo RK. Spectrum of acute viral hepatitis in southern India. Medical Journal, Armed Forces India.

hepatitis in India: Armed forces perspective. Medical Journal, Armed Forces India. 2016;**72**(3):201-203

including hepatitis A. The New Microbiologica. 2008;**31**(3):337-334

[26] Divizia M, Cencioni B,

2001;**58**(12):762-768

2014;**70**:225-229

2009;**65**:7-9

[30] Nandi B, Hadimani P,

[31] Whiteman D, McCall B, Falconer A. Prevalence and determinants of hepatitis A virus exposure among prison entrants in Queensland, Australia: Implications for public health control. Journal of Viral

Hepatitis. 1998;**5**(4):277-283

Medicine and Hemotherapy.

Conference, Roma, 1995. The Italian Journal of Gastroenterology.

2016;**43**(2):137-141

1996;**28**:181-184

[32] Gonçalves S, Leon L, Alves G, et al. A rare case of transfusion transmission of hepatitis A virus to two patients with Haematological disease. Transfusion

[33] Anonymous. Workshop Consensus

[17] Ruscher C, Werber D, Thoulass J, et al. Dating apps and websites as tools to reach anonymous sexual contacts during an outbreak of hepatitis A among men who have sex with men, Berlin, 2017. Euro Surveillance.

[18] Spada E, Genovese D, Tosti ME, et al. An outbreak of hepatitis A virus infection with a high case-fatality rate among injecting drug users. Journal of Hepatology. 2005;**43**(6):958-964

[19] Sharapov UM, Kentenyants K, Groeger J, Roberts H, Holmberg SD, Collier MG. Hepatitis A infections among food handlers in the United States, 1993-2011. Public Health Reports. 2016;**131**(1):26-29

[20] Fiore AE. Hepatitis A transmitted by food. Clinical Infectious Diseases. 2004;**38**(5):705-715. Epub 2004 Feb 11

[21] Meltzer MI, Shapiro CN, Mast EE, Arcari C. The economics of vaccinating restaurant workers against hepatitis A. Vaccine. 2001;**19**:2138-2145

[23] Smith S, Weber S, Wiblin T, et al. Cost-effectiveness of hepatitis A vaccination in healthcare workers. Infection Control and Hospital Epidemiology. 1997;**18**:688-691

[24] Chodick G, Ashkenazi S, Lerman Y. The risk of hepatitis A infection among

epidemiologic studies. The Journal of Hospital Infection. 2006;**62**(4):414-420.

[25] Borg MA, Portelli A. Hospital laundry workers-an at-risk group for

healthcare workers: A review of reported outbreaks and sero-

Epub 2006 Feb 20

[22] Shapiro CN, Coleman PJ, McQuillan GM, et al. Epidemiology of hepatitis A: Seroepidemiology and risk groups in the USA. Vaccine.

1992;**10**(Suppl):S59-S62

2019;**24**(21):1800460

**30**

[35] Lawlor E, Graham S, Davidson F, et al. Hepatitis A transmission by factor IX concentrates. Vox Sanguinis. 1996;**71**:126-128

[36] Guilaume TA. Outbreaks of hepatitis A and emergence of new AIDS-associated agents: The need to add terminal 100°C dry-heat sterilization to factor VIII and factor IX concentrates. Vox Sanguinis. 1993;**65**:158

[37] Wasley A, Fiore A, Bell BP. Hepatitis A in the era of vaccination. Epidemiologic Reviews. 2006;**28**:101- 111. Epub 2006 Jun 14

[38] Mank P, Verheyen J, Gerken G, Canbaya A. Liver failure due to acute viral hepatitis (A-E). Visceral Medicine. 2016;**32**(2):80-85

[39] Canbay A, Chen SY, Gieseler RK, et al. Overweight patients are more susceptible for acute liver failure. Hepato-Gastroenterology. 2005-Oct;**52**(65):1516-1520

[40] Strikas RA, Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices (ACIP), ACIP Child/ Adolescent Immunization Work Group. Advisory Committee on immunization practices recommended immunization schedules for persons aged 0 through 18 years—United States. MMWR. Morbidity and Mortality Weekly Report. 2015;**64**(4):93

[41] Shim M, Khaykis I, Park J, Bini EJ. Susceptibility to hepatitis A in patients with chronic liver disease due to hepatitis C virus infection: Missed opportunities for vaccination. Hepatology. 2005;**42**(3):688-695

[42] Collier MG, Tong X, Xu F. Hepatitis A hospitalizations in the United

States, 2002-2011. Hepatology. 2015;**61**(2):481-485

[43] CDC. Adult vaccination coverage— United States, 2010. MMWR. Morbidity and Mortality Weekly Report. 2012;**61**:66-72

[44] Ida S, Tachikawa N, Nakajima A, Daikoku M, Yano M, Kikuchi Y, et al. Influence of human immunodeficiency virus type 1 infection on acute hepatitis A virus infection. Clinical Infectious Diseases. 2002;**34**:379-385

[45] Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine Association of the Infectious Diseases Society of America. Clinical Infectious Diseases. 2014;**58**(1):e1-e34

[46] Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centres for Disease Control and Prevention, The National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2018

**33**

**1. Introduction**

**Chapter 3**

**Abstract**

understand HAV epidemiology in Tunisia.

**Keywords:** hepatitis A virus, epidemiology, Tunisia, incidence, RT-PCR,

Hepatitis A is the most common cause of acute viral hepatitis in the world. This acute necro-inflammatory process of the liver is due to a picornavirus transmitted by the fecal-oral route, which is the hepatitis A virus (HAV). The severity and the clinical outcome of hepatitis A are closely related to the age of infection, with older ages being at risk for symptomatic disease and even acute liver failure. Improvements in socioeconomic and hygienic conditions, during the two last decades, have led to a change in the epidemiology of HAV infection worldwide [1]. This change is associated with a great potential for outbreaks and an increase in the mortality rate due to HAV. Consequently, hepatitis A can currently represent a serious public health problem, especially in regions undergoing this epidemiological change. Thus, it is crucial to recognize this evolution in the HAV epidemiology,

phylogenetic analysis, genetic relatedness, genotype, outbreak

Epidemiological Aspects of

and Molecular Epidemiology

*Saba Gargouri, Lamia Fki-Berrajah, Imen Ayadi,* 

Hepatitis A: Endemicity Patterns

*Amel Chtourou, Adnene Hammami and Héla Karray-Hakim*

Improvements in hygiene and socio-economic conditions in many parts of the world have led to an epidemiological shift in hepatitis A with a transition from high to low endemicity. Consequently, in these areas, higher proportion of symptomatic disease among adolescents resulting in large-scale community outbreaks has been described. In Tunisia, an increase in the average age at the time of infection has been reported, hence resulting in regular outbreaks, especially household and primary school epidemics. Molecular investigation of such outbreaks, based on the determination of viral genotype and genetic relatedness between hepatitis A virus (HAV) strains, is a useful tool to identify the potential source of HAV contamination but also to assess the virus molecular dynamics over time, such as the introduction of a new genotype or a specific clustering of HAV strains according to the geographical origin. In Sfax city, (Center-East of Tunisia), only HAV strains of genotype IA are circulating. In rural areas, HAV infection is still highly endemic with probably a water-borne transmission pattern. Nevertheless, the considerable genetic heterogeneity observed in urban areas highlights the changing pattern of hepatitis A epidemiology in these settings. Further molecular studies are strongly needed to better

#### **Chapter 3**

## Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology

*Saba Gargouri, Lamia Fki-Berrajah, Imen Ayadi, Amel Chtourou, Adnene Hammami and Héla Karray-Hakim*

#### **Abstract**

Improvements in hygiene and socio-economic conditions in many parts of the world have led to an epidemiological shift in hepatitis A with a transition from high to low endemicity. Consequently, in these areas, higher proportion of symptomatic disease among adolescents resulting in large-scale community outbreaks has been described. In Tunisia, an increase in the average age at the time of infection has been reported, hence resulting in regular outbreaks, especially household and primary school epidemics. Molecular investigation of such outbreaks, based on the determination of viral genotype and genetic relatedness between hepatitis A virus (HAV) strains, is a useful tool to identify the potential source of HAV contamination but also to assess the virus molecular dynamics over time, such as the introduction of a new genotype or a specific clustering of HAV strains according to the geographical origin. In Sfax city, (Center-East of Tunisia), only HAV strains of genotype IA are circulating. In rural areas, HAV infection is still highly endemic with probably a water-borne transmission pattern. Nevertheless, the considerable genetic heterogeneity observed in urban areas highlights the changing pattern of hepatitis A epidemiology in these settings. Further molecular studies are strongly needed to better understand HAV epidemiology in Tunisia.

**Keywords:** hepatitis A virus, epidemiology, Tunisia, incidence, RT-PCR, phylogenetic analysis, genetic relatedness, genotype, outbreak

#### **1. Introduction**

Hepatitis A is the most common cause of acute viral hepatitis in the world. This acute necro-inflammatory process of the liver is due to a picornavirus transmitted by the fecal-oral route, which is the hepatitis A virus (HAV). The severity and the clinical outcome of hepatitis A are closely related to the age of infection, with older ages being at risk for symptomatic disease and even acute liver failure. Improvements in socioeconomic and hygienic conditions, during the two last decades, have led to a change in the epidemiology of HAV infection worldwide [1]. This change is associated with a great potential for outbreaks and an increase in the mortality rate due to HAV. Consequently, hepatitis A can currently represent a serious public health problem, especially in regions undergoing this epidemiological change. Thus, it is crucial to recognize this evolution in the HAV epidemiology, in order to implement adequate preventive measures. Currently, seroprevalence surveys of hepatitis A, in addition to molecular investigation of HAV strains, are very useful tools to assess HAV epidemiology in a given area in the world [2].

#### **2. Endemicity patterns of hepatitis A virus infection**

HAV is a small positive-strand RNA virus that is shed in feces as naked nonenveloped virions [2]. Consequently, this virus is characterized by a high resistance in the environment and is primarily transmitted by the fecal-oral route, through direct contact with an infected person or ingestion of contaminated water or food [3].

This transmission explains the fact that the endemicity level of HAV infection, in a particular region in the world, is closely related to socioeconomic indicators and standards of hygiene and sanitation, especially access to clean drinking water. Serological prevalence surveys, based on the detection of total anti-HAV antibodies in serum samples at different ages, are the most useful tool to assess the endemicity of HAV infection. Up to date, four levels of HAV endemicity are defined according to the World Health Organization (WHO) [3]: high (≥90% by age 10 years); intermediate (≥50% by age 15 years, with <90% by age 10 years); low (≥50% by age 30 years, with <50% by age 15); and very low (<50% by age 30 years).

The clinical expression of HAV infection is highly age-dependent, ranging from asymptomatic form, frequently observed in early childhood, to fulminant hepatitis which particularly occurs in older age groups with chronic liver disease [4]. In low-income areas, including sub-Saharan Africa and South Asia, which are characterized by a high level of endemicity, HAV infection is acquired in young children, the age at which infection is often entirely asymptomatic. Thus, in these regions, the burden of hepatitis A is relatively low, and outbreaks are not common [1, 3]. By contrast, in high-income areas, including the United States, Western Europe, and Japan, which are characterized by a very low-endemicity pattern, HAV mainly circulates among specific groups at risk such as men who have sex with men, travelers in highly endemic countries, and intravenous drug users, leading to occasional relatively limited outbreaks [4]. Importantly, in many regions of the world, which are experiencing a deep change in HAV epidemiology such as some parts of Latin America, the Middle East, and Eastern Europe, large-scale community outbreaks are commonly observed. Indeed, improvements in socioeconomic status and hygienic conditions have led to an increase in average age at the time of infection, with adolescents and young adults being the predominant susceptible population, resulting in more symptomatic disease and therefore the occurrence of large epidemics in the community. These hepatitis A epidemics are often very difficult to control and represent a huge public health problem in these countries because of an increase in the incidence of severe illnesses, hospitalizations, and deaths related to this infection. These observations suggest what is known as "the epidemiological transition or shift" [1], which means that the decrease in HAV transmission rate is paradoxically associated to an increase in the incidence of symptomatic hepatitis A.

In Tunisia, HAV infection is still common, but its epidemiology is undergoing a gradual shift. Indeed, improvements in hygiene and socioeconomic conditions have led to changes in the pattern of the age-specific seroprevalence of anti-HAV antibodies; specifically, the prevalence of anti-HAV antibodies in the age group under 10 years declined from 91% in the 1980s [5] to 44% in 2001 [6]. These results suggest that HAV transmission is decreasing among younger children, leading to the occurrence of a larger number of symptomatic cases among adolescents and adults and even more frequent large outbreaks. During the years 2007–2010, community-wide outbreaks of hepatitis A have been recorded in Sfax Governorate

**35**

exists [9].

*Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology*

observed, especially household and primary school epidemics.

epidemiological link found between HAV confirmed cases.

**3. Molecular epidemiology of hepatitis A virus infection**

(center east of Tunisia), with the occurrence of severe forms [7]. The increase in the incidence of hepatitis A cases involved nearly all regions of the governorate, including urban and rural areas. During this period, well-delimited outbreaks were

The annual and monthly distribution of hepatitis A cases from 2000 to 2011 showed an endemic circulation of HAV with an increase in the incidence of the disease during the fall and winter season [7]. Importantly, this distribution highlighted similar waves of large outbreaks during 2002–2005, in comparison with those of 2007–2010, suggesting the cyclical trend of HAV infection in Tunisia. The regular evolution of hepatitis A is typical of HAV epidemiological shift; the delay in the exposure to the virus has generated a huge number of susceptible adolescents and adults and significantly increased the average age at infection. As the severity of disease increases with age, this has led to outbreaks of hepatitis A [4]. Consequently, nearly all population will be immunized against HAV until growing cohorts of susceptible young people become predominant after several years, hence

Among the patients diagnosed during 2007–2010 [7], 35 and 33% belonged to age groups 6–10 years and 11–15 years, respectively, which confirms that susceptibility to HAV is shifting from early age to older children and even adolescents and young adults. However, this shift was more prominent in urban areas than rural ones since the mean age of patients in these regions was 14.8 and 8.5 years, respectively. Two primary school epidemics were reported in rural settings, as well as several household outbreaks. Epidemiological investigation in this study suggested that rural outbreaks may be related to a common source contamination of water. By contrast, in urban areas, the situation was quite different from that observed in rural ones, since the epidemic consisted of many sporadic small outbreaks with no

Indeed, in countries with HAV epidemiological transition, different endemicity patterns simultaneously exist due to differences in socioeconomic development and hygienic practices between regions [1]. Urban areas may benefit the most from improvements in sanitary conditions, especially access to improved water sources and improvements in sewage treatment methods, hence increasing the risk of large outbreaks among adolescents and adults. The heterogeneity in HAV endemicity patterns between rural and urban areas is typical of HAV epidemiological shift.

HAV has a single-stranded positive-sense RNA genome of 7.5 kilobases (kb) long [2]. The viral genome has a single open reading frame (ORF), divided into three functional regions, designated P1, P2, and P3. The P1 region encodes capsid polypeptides (VP1, VP2, VP3, and a putative VP4), whereas the P2 and P3 regions encode nonstructural proteins associated with viral replication [8]. Six HAV genotypes are up to now identified; three genotypes (I, II, and III) are of human origin, and three (IV, V, and VI) are of simian origin [8]. When these genotypes are defined by sequence variation within the VP1/P2A junction, there is 15% nucleotide variation between genotypes and 7–7.5% nucleotide variation between subgenotypes. Despite genetic heterogeneity at the nucleotide level, only a single serotype of HAV

Although HAV is primarily shed in feces, there is a strong viremic phase during infection which has allowed easy access to virus isolates and the use of molecular markers to determine their genetic relatedness [9]. Currently, molecular epidemiological investigations are widely performed and are considered as a very useful tool

*DOI: http://dx.doi.org/10.5772/intechopen.90431*

leading to new outbreaks.

#### *Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology DOI: http://dx.doi.org/10.5772/intechopen.90431*

(center east of Tunisia), with the occurrence of severe forms [7]. The increase in the incidence of hepatitis A cases involved nearly all regions of the governorate, including urban and rural areas. During this period, well-delimited outbreaks were observed, especially household and primary school epidemics.

The annual and monthly distribution of hepatitis A cases from 2000 to 2011 showed an endemic circulation of HAV with an increase in the incidence of the disease during the fall and winter season [7]. Importantly, this distribution highlighted similar waves of large outbreaks during 2002–2005, in comparison with those of 2007–2010, suggesting the cyclical trend of HAV infection in Tunisia. The regular evolution of hepatitis A is typical of HAV epidemiological shift; the delay in the exposure to the virus has generated a huge number of susceptible adolescents and adults and significantly increased the average age at infection. As the severity of disease increases with age, this has led to outbreaks of hepatitis A [4]. Consequently, nearly all population will be immunized against HAV until growing cohorts of susceptible young people become predominant after several years, hence leading to new outbreaks.

Among the patients diagnosed during 2007–2010 [7], 35 and 33% belonged to age groups 6–10 years and 11–15 years, respectively, which confirms that susceptibility to HAV is shifting from early age to older children and even adolescents and young adults. However, this shift was more prominent in urban areas than rural ones since the mean age of patients in these regions was 14.8 and 8.5 years, respectively. Two primary school epidemics were reported in rural settings, as well as several household outbreaks. Epidemiological investigation in this study suggested that rural outbreaks may be related to a common source contamination of water. By contrast, in urban areas, the situation was quite different from that observed in rural ones, since the epidemic consisted of many sporadic small outbreaks with no epidemiological link found between HAV confirmed cases.

Indeed, in countries with HAV epidemiological transition, different endemicity patterns simultaneously exist due to differences in socioeconomic development and hygienic practices between regions [1]. Urban areas may benefit the most from improvements in sanitary conditions, especially access to improved water sources and improvements in sewage treatment methods, hence increasing the risk of large outbreaks among adolescents and adults. The heterogeneity in HAV endemicity patterns between rural and urban areas is typical of HAV epidemiological shift.

#### **3. Molecular epidemiology of hepatitis A virus infection**

HAV has a single-stranded positive-sense RNA genome of 7.5 kilobases (kb) long [2]. The viral genome has a single open reading frame (ORF), divided into three functional regions, designated P1, P2, and P3. The P1 region encodes capsid polypeptides (VP1, VP2, VP3, and a putative VP4), whereas the P2 and P3 regions encode nonstructural proteins associated with viral replication [8]. Six HAV genotypes are up to now identified; three genotypes (I, II, and III) are of human origin, and three (IV, V, and VI) are of simian origin [8]. When these genotypes are defined by sequence variation within the VP1/P2A junction, there is 15% nucleotide variation between genotypes and 7–7.5% nucleotide variation between subgenotypes. Despite genetic heterogeneity at the nucleotide level, only a single serotype of HAV exists [9].

Although HAV is primarily shed in feces, there is a strong viremic phase during infection which has allowed easy access to virus isolates and the use of molecular markers to determine their genetic relatedness [9]. Currently, molecular epidemiological investigations are widely performed and are considered as a very useful tool

*Hepatitis A and Other Associated Hepatobiliary Diseases*

**2. Endemicity patterns of hepatitis A virus infection**

30 years, with <50% by age 15); and very low (<50% by age 30 years).

in order to implement adequate preventive measures. Currently, seroprevalence surveys of hepatitis A, in addition to molecular investigation of HAV strains, are very useful tools to assess HAV epidemiology in a given area in the world [2].

HAV is a small positive-strand RNA virus that is shed in feces as naked nonenveloped virions [2]. Consequently, this virus is characterized by a high resistance in the environment and is primarily transmitted by the fecal-oral route, through direct contact with an infected person or ingestion of contaminated water or food [3]. This transmission explains the fact that the endemicity level of HAV infection, in a particular region in the world, is closely related to socioeconomic indicators and standards of hygiene and sanitation, especially access to clean drinking water. Serological prevalence surveys, based on the detection of total anti-HAV antibodies in serum samples at different ages, are the most useful tool to assess the endemicity of HAV infection. Up to date, four levels of HAV endemicity are defined according to the World Health Organization (WHO) [3]: high (≥90% by age 10 years); intermediate (≥50% by age 15 years, with <90% by age 10 years); low (≥50% by age

The clinical expression of HAV infection is highly age-dependent, ranging from asymptomatic form, frequently observed in early childhood, to fulminant hepatitis which particularly occurs in older age groups with chronic liver disease [4]. In low-income areas, including sub-Saharan Africa and South Asia, which are characterized by a high level of endemicity, HAV infection is acquired in young children, the age at which infection is often entirely asymptomatic. Thus, in these regions, the burden of hepatitis A is relatively low, and outbreaks are not common [1, 3]. By contrast, in high-income areas, including the United States, Western Europe, and Japan, which are characterized by a very low-endemicity pattern, HAV mainly circulates among specific groups at risk such as men who have sex with men, travelers in highly endemic countries, and intravenous drug users, leading to occasional relatively limited outbreaks [4]. Importantly, in many regions of the world, which are experiencing a deep change in HAV epidemiology such as some parts of Latin America, the Middle East, and Eastern Europe, large-scale community outbreaks are commonly observed. Indeed, improvements in socioeconomic status and hygienic conditions have led to an increase in average age at the time of infection, with adolescents and young adults being the predominant susceptible population, resulting in more symptomatic disease and therefore the occurrence of large epidemics in the community. These hepatitis A epidemics are often very difficult to control and represent a huge public health problem in these countries because of an increase in the incidence of severe illnesses, hospitalizations, and deaths related to this infection. These observations suggest what is known as "the epidemiological transition or shift" [1], which means that the decrease in HAV transmission rate is paradoxically associated to an increase in the incidence of symptomatic hepatitis A. In Tunisia, HAV infection is still common, but its epidemiology is undergoing a gradual shift. Indeed, improvements in hygiene and socioeconomic conditions have led to changes in the pattern of the age-specific seroprevalence of anti-HAV antibodies; specifically, the prevalence of anti-HAV antibodies in the age group under 10 years declined from 91% in the 1980s [5] to 44% in 2001 [6]. These results suggest that HAV transmission is decreasing among younger children, leading to the occurrence of a larger number of symptomatic cases among adolescents and adults and even more frequent large outbreaks. During the years 2007–2010, community-wide outbreaks of hepatitis A have been recorded in Sfax Governorate

**34**

for the identification of HAV transmission patterns and the potential source of the water or food-borne hepatitis A outbreaks. A molecular investigation approach is primarily based on the determination of viral genotype and the genetic relatedness between HAV strains.

Up to date, few investigations on the molecular epidemiology have been performed in Tunisia. In order to characterize HAV strains during the large outbreaks occurred in Sfax, Tunisia, during 2007–2010 [7], a molecular epidemiological study was carried out [10]. Amplification of VP1/2A region of HAV RNA by nested RT-PCR was performed on the serum samples for 159 patients with available epidemiological information [7]. HAV RNA was detected in 80.5% of cases. No relationship was documented between the positivity of HAV RNA and both age and sex (p = 0.179 and 0.553, respectively). For HAV RNA-negative cases, the mean delay between onset of symptoms and sampling was 25.5 days (range, 5–47 days), whereas for HAV RNA-positive cases, this delay was significantly lower, with a mean of 10.2 days (range, 1–49 days, p < 0.001). These findings suggest, as previously described, that the positivity of HAV RNA is correlated to the sampling time [11–13]. This result can be explained by the short duration of viremia, during natural history of HAV infection. Indeed, viral RNA could be detected on an average of 18 ± 14 days following the onset of clinical symptoms [14]. Another reason for the negativity of HAV RNA is the storage conditions of serum samples (the optimal temperature for the storage of RNAs is −80°C), leading to the degradation of the viral RNA and consequently to the negativity of PCR.

Nucleotide sequencing was performed for positive samples by RT-PCR. Strain genotyping was carried out by the phylogenetic analysis of a 394-nucleotide fragment, encompassing the VP1/2A junction (from nucleotide 2896 to nucleotide 3289, according to HAV strain HM175). Phylogenetic tree was constructed with MEGA software version 6.05, by using Kimura's two-parameter model, with the neighbor-joining algorithm (**Figure 1**). The reliability of the tree was tested by bootstrap resampling of 1000 replications. Nine reference sequences were included in the phylogenetic tree. Nucleotide identity percentages were computed, using the p-distance model included in the MEGA software (**Table 1**).

All clinical HAV strains from different regions of Sfax Governorate belonged to genotype IA [10]. This result is in an agreement with those of other Tunisian studies, which demonstrated that the predominant genotype still continues to be IA [15–17]. In addition, HAV sequences were closer to GBM reference strain (isolated in Germany) than to Asian sequences, suggesting a close genetic relatedness with HAV strains isolated in Mediterranean countries. This concept of related HAV strains according to geographical origin has been previously mentioned in China [18]. Indeed, Asian HAV strains were closer to each other than to the other reported sequences in the United States and Germany.

The mean identity percentage between HAV sequences was 98.1% indicating that clinical HAV strains isolated during 2007–2010 outbreaks were closely related, which confirms the endemic circulation of HAV in Sfax. Nevertheless, phylogenetic analysis evidenced the presence of genetic heterogeneity among HAV strains and identified three different clusters; rural strains clustered together with high bootstrap value (regardless of the outbreak period), suggesting the highly endemic circulation of the same HAV strains in these settings. This close genetic relatedness is most likely related to a common source of contamination [18–20]. Interestingly, the majority of HAV strains isolated during school epidemics shared 100% sequence identity. Of note, the abrupt increase in the number of jaundiced persons, in rural schools, has occurred within a short period of time in two geographically distant settings (Sidi Abdelkefi and Menzel Chaker (Bir Mallouli)). This transmission pattern strongly suggests the presence of a single source for school outbreaks [8].

**37**

**Figure 1.**

*Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology*

Indeed, the epidemiological investigation highlighted the use by inhabitants of the same source of drinking water (private well) [7]. Inadequate sanitation, evidenced by fecal contamination of drinking water, in addition to the poor hygiene conditions

*Phylogenetic tree analysis of VP1/2A junction (394 bp) of HAV genome using Kimura's two-parameter model with the neighbor-joining algorithm. Numbers at tree nodes show bootstrap percentages obtained from 1000 resamplings. Bootstrap values <70% are hidden. Bars indicate genetic distances. Genotypes are shown in parentheses for HAV reference strains (see Table 1). The Tunisian sequences are designated by their lab code followed by their region of origin, outbreak period (O, outbreak), and month and year of isolation. Sequences marked with a black circle indicate HAV strains recovered from rural areas, whereas those marked with a black triangle indicate HAV strains recovered from urban areas. For strains sharing 100% sequence identity, only one* 

indicates that the mainly route of HAV contamination is water transmission.

*representative strain was included in the phylogenetic tree.*

*DOI: http://dx.doi.org/10.5772/intechopen.90431*

*Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology DOI: http://dx.doi.org/10.5772/intechopen.90431*

#### **Figure 1.**

*Hepatitis A and Other Associated Hepatobiliary Diseases*

viral RNA and consequently to the negativity of PCR.

p-distance model included in the MEGA software (**Table 1**).

sequences in the United States and Germany.

between HAV strains.

for the identification of HAV transmission patterns and the potential source of the water or food-borne hepatitis A outbreaks. A molecular investigation approach is primarily based on the determination of viral genotype and the genetic relatedness

Up to date, few investigations on the molecular epidemiology have been performed in Tunisia. In order to characterize HAV strains during the large outbreaks occurred in Sfax, Tunisia, during 2007–2010 [7], a molecular epidemiological study was carried out [10]. Amplification of VP1/2A region of HAV RNA by nested RT-PCR was performed on the serum samples for 159 patients with available epidemiological information [7]. HAV RNA was detected in 80.5% of cases. No relationship was documented between the positivity of HAV RNA and both age and sex (p = 0.179 and 0.553, respectively). For HAV RNA-negative cases, the mean delay between onset of symptoms and sampling was 25.5 days (range, 5–47 days), whereas for HAV RNA-positive cases, this delay was significantly lower, with a mean of 10.2 days (range, 1–49 days, p < 0.001). These findings suggest, as previously described, that the positivity of HAV RNA is correlated to the sampling time [11–13]. This result can be explained by the short duration of viremia, during natural history of HAV infection. Indeed, viral RNA could be detected on an average of 18 ± 14 days following the onset of clinical symptoms [14]. Another reason for the negativity of HAV RNA is the storage conditions of serum samples (the optimal temperature for the storage of RNAs is −80°C), leading to the degradation of the

Nucleotide sequencing was performed for positive samples by RT-PCR. Strain genotyping was carried out by the phylogenetic analysis of a 394-nucleotide fragment, encompassing the VP1/2A junction (from nucleotide 2896 to nucleotide 3289, according to HAV strain HM175). Phylogenetic tree was constructed with MEGA software version 6.05, by using Kimura's two-parameter model, with the neighbor-joining algorithm (**Figure 1**). The reliability of the tree was tested by bootstrap resampling of 1000 replications. Nine reference sequences were included in the phylogenetic tree. Nucleotide identity percentages were computed, using the

All clinical HAV strains from different regions of Sfax Governorate belonged to genotype IA [10]. This result is in an agreement with those of other Tunisian studies, which demonstrated that the predominant genotype still continues to be IA [15–17]. In addition, HAV sequences were closer to GBM reference strain (isolated in Germany) than to Asian sequences, suggesting a close genetic relatedness with HAV strains isolated in Mediterranean countries. This concept of related HAV strains according to geographical origin has been previously mentioned in China [18]. Indeed, Asian HAV strains were closer to each other than to the other reported

The mean identity percentage between HAV sequences was 98.1% indicating that clinical HAV strains isolated during 2007–2010 outbreaks were closely related, which confirms the endemic circulation of HAV in Sfax. Nevertheless, phylogenetic analysis evidenced the presence of genetic heterogeneity among HAV strains and identified three different clusters; rural strains clustered together with high bootstrap value (regardless of the outbreak period), suggesting the highly endemic circulation of the same HAV strains in these settings. This close genetic relatedness is most likely related to a common source of contamination [18–20]. Interestingly, the majority of HAV strains isolated during school epidemics shared 100% sequence identity. Of note, the abrupt increase in the number of jaundiced persons, in rural schools, has occurred within a short period of time in two geographically distant settings (Sidi Abdelkefi and Menzel Chaker (Bir Mallouli)). This transmission pattern strongly suggests the presence of a single source for school outbreaks [8].

**36**

*Phylogenetic tree analysis of VP1/2A junction (394 bp) of HAV genome using Kimura's two-parameter model with the neighbor-joining algorithm. Numbers at tree nodes show bootstrap percentages obtained from 1000 resamplings. Bootstrap values <70% are hidden. Bars indicate genetic distances. Genotypes are shown in parentheses for HAV reference strains (see Table 1). The Tunisian sequences are designated by their lab code followed by their region of origin, outbreak period (O, outbreak), and month and year of isolation. Sequences marked with a black circle indicate HAV strains recovered from rural areas, whereas those marked with a black triangle indicate HAV strains recovered from urban areas. For strains sharing 100% sequence identity, only one representative strain was included in the phylogenetic tree.*

Indeed, the epidemiological investigation highlighted the use by inhabitants of the same source of drinking water (private well) [7]. Inadequate sanitation, evidenced by fecal contamination of drinking water, in addition to the poor hygiene conditions indicates that the mainly route of HAV contamination is water transmission.


#### **Table 1.**

*Nucleotide identity between clinical and reference HAV strains.*

Nevertheless, in these rural settings, interhuman transmission of HAV may also play a major role in the endemic circulation of the virus. In closed institutions such as schools, the agglomeration of individuals, sharing of objects, inadequate hygienic conditions, and high proportion of individuals susceptible to hepatitis A facilitate transmission [8].

HAV strains isolated in urban areas showed more genetic variability, since they were grouped into two different clusters, suggesting that urban outbreak may have originated from more than one source. In Sfax city, the epidemic consisted of many sporadic small outbreaks, which made it difficult to carry out a field investigation; thus, the information got from patients might not represent the whole situation in this large area. The genetic diversity of HAV strains was also reported in other regions in the world, where hepatitis A outbreaks observed in urban settings of industrialized countries cannot be linked to one source of contamination [18, 21]. The changing epidemiological pattern in HAV infection throughout Tunisia, particularly in urban areas, may result in more clinical cases in adolescents and adults and greater potential for new outbreaks. This changing pattern seems to be mainly related to improvements in hygiene conditions, since this study confirmed that genotype IA is widely circulating in Tunisia [10]. Thus, urban outbreaks are not linked to the other genotype emerging strains as it was reported by a Korean study [22], which showed that genotype IIIA becomes more prevalent than previously reported and may be the reason for the HAV outbreaks reported in Korea. Nevertheless, the higher genetic variability among HAV strains isolated in urban areas compared to rural ones in Sfax needs to be more evaluated by further molecular studies, in order to increase the understanding of hepatitis A epidemiology in these particular regions.

During urban outbreak, two fulminant hepatitis A cases were reported with fatal outcome, in one case due to an acute liver failure [7]. Unfortunately, only HAV strain from one patient was isolated. Since the time course between onset of symptoms and blood sample collection was very long (47 days), this could possibly explain the disappearance of viremia. It was previously suggested that viral determinants, in addition to host factors, could be involved in HAV disease severity, especially 5'UTR and 2B and 2C nucleotide substitutions [23, 24]. However, no correlation was found between HAV genotype and the different clinical outcomes [25].

**39**

*Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology*

Indeed, HAV strain recovered from one patient had 100% sequence identity with two other strains from patients with self-limited acute hepatitis A, indicating that infection with identical HAV strains within VP1/2A junction can result in drasti-

The findings of HAV molecular epidemiology study carried out in both rural and urban settings during large outbreaks in Sfax, Tunisia, in 2007–2010 strongly suggest that HAV infection is still highly endemic in rural settings, mainly related to the use of untreated water from contaminated sources, in addition to person-toperson transmission. However, genetic HAV diversity reported in urban areas, in comparison with rural ones, may reflect the epidemiological shift in these settings. Therefore, a close monitor of molecular HAV epidemiology is needed for a better

The authors thank Mrs. Houda Abdelmoula for the English proofreading of this

, Imen Ayadi2

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Amel Chtourou1

,

*DOI: http://dx.doi.org/10.5772/intechopen.90431*

cally different clinical outcomes [8].

understanding of HAV epidemiology in Tunisia.

The authors declare no conflict of interest.

\*, Lamia Fki-Berrajah1

Faculty of Medicine, University of Sfax, Sfax, Tunisia

\*Address all correspondence to: sabagargouri@yahoo.fr

Centre of Biotechnology of Sfax, Sfax, Tunisia

provided the original work is properly cited.

2 Laboratory of Molecular and Cellular Screening Processes,

and Héla Karray-Hakim1

1 Laboratory of Microbiology, Habib Bourguiba University-Hospital,

**4. Conclusions**

**Acknowledgements**

**Conflict of interest**

**Author details**

Saba Gargouri1

Adnene Hammami1

chapter.

*Epidemiological Aspects of Hepatitis A: Endemicity Patterns and Molecular Epidemiology DOI: http://dx.doi.org/10.5772/intechopen.90431*

Indeed, HAV strain recovered from one patient had 100% sequence identity with two other strains from patients with self-limited acute hepatitis A, indicating that infection with identical HAV strains within VP1/2A junction can result in drastically different clinical outcomes [8].

#### **4. Conclusions**

*Hepatitis A and Other Associated Hepatobiliary Diseases*

GBM (IA) 96.9–98.7

LY6 (IA) 93.3–94.9 HM175 (IB) 90.7–92.3

SLF88 (IIB) 84.3–86.4

HAJ85-1F (IIIB) 79.4–81.5

*Computed using the p-distance model included in the MEGA software.*

*Nucleotide identity between clinical and reference HAV strains.*

Nevertheless, in these rural settings, interhuman transmission of HAV may also play a major role in the endemic circulation of the virus. In closed institutions such as schools, the agglomeration of individuals, sharing of objects, inadequate hygienic conditions, and high proportion of individuals susceptible to hepatitis A facilitate

AH1 (IA) 92.8–94.3 (95.3 ± 0.7)

MBB (IB) 91.5–93.3 (92.3 ± 1.1) CF53 (IIA) 84.3–86.1 (85.5 ± 1.5)

HMH (IIIA) 78.1–80.5 (80.3 ± 1.8)

**Clinical sequences % Nucleotide identitya (Mean ± SD)b**

HAV strains isolated in urban areas showed more genetic variability, since they were grouped into two different clusters, suggesting that urban outbreak may have originated from more than one source. In Sfax city, the epidemic consisted of many sporadic small outbreaks, which made it difficult to carry out a field investigation; thus, the information got from patients might not represent the whole situation in this large area. The genetic diversity of HAV strains was also reported in other regions in the world, where hepatitis A outbreaks observed in urban settings of industrialized countries cannot be linked to one source of contamination [18, 21]. The changing epidemiological pattern in HAV infection throughout Tunisia, particularly in urban areas, may result in more clinical cases in adolescents and adults and greater potential for new outbreaks. This changing pattern seems to be mainly related to improvements in hygiene conditions, since this study confirmed that genotype IA is widely circulating in Tunisia [10]. Thus, urban outbreaks are not linked to the other genotype emerging strains as it was reported by a Korean study [22], which showed that genotype IIIA becomes more prevalent than previously reported and may be the reason for the HAV outbreaks reported in Korea. Nevertheless, the higher genetic variability among HAV strains isolated in urban areas compared to rural ones in Sfax needs to be more evaluated by further molecular studies, in order to increase the understanding of hepatitis A epidemiology in

During urban outbreak, two fulminant hepatitis A cases were reported with fatal outcome, in one case due to an acute liver failure [7]. Unfortunately, only HAV strain from one patient was isolated. Since the time course between onset of symptoms and blood sample collection was very long (47 days), this could possibly explain the disappearance of viremia. It was previously suggested that viral determinants, in addition to host factors, could be involved in HAV disease severity, especially 5'UTR and 2B and 2C nucleotide substitutions [23, 24]. However, no correlation was found between HAV genotype and the different clinical outcomes [25].

**38**

transmission [8].

*SD: Standard Deviation.*

*a*

*b*

**Table 1.**

**Reference sequences**

these particular regions.

The findings of HAV molecular epidemiology study carried out in both rural and urban settings during large outbreaks in Sfax, Tunisia, in 2007–2010 strongly suggest that HAV infection is still highly endemic in rural settings, mainly related to the use of untreated water from contaminated sources, in addition to person-toperson transmission. However, genetic HAV diversity reported in urban areas, in comparison with rural ones, may reflect the epidemiological shift in these settings. Therefore, a close monitor of molecular HAV epidemiology is needed for a better understanding of HAV epidemiology in Tunisia.

#### **Acknowledgements**

The authors thank Mrs. Houda Abdelmoula for the English proofreading of this chapter.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Saba Gargouri1 \*, Lamia Fki-Berrajah1 , Imen Ayadi2 , Amel Chtourou1 , Adnene Hammami1 and Héla Karray-Hakim1

1 Laboratory of Microbiology, Habib Bourguiba University-Hospital, Faculty of Medicine, University of Sfax, Sfax, Tunisia

2 Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, Sfax, Tunisia

\*Address all correspondence to: sabagargouri@yahoo.fr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[2] Lemon SM, Ott JJ, Van Damme P, et al. Type a viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention. Journal of Hepatology. 2018;**68**(1):167-184. DOI: 10.1016/j. jhep.2017.08.034

[3] WHO position paper on hepatitis A vaccines-June 2012. Weekly Epidemiological Record. 2012;**87**(28/29):261-276. Available from: http://www.who.int/wer/2012/ wer8728\_29.pdf

[4] Franco E, Meleleo C, Serino L, et al. Hepatitis A: Epidemiology and prevention in developing countries. World Journal of Hepatology. 2012;**4**: 68-73. DOI: 10.4254/wjh.v4.i3.68

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and evolution. Infection, Genetics and Evolution. 2014;**21**:227-243. DOI:

[9] Nainan OV, Xia G, Vaughan G, et al. Diagnosis of hepatitis A virus infection:

[10] Gargouri S. Epidémiologie clinique et moléculaire de l'infection par le virus de l'hépatite A dans la région de Sfax de 2007 à 2009 [thesis]. Faculté de

[11] Hussain Z, Husain SA, Almajhdi FN, et al. Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A. Virology Journal. 2011;**8**:254. DOI:

[12] Nainan OV, Armstrong GL, Han X-H, et al. Hepatitis A molecular epidemiology in the United States, 1996-1997: Sources of infection and implications of vaccination policy. The Journal of Infectious Diseases. 2005;**191**:957-963. DOI: 10.1086/427992

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pm0009398009

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**43**

Section 2

Hepatitis A: From

Laboratory to Clinics

Section 2
