Seroprevalence and Shifting Endemicities of Hepatitis A Virus Infection in Two Different Geographical Areas in the Philippines

Hepatitis A is an infectious disease caused by the hepatitis A virus (HAV), which is an RNA virus belonging to the picornavirus family, and infects primarily humans as its only natural host [1]. HAV is transmitted primarily by the fecal-oral route, through either close contact with infected individuals or ingestion of contaminated food and water. Infected individuals may develop symptoms of hepatitis, including fever, malaise, abdominal discomfort, diarrhea, loss of appetite, dark-colored urine and jaundice [2, 3]. While young children often remain asymptomatic, most older children and adults will develop symptoms [2, 4, 5]. HAV infection does not cause chronic liver disease; however, in rare cases, acute liver failure occurs, and a small proportion of patients die from fulminant hepatitis [6]. Risk factors for severe disease are older age (> 40 years) and pre-existing liver conditions [6]. Case fatality rate increases from 0.1% in children < 15 years of age to 1.8–5.4% in individuals ≥ 50 years old [2].

The global burden of hepatitis A disease was estimated at 159 million acute infections and 39,000 deaths in 2019 [5, 7]. The highest burden was observed in low- to middle-income countries, in particular in Southeast Asia, where 42 million acute hepatitis A cases and 24,000 deaths were reported, corresponding to 60% of deaths worldwide [5].

HAV survives several weeks outside of its host and is highly resistant to environmental conditions [5]. Contaminated drinking water or food processed under non-hygienic conditions represents a common source of infection. After HAV infection, people develop virus-specific antibodies that confer life-long immunity. The presence of HAV-specific immunoglobulin G (IgG) antibodies can be easily measured, and age-specific seroprevalence is used to categorize regions into endemicity levels [8]. The latter have been defined by the World Health Organization (WHO) as high: ≥ 90% seroprevalence by the age of 10 years; intermediate: ≥ 50% seroprevalence by the age of 15 years; low: ≥ 50% seroprevalence by the age of 30 years, respectively [5].

Due to improved sanitation and access to clean drinking water, hepatitis A infection in children has decreased worldwide, including in Southeast Asia, leading to an epidemiologic shift from high to intermediate or low endemicity [9‐11]. Therefore, the proportion of adolescents and adults susceptible to HAV infection increases in regions with intermediate to low endemicity [8, 9, 11‐13]. The downside of this trend is increased morbidity and mortality due to a more severe disease course in older age groups [14]. For example, in the US, incidence of HAV infection declined between 1999 to 2011 from 6.0/100,000 people to 0.4/100,000 people [15]. At the same time, mean age at HAV infection increased from 36.0 to 45.1 years, and the proportion of people being hospitalized increased from 7.3 to 24.5%. These numbers emphasize the risk of hepatitis A outbreaks in intermediate/low endemicity regions and the need for specific vaccination strategies considering local endemicity and risk factors [16].

Tailoring preventive strategies against HAV infection requires current knowledge of region-specific endemicity levels and risk factors for HAV infection. In the Philippines, surveillance of hepatitis A disease is not mandatory, and seroprevalence data are scarce [12]. A seroprevalence study carried out in 1996 in Metro Manila showed that 42% of inhabitants were seropositive before the age of 15 years, and ≥ 50% were seropositive before the age of 20 years, corresponding to an intermediate-endemicity status [17]. This pattern has likely changed in the last 2 decades, similar to shifts reported in other countries of the Southeast Asian region [10‐12].

The objective of this study was to assess age-specific HAV seroprevalence in the Philippines in two distinct geographic regions and to identify associations between sociodemographic parameters and HAV seroprevalence.

This was a cross-sectional, observational study to determine age-specific HAV IgG seroprevalence in inhabitants of the Philippines. The primary objective was to determine age-specific prevalence of HAV infection. Other objectives were to calculate the age at midpoint of population immunity (AMPI), i.e., the age at which 50% of the population has been infected with HAV. A secondary objective was to evaluate the association with known risk factors with HAV infection.

Two distinct geographic areas were selected, one rural and one urban, to obtain a representative estimate of the national seroprevalence.

Lumban municipality in the province of Laguna was selected as the rural site. Subjects were recruited from 14 Barangays. Age-stratified enrollment was coordinated by study staff and community health officers responsible for the area.

For the urban area, mass invitations were sent via a single institution, the UERM Memorial Medical Center located in Quezon City, which serves several cities and municipalities in Metro Manila and the Greater Manila area. A full list of cities considered by the recruitment process is provided in Supplementary information (SI) Table S1. To enhance recruiting into pre-specified age groups and increase the distribution of participants, community officials assisted in the recruitment process by inviting community members to participate in the study.

The study was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Health-related Research Involving Humans, Council for International Organizations of Medical Sciences. The protocol and related documents were approved by the UERMMMCI Ethics Review Committee, and the protocol was registered in the Philippines Health Research Registry (PHRR211106-004046) [18].

Overall, 1242 participants were included in the analysis, 602 participants from urban areas and 640 from rural regions.

Sociodemographic characteristics were significantly different between rural and urban populations in terms of education, years of schooling of the mother, profession, number of habitable rooms and building materials used on walls and floors (Table 1). Age and gender distribution were similar.

Components of the WAMI index were statistically significantly different between rural and urban populations (Table 2). Maximum score in water sanitation was observed for 99.5% of participants in urban areas compared with 90.8% in rural regions. The average number of household assets (i.e., refrigerator, bank account, iron, desktop/laptop, radio, sofa, sewing machine) was higher for participants living in cities compared to their rural counterparts. Maternal education and income were significantly lower in rural areas compared with city dwellers.

In 1996, the Philippines had intermediate HAV endemicity with more than half of people being seropositive at the age of 20 years [17]. Recent epidemiologic data on hepatitis A disease for the Philippines are lacking. Results from this study showed a shift in seroconversion towards older age groups (median age at conversion: 36 years), suggesting that the Philippines has transitioned to a low HAV endemicity level as observed in other Southeast Asian countries [10, 23].

Several East Asian countries have witnessed a shift in hepatitis A epidemiology to intermediate/low endemicity. In Thailand, AMPI increased from 4.5 years in 1971 to 42.0 years in 2014 [11]. Recent cross-sectional studies carried out in Laos, Indonesia, Vietnam and the Philippines also pointed towards an increase in age at seroconversion compared with earlier studies [23‐25].

In this study, age-specific seroprevalence showed a distinct pattern depending on geographic location: seroprevalence was lower in rural regions compared with urban areas in young age groups up to 19 years, but it was higher in older age groups. Rural to urban migration may have confounded age-specific seroprevalence by region and artificially increased seroprevalence rates in urban regions. Indeed, not living in the same region during the last 5 years significantly correlated with seroprevalence. Another explanation might be that urban children are more likely to receive vaccination and in turn be reactive for HAV IgG antibodies. However, due to the limited number of participants with confirmed vaccination status, this hypothesis could not be confirmed based on our study results. Importantly, both regions witnessed an increase in age at seroconversion, pinpointing the important sanitary improvements achieved in recent decades. A recent report showed that as of 2019, 91% of the Philippine population has access to basic sanitation services, up from 68% in 2000 [26]. The AMPI was similar in rural and urban regions (median age at conversion: 35 and 37 years, respectively), confirming the low endemicity status. Several sociodemographic factors and behaviors in hygiene and food preparation/consumption were associated with HAV seroprevalence.

Several studies have shown that hepatitis A endemicity correlated with socioeconomic factors, with high endemicity observed in developing countries and low endemicity in high-income countries [8, 12, 13, 27]. Socioeconomic status is linked to access to clean drinking water and sanitation, educational level and income. Besides age group, factors that statistically significantly correlated with seroprevalence in this study were educational level, disease knowledge, living in the same area for the last 5 years, vaccination status, street food consumption and hygienic factors (washing hands after defecation and improved pour/flush toilets). The impact of eating habits and observation of hygienic gestures corroborates the fecal-oral route of HAV transmission. HAV-contaminated food or water represents the main source of infection and may lead to hepatitis A outbreaks even in regions with low endemicity [28]. The increased seroprevalence observed in people who moved during the last 5 years is likely due to an increased risk of transmission for travelers to endemic regions [14, 29]. Educational level and disease knowledge are indicators of socioeconomic status, access to clean water and sanitation, and awareness of disease transmission. In this study, people with the lowest seroprevalence ratio had a graduate or postgraduate degree in agreement with other studies reporting lower seroprevalence in people with higher educational level [30‐32]. However, some factors appeared counterintuitive; for example, people knowing that hepatitis was a communicable disease had a higher prevalence ratio. This result suggests that disease knowledge is not sufficient to prevent infection but needs to be accompanied by supportive actions. Finally, vaccination status also correlated with HAV IgG positivity. Most people who received hepatitis A vaccines will have detectable HAV-specific IgG antibodies, even years after vaccination; therefore, seroprevalence is higher in the vaccinated population compared with unvaccinated individuals [5, 33].

In regions with low endemicity, a sizeable proportion of adolescents and adults remains susceptible to HAV infection, which may lead to hepatitis A outbreaks often linked to more severe disease and increased healthcare resource use [34, 35]. This situation leads to the so-called paradox of hepatitis A epidemiology where disease burden is higher in low endemicity regions [5, 14]. Hepatitis A is a vaccine-preventable disease; both inactivated and live attenuated vaccines exist, which are highly immunogenic and well tolerated [33]. Immunization strategies vary across countries from partial immunization programs in high-risk groups to universal childhood immunization [36]. Vaccination is not recommended in high-endemicity regions; however, in countries with intermediate to low endemicity, WHO recommends universal childhood immunization if there is (1) an increase of acute and/or severe hepatitis A cases, including adolescents and adults, (2) a shift in epidemiology from high to intermediate endemicity and (3) if cost-effectiveness analyses favor introduction of universal hepatitis A vaccination. While results from this study demonstrated a shift in endemicity in the Philippines, the study did not assess the incidence of acute cases and healthcare resource use due to hepatitis A disease. Future studies are required to monitor HAV-related healthcare resource use and hepatitis-related burden of disease. Such information may inform cost-effectiveness models to estimate the value of hepatitis A vaccination in the Philippine context. In Indonesia, which experienced a similar shift in hepatitis A epidemiology, cost-effectiveness analysis suggested that universal childhood hepatitis A immunization would be cost-effective [37].

There are several limitations to this study. Findings are based on an age-stratified convenience sample from two geographic regions, and this might limit generalizability to the entire Philippine population. People could refuse to participate in the study, and this could have led to selection bias. However, the implication of community health officers from different Barangay(s) in the enrollment of participants and the use of mass invitations in urban areas ensured inclusion of participants with diverse sociodemographic backgrounds. Networking and collaborations among governing medical institutions and regional health offices aimed at increasing diversity among enrolled subjects thereby improving generalizability of results.

Some questions asked for information that could be perceived as sensitive or embarrassing by of participants, such as income, eating habits and hygienic behavior. This may have led to response bias or measurement error since participants might be inclined to provide more socially acceptable answers [38]. Finally, documentation of vaccines received was often missing, and vaccination status might be underreported.

An epidemiologic shift has occurred in the Philippines towards low HAV endemicity. People tend to get infected later in life leaving a large proportion of adolescents and adults at risk of infection and potentially more severe disease. Risk factors for HAV infection include frequent traveling, consumption of street food and insufficient hygienic measures. Vaccination strategies against HAV should be considered early in life to prevent hepatitis A outbreaks and severe disease in high-risk groups.