Hepatitis A is an acute inflammation of the liver, caused by infection with hepatitis A virus (HAV). The disease is usually self-limited. Globally, it is estimated to cause 126 million cases of acute hepatitis and 35 000 deaths annually . The epidemiology of this disease has changed over the last two decades in several developing countries. This article reviews various aspects of risk factors for hepatitis A and its prevention, particularly in resource-poor settings.
HAV is the sole member of genus Hepatovirus, which is placed in family Picornaviridae.
Viral structure and genome
HAV virions are small (∼27 nm), icosahedral particles with a positive-stranded and single-stranded, 7.5-kilobase long RNA genome which codes for a single polyprotein of approximately 240 kDa [2▪]. This protein undergoes cotranslational and posttranslational processing to yield several structural and nonstructural proteins [2▪].
HAV virions were traditionally believed to be nonenveloped. However, recent data indicate the existence of both nonenveloped and enveloped forms. The enveloped virions are chloroform-sensitive, have a discernible membrane at electron microscopy, and are not detected by immunoassays that use anti-HAV antibodies [3,4▪]. They appear to arise by surface budding from infected hepatocytes, circulate in the blood of infected humans, and enter the hepatocytes by endocytosis. Their exact role in disease pathogenesis is unclear, although they may help intrahepatic viral spread.
The virus is fairly resistant to heat  and acid , and can persist for several weeks in fecal matter and contaminated foods , and on food-contact surfaces . In one study, thorough physical treatment of contaminated farm produce, such as scrubbing under running water (honeydew melons, cantaloupes, carrots, and celery) and peeling (carrots and celery) with a peeler led to only partial reduction in viral contamination; also, utensil cross-contamination led to contamination of items handled subsequently .
Isolates of HAV were initially classified into seven genotypes (I–VII), based on sequences of a 168-nucleotide fragment containing the VP1/P2A junction . However, subsequently, a new classification with six genotypes (I–VI), based on sequences of the entire VP1 region, was proposed . In this system, which is currently widely used, the original genotype VII forms a subtype of genotype II. Genotypes I–III, each divided into two subgenotypes (A and B), infect only humans, whereas genotypes IV–VI cause simian infections. Genotypes I and III are more prevalent worldwide, with genotype II being limited to some parts of Africa [2▪]. Genotype IIIA appears to be particularly prevalent in several Asian countries, such as South Korea [12–14] and India [15–17]; in South Korea, its frequency appears to have increased in recent years .
Existence of genetic heterogeneity allows the use of viral genotyping and sequencing for identification of the origin of hepatitis A outbreaks and routes of viral transmission . Using such methods, some outbreaks in the developed world have been traced to importation of contaminated food from resource-poor regions. For instance, outbreaks of hepatitis A in Europe and the United States have been traced to sun-dried tomatoes [19,20] and pomegranates [21▪▪], respectively, imported from Turkey. However, such studies from resource-poor countries are not available because of limited availability of genomic sequencing facilities.
Despite genetic heterogeneity, all HAV genotypes share one highly conserved antigenic neutralization site  and have a single serotype; hence, vaccines developed using one strain of HAV protect against all genotypes.
After oral ingestion, the virus reaches the host liver through portal circulation, possibly following viral replication in intestinal cells. There, it enters into and replicates in the hepatocytes, from where viral progeny is released into bile, reaches the intestine, and is excreted in feces. The hepatocyte injury and liver damage during HAV infection appear to be mediated by host immune response.
HAVCR1, a protein expressed on the hepatocyte surface, is the cellular receptor for HAV . A six-amino-acid insertion at residue 157 of this protein (termed 157insMTTTVP) has been associated with more severe disease , possibly because the longer HAVCR1 variant protein allows the hepatocytes to bind to HAV more efficiently and increases the cytotoxicity of natural killer T cells against HAV-infected cells .
HAV infection is associated with development of specific antibodies belonging to immunoglobulin M (IgM), G (IgG) and A (IgA) classes shortly preceding or concurrent with the onset of symptoms. IgM antibodies are used as a marker of recent HAV infection; these usually disappear in a few months but may occasionally persist beyond 1 year. By contrast, IgG antibodies persist for several years and reflect prior exposure, either recent or distant, to HAV. Vaccination-induced anti-HAV antibodies may confound the interpretation of seroepidemiologic studies; however, in most of the resource-poor settings, vaccination is not yet widespread.
In a recent study of 1227 members of 45 Mexican American families (73% anti-HAV positive), anti-HAV serostatus had a high (48%) heritability . This association may represent the influence of genetic factors either on susceptibility to infection or on development of humoral immune response. Further work is needed to understand the implication of this finding for HAV epidemiology.
SOURCE, TRANSMISSION, AND ROUTES OF SPREAD OF HEPATITIS A VIRUS
The transmission of human HAV is primarily fecal–oral, with the feces of infected humans being the only source. The fecal excretion is at its maximum during 2 weeks prior to and a few days immediately after the onset of symptoms, but may continue for a few weeks thereafter .
The most important mode of acquisition of HAV is through close contact with an infected person. High infection rates (25–50%) among family and school contacts of hepatitis A cases, even in developed countries with good personal hygiene, indicate that the infective dose is low and interpersonal spread is highly efficient.
The other major mode of transmission is through contaminated food and water. A variety of foods have been implicated in hepatitis A outbreaks; including seafood , farm products [21▪▪], milk, hamburgers, ice-slush beverages, and salads. These outbreaks can be large; in 1988, an outbreak in China, which was related to ingestion of raw clams, affected nearly 300 000 persons . In several cases, no source is discernible; these are most likely related to contact with persons with asymptomatic infection.
Theoretically, HAV infection can occur following transfusion of blood or blood products from an infected person; however, this is infrequent in practice. Outbreaks of HAV infection have been reported among intravenous drug users and among men having sex with men; however, several mechanisms including close contact can account for such transmission.
CLINICAL MANIFESTATIONS OF HEPATITIS A VIRUS INFECTION AND THEIR DETERMINANTS
The incubation period of hepatitis A is 15–50 (mean 30) days. Similar to other hepatotropic viruses, clinical manifestations of HAV infection are highly varied and include entirely asymptomatic infection, mild anicteric hepatitis, acute viral hepatitis, and acute liver failure.
Some patients with hepatitis A have one or more clinical relapses after an initial partial or complete resolution. The relapses are associated with continued viral replication, are usually milder than the initial illness, and eventual recovery is the rule [29,30]. Some patients develop extrahepatic manifestations, such as arthralgias, cutaneous vasculitis, cryoglobulinemia, Guillain–Barré syndrome, myelopathy, mononeuritis, or meningoencephalitis, with or without clinical evidence of hepatitis. Chronic HAV infection, and long-term sequelae such as liver cirrhosis and liver cancer, do not occur.
HAV infection, whether asymptomatic or associated with disease, is associated with development of a robust immune response, which provides lifelong protection against future reinfection with the virus.
Age dependence of hepatitis A disease
The risk of clinical disease following HAV infection is determined primarily by age of the infected person. Thus, infection during early childhood is most often entirely asymptomatic. By contrast, infection during late childhood, adolescence, or as adults is more likely to cause icteric illness; the risk of fulminant hepatitis and death is also higher in these age groups.
In an analysis of data from seven community-wide hepatitis A outbreaks , the age-specific probability of developing jaundice among those infected was estimated as being 0.852 × (1 – exp[–0.01244 × age1.903]); this translated to average probabilities of jaundice of 7.2, 37.1, 70.7, and 85.2% in the 0–4, 5–9, 10–17, and at least 18 year age-groups. Figure 1 shows a curve drawn using this equation.
METHODS FOR ASSESSING HEPATITIS A VIRUS EPIDEMIOLOGY
Epidemiology of HAV infection and disease can be studied using disease reporting systems that measure the incidence of morbidity or mortality from acute hepatitis A, and serological surveys that estimate the prevalence of past infection at different ages. In several resource-poor countries, the former data do not exist because the facilities for IgM anti-HEV test are not readily available. In comparison, IgG anti-HAV serosurveys among healthy persons being easier to do are more widely available. Since IgG anti-HAV persists lifelong, the profile of age-specific seroprevalence rates in a population provides an excellent measure of cumulative lifetime exposure to HAV of persons born in different time periods.
EPIDEMIOLOGIC PATTERNS OF HEPATITIS A VIRUS INFECTION
HAV infection is distributed worldwide. However, its rate of transmission varies widely between populations, being determined primarily by socioeconomic status. In areas with better access to clean drinking water and sewage disposal, smaller family size, and better personal hygiene, the rate of transmission of HAV infection is lower. However, this does not necessarily translate into less frequent disease. Instead, a combination of three factors discussed above, namely the association of risk of hepatitis A with hygiene and sanitation, the higher likelihood of disease and mortality following infection at older age, and the induction of lifelong immunity following HAV infection, results in different epidemiologic patterns of hepatitis A around the world (Fig. 2) .
High endemicity pattern
In low-resource areas with poor sanitation (most of Africa and parts of Asia, South America, and Eastern Europe), rates of transmission of HAV are very high. Nearly everyone gets infected in early childhood, the age at which infection hardly causes clinical hepatitis A. Furthermore, such infection leads to universal protection against HAV subsequently in life. Thus, in these areas, despite frequent circulation of the virus, hepatitis A disease is infrequent and does not pose a public health problem.
Low endemicity pattern
By contrast, in resource-rich countries (North America, Western Europe, Australia, Japan, etc.), because of good sanitation and hygienic conditions, there is little circulation of HAV. This also implies that a fair-to-large proportion of people in all age groups lack anti-HAV antibodies. Therefore, any introduction of HAV in the population, although infrequent, can trigger serial waves of transmission of HAV. These outbreaks are often common-source, for example, through importation of contaminated foods, with extended person-to-person transmission, and preferentially affect adolescents and young adults.
Intermediate endemicity pattern
In areas with intermediate socioeconomic conditions, HAV circulates at a fairly high rate although lower than that in high-endemicity areas. This circulation, in combination with presence of a fair number of susceptible older children and young adults in the population, leads to a high incidence of clinical disease. This results in large outbreaks, related either to person-to-person transmission or to common-source contamination of food or water.
A classification of HAV endemicity has been proposed based on seroprevalence rates: high (≥90% seropositivity by age 10 years); intermediate (≥90% by 15 years, with <50% by 10 years); low (≥50% by 30 years, with <50% by 15 years); and very low (<50% by age 30 years) . More recently, it has been proposed that such classification can be based on ‘age at midpoint of population susceptibility’, that is, median age at seroconversion or age at which 50% seroprevalence is reached as: very high (<5 years), high (5–14 years), intermediate (15–34 years), and low (≥35 years) .
EPIDEMIOLOGIC TRANSITION AND ITS CONSEQUENCES
Socioeconomic development in a resource-poor population, through improved hygiene, may lead to transition from high-endemicity pattern to intermediate-endemicity pattern, a phenomenon known as ‘epidemiologic transition’. This is associated with a paradoxical increase in the incidence of disease, hospitalizations and mortality due to hepatitis A, despite a reduction in HAV transmission rate.
A systematic review of hepatitis A epidemiology , as a part of the Global Burden of Disease Study, revealed that the median age at seroconversion had increased between the years 1990 and 2005 in many parts of the world. In particular, several countries in South America, northern Africa, and western Asia experienced a shift from very high or high endemicity pattern to the intermediate pattern (Fig. 3a and b) . This was accompanied by increased rates of hepatitis A disease, and of fulminant liver failure and liver transplantation secondary to HAV infection in several countries, such as Argentina [34,35], Brazil , and Korea .
For the current review, we extrapolated the data on age-related seroprevalence rates from that study to 2015, assuming that the annual rate of change in these rates in various regions had remained unchanged (Fig. 3c). Although, admittedly, such extrapolation has inherent limitations, it shows that several other countries in the northern part of South America, Central America, and Asia can now be expected to have crossed the threshold between high and intermediate endemicity. Also, with continued decline in virus circulation, China can now be expected to have moved further on to a low-endemicity pattern.
Recent serological data from several other countries, such as Iran [38▪], Jordan , Nicaragua [40▪], and regions, including the Middle East and northern African countries [41▪] and western Africa , have shown a reduction in seroprevalence rates. However, disease surveillance data in these areas are too limited to determine the clinical consequences of changed epidemiology.
In addition to the decline in HAV infection rates, heterogeneity within a population also has an important role in determining disease epidemiology. It leads to simultaneous existence of subgroups with different endemicity patterns, due to differences in socioeconomic status, family size, and hygienic practices [43,44▪▪,45▪]. Contacts between members of such subpopulations, one with low infection rate and thus high disease susceptibility among older people and the other with a high rate of virus circulation among young members, is likely to lead to clinical cases in the former. Thus, when the epidemiologic transition begins, the increased morbidity and mortality because of hepatitis A may be paradoxically more prominent among the hygiene-conscious, economically advantaged subgroups.
Heterogeneity may also explain findings in countries such as India, where cases and outbreaks of hepatitis A have been recorded in some geographical areas in recent years [46,47], whereas seroepidemiologic studies in other parts continue to show a high-endemicity pattern .
Both active and passive immunoprophylaxis are available. Serum immune globulin is effective for both preexposure and postexposure prophylaxis. However, as HAV vaccines are equally effective , provide longer-term protection and are cheaper, these have replaced passive prophylaxis, except in individuals in whom the response to vaccine is likely to be suboptimal e.g. in immunosuppressed persons.
Both formalin-inactivated and live-attenuated HAV vaccines are available. Both types of vaccines are very safe and highly immunogenic. Traditionally, two doses with an interval of 6–12 months are recommended, beginning after 12 months of age to avoid interference by passively acquired maternal antibodies. The vaccines have a protective efficacy of nearly 95%. In low-endemicity countries, such as Australia, Israel, Italy, and Spain, universal childhood administration of these vaccines was associated with a major reduction in the incidence of hepatitis A [50–52], not only among those immunized but also in older cohorts, through improved herd immunity. The vaccine-induced protection has been shown to last for at least 10 years; modeling studies suggest that it may extend beyond 30 years or even lifelong [53,54▪▪].
Several observations suggest that only one vaccine dose may offer sufficient protection. These include appearance of high antibody titres within 2–4 weeks of the first vaccine dose, prolonged persistence of antibodies among European travelers who had received only one vaccine dose, and a high protective efficacy of a one-dose schedule in a trial in Nicaragua . Based on these, Argentina, faced with an increasing incidence of hepatitis A due to epidemiologic transition, began universal immunization of 12-month-old children with a single dose of inactivated HAV vaccine in 2005, achieving a high vaccination coverage of more than 95%. This led to a quick and marked reduction in the incidence rates of symptomatic hepatitis A, fulminant hepatitis, and liver transplantation [56,57]. A recent, more detailed analysis showed a reduction of 88.1% in the incidence of hepatitis A in all age groups and across various geographical subregions of Argentina; no fulminant disease or liver transplantation due to HAV infection was recorded over 6 years since March 2007 [58▪▪]. Furthermore, an economic analysis of the Argentine program showed that savings in medical and nonmedical costs exceeded the expenditure on immunization [59▪▪].
This success has led the World Health Organization to recommend integration of HAV vaccine into the national immunization schedule for children aged at least 1 year based on change in endemicity from high to intermediate, incidence of hepatitis A disease, and cost-effectiveness calculations . This implies that resource-poor countries should carefully track the epidemiology of HAV infection in their countries (as a whole and in subregions) using periodic age-specific serosurveys and surveillance systems capturing incidence rates of acute hepatitis A, and hepatitis A related fulminant hepatic failure, and cause of liver transplantation.
Introduction of a hepatitis A vaccine in resource-poor populations is however a tricky issue, as the resultant reduction in HAV transmission is a double-edged sword. Whereas it may reduce the risk of disease by reducing the risk of HAV infection, it also has the potential to push up the average age at which HAV infection occurs, thereby increasing the risk of disease. Thus, introduction of vaccination with low coverage rate in a high-endemicity area would change the epidemiology to the intermediate-endemicity pattern – an undesirable outcome. In contrast, vaccination with a high rate of coverage in an intermediate-endemicity area would result in a low-endemicity pattern – a desirable goal. Such issues can be resolved through the use of mathematical tools such as modeling of disease transmission and economic analyses, which allow better understanding of the epidemiologic situation and assessment of the impact of various possible immunization strategies [60–62]. In a review of studies on cost-effectiveness of hepatitis A vaccination in middle-income countries, vaccine price, medical costs, disease incidence and discount rate were found to be the most important determinants of cost-effectiveness; of these, disease incidence and medical costs are most likely to vary between countries.
In this context, it is important to note that the Argentine HAV vaccination program that aborted the burden of hepatitis A had a high and sustained nationwide vaccine coverage rate (96.8% over a 5-year period) [58▪▪] and began when ‘epidemiologic transition’ was already underway. The results may not have been as favorable if the vaccination coverage had been lower, or if the epidemiological situation had been different.
Epidemiology of hepatitis A in resource-poor settings is changing with improvement in socioeconomic and hygienic conditions. This epidemiologic transition has led to hepatitis A becoming a public health problem in some countries, a phenomenon that is likely to occur in future in other countries too. This problem can be dealt with by using universal childhood HAV vaccination, as exemplified by the experience in Argentina. However, such interventions need to be timed properly. This can be done by a careful watch on the disease epidemiology using periodic seroepidemiologic surveys and disease surveillance, and through the use of disease modelling and cost-effectiveness analyses. Furthermore, a high vaccine coverage is critical. With careful application of these principles, it should be possible for the public health community to replicate the Argentine success in other resource-poor countries.
The authors thank Mr A.N. Sarangi, Biomedical Informatics Center, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India for his assistance withFig. 3.
Financial support and sponsorship
No financial support was received from any source for this work.
Conflicts of interest
There are no conflicts of interest.
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