Increasing Burden of Hepatitis A in Adolescents and Adults and the Need for Long-Term Protection: A Review from the Indian Subcontinent

Hepatitis A virus (HAV) accounts for most acute viral hepatitis (AVH) globally, with around 1.5 million clinical cases each year and a rate of infection likely to be ten times higher because of underreporting [1]. The Global Burden of Disease study estimated that acute hepatitis A infections increased by 4.2% between 2005 and 2015 (from 109.6 to 114.2 million cases) [2].

Hepatitis A, an acute self-limiting inflammatory disease of the liver, is typically asymptomatic in children, while symptomatic infection including jaundice is common in adolescents and adults. Clinical disease can be severe, leading to acute liver failure [ALF, or fulminant hepatic failure (FHF)] and death in some cases, with severity strongly age-dependent [1, 3]. As affected individuals can take weeks or months to recover, there is an impact on ability to go to work or school and on quality of life, which can have important economic and social consequences in communities [4].

The incidence of hepatitis A is associated with socioeconomic status, sanitation and lack of access to safe drinking water [1, 5]. Low endemicity regions are high-income countries with good sanitation and hygienic conditions (infection rates are low, i.e., < 50% by age 30 years). Due to poor sanitary conditions and access to clean water, most of the population in developing countries is infected in early childhood (i.e., seroprevalence up to about 90% in children), classifying the regions as highly endemic [1, 6]. In some countries, like India, parts of the populations have recently undergone rapid socioeconomic development, which may have an impact on endemicity shift and the resulting burden of disease [1].

Many seroepidemiologic studies and reviews of hepatitis A exist up to the early 2000s; however, there is a lack of recent data to assess the endemicity level and its impact in older age groups. A fresh look at the up-to-date epidemiology of HAV in this older age group, including its complications, is warranted. This is to assess the potential shift in endemicity and increased risk of HAV infection and also the need for enhanced prevention strategies (e.g., vaccination) in the Indian subcontinent.

HAV and its Important Features

HAV is a nonenveloped single-stranded ribonucleic acid virus belonging to the genus Hepatovirus of the Picornaviridae family. A single HAV serotype exists. Thus, HAV infection in any part of the world results in protection from reinfection globally [7], and so does vaccination. [8].

Transmission is via close contact with an infected person, primarily via the fecal-oral route or ingestion of contaminated food or water [9]. The virus can survive in contaminated media for months as it remains stable and is resistant to acid, heat (60 °C for 60 min) and freezing environments [8, 10].

Following oral ingestion, the virus may enter the gut mucosa and replicate in intestinal cells, after which it reaches the liver via the portal blood. Here, viral replication occurs in hepatocytes; viral progeny is released into bile where it reaches the intestines and is shed in feces, weeks before the onset of symptoms. The mechanism of hepatocyte injury is thought to be immune mediated [1, 8, 9]. The average incubation period is around 30 days (range 15–50 days), with signs and symptoms appearing within 3–5 weeks of exposure [8, 10]. HAV viremia is followed by shedding in feces, increases in serum alanine aminotransferase level, a short-term increase in immunoglobulin (Ig) M antibody level and a gradual long-term increase in IgG antibody response (Fig. 2) [10].

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A comprehensive literature review was conducted to identify studies on the seroepidemiology and burden of hepatitis A in the Indian subcontinent countries (India, Bangladesh, Nepal, Pakistan, Sri Lanka, Bhutan and Maldives). PubMed and Embase databases and the Cochrane Library were searched in April 2019. Search terms were combined to identify (1) seroprevalence of hepatitis A, (2) outbreaks of hepatitis A and (3) burden (complications, hospitalization, mortality and costs) of acute liver failure. The following keywords were used in PubMed: ((((((((((“complications” [Subheading]) OR “Hospitalization”[Mesh]) OR “Mortality”[Mesh]) OR “Economics”[Mesh]) OR “Cost of Illness”[Mesh])) AND “Liver Failure, Acute”[Mesh])) OR ((seroprevalence) AND ((((“Seroepidemiologic Studies”[Mesh]) OR “Global Burden of Disease”[Mesh]) OR “Disease Outbreaks”[Mesh]) OR “Epidemiology”[Mesh]))) AND ((“Hepatitis”[Mesh]) OR “Hepatitis A”[Mesh])) AND (((((((“India”[Mesh]) OR “Bangladesh”[Mesh]) OR “Nepal”[Mesh]) OR “Pakistan”[Mesh]) OR “Sri Lanka”[Mesh]) OR “Bhutan”[Mesh]) OR “Maldives”[Mesh]).

The search identified 335 publications. Titles and abstracts were screened for studies with data on hepatitis A in adolescents and adults on the outcomes of interest above. Reviews and vaccination studies were excluded. Publications from 2005 onwards were included. This cutoff was selected to provide an update of the large amount of data available up to the early 2000s and because recent epidemiologic data are more relevant to healthcare policy and decision-making. Full-text articles selected during screening were reviewed, and reference lists were hand-searched for additional publications of interest. There were 38 publications included in this review: 19 on seroprevalence, 10 on outbreaks, 10 on clinical burden and 1 on economic burden.

This review article intended to document the current status of hepatitis A epidemiology in the Indian subcontinent. The review of the epidemiology studies identified suggested a changing trend in endemicity, with more susceptible adolescents/adults than previously seen in these countries [1, 9]. As a result, higher HAV infection rates were observed in these age groups and more outbreaks than in the past (although outbreak reporting could be the result of better surveillance). The first AVH outbreak due to HAV was seen in Kerala in 2004, while previous outbreaks were due to HEV infection [40]. Another study in South India reported that HAV was responsible for more AVH than HEV among young adults [20]. It was a significant cause of AVH predominantly in young people in Pakistan [27] and in India [15, 16, 17, 18, 20]. An increasing trend of HAV infection rates between 1999 and 2003 in both adolescent and adults in India suggests fewer children were naturally infected than before [11]. Economic progress and improvements in water supply and sanitation were likely reasons for the decrease in HAV exposure seen in some groups such as those with higher SES or living in urban areas [12, 19, 21, 25, 26]. Only two studies found levels of natural infection (and thus protection) remained high by adolescence. One was in Bangladesh, although the authors identified significant differences between urban and rural and between high and low SES groups’ seroprevalence during childhood, suggesting changes beginning in some groups [25]. The other was a study in military trainees in India where most subjects (79%) were from rural areas [22]. In other studies comparing urban and rural seroprevalence, significantly higher exposure was found in rural areas [19, 25, 26]. Therefore, there appears to be growing pockets of susceptible populations who are potentially at high risk of infection and frequent outbreaks from the rural populations where hepatitis A is still highly endemic.

Furthermore, the literature makes evident that the older age groups could present with more hepatomegaly [18, 32, 33], splenomegaly [18, 30, 33] and acute renal injury [35]. The recovery time in most cases without complications was 4–10 weeks and for acute liver failure 16 weeks [11] with extended hospital stays [32]. Deaths have been reported in young adults with HAV-induced AVH [11, 35] as well as in outbreaks [4, 40]. HAV-induced ACLF was also associated with high mortality [37].

This review provides a much needed update to document the changing situation in the Indian subcontinent and to inform policy-makers about the increasing evidence that a shift in HAV endemicity is taking place in different subgroups, particularly among high SES urban populations. In 2005, Argentina was transitioning from high to intermediate endemicity, resulting in an increase in the hepatitis A burden of disease. Universal childhood vaccination was introduced, achieving high and sustained coverage. As a result, the incidence of hepatitis A decreased by nearly 90% in all age groups with no cases of FHF or liver transplants recorded up to 6 years later. The vaccination program was found to be cost-effective with one dose of inactivated vaccine. Subsequently, the World Health Organization recommended HAV universal mass vaccination (UMV) in countries where endemicity was shifting from high to intermediate levels, following epidemiology and cost-effectiveness considerations [8]. Very few countries have implemented UMV to date; however, individual protection through targeting at-risk persons is an effective interim alternative. While cost is perceived as a barrier to vaccination, the economic burden of hepatitis A to a household in India was significant at nearly 25,000 rupees due to out-of-pocket payments for medical care as well as lost wages and caregiver expenses [46].

This review has highlighted the recent changes in the hepatitis A epidemiology and burden of disease in the Indian subcontinent, with a shift in epidemiology, especially in particular pockets of the population, leading to more serious hepatitis A cases in susceptible adolescents and adults. This new situation renders vaccination of individuals belonging to these groups of the population even more important than before. Further sanitation, and eventually, universal hepatitis A vaccination introduction, will contribute to lowering the burden of hepatitis A disease by protecting more patients in the Indian subcontinent.