|Year : 2016 | Volume
| Issue : 2 | Page : 75-80
Changing seroepidemiology of hepatitis A infection and its prevention in endemic regions
Anup Kumar Das
Department of Medicine, Assam Medical College, Dibrugarh, Assam, India
|Date of Web Publication||14-Apr-2016|
Anup Kumar Das
Department of Medicine, Assam Medical College, Dibrugarh - 786 002, Assam
Source of Support: None, Conflict of Interest: None
Hepatitis A is the most common cause of acute viral hepatitis worldwide although a preventive vaccine is available. Infection generally confers life-long immunity. It causes severe, often fatal, disease in adults, especially in those with underlying liver dysfunction, but is mostly asymptomatic in children. Endemicity is determined by anti-hepatitis A seroprevalence in different regions of the world. Hence, industrialized nations fall under hypoendemic category, but tropical, Asian, or African countries are hyperendemic. Hyperendemic countries have an adult population who develop immunity to hepatitis A as they are usually infected in childhood due to poor sanitation, in contrast to developed nations where adults remain susceptible. Vaccination strategies differ across the world depending on the endemicity. Usually, universal vaccination is still not advocated in endemic developing countries, unlike in USA or Europe. However, data are emerging from developing nations such as India where more adults are probably becoming susceptible to hepatitis A due to improving economy, better sanitation, and personal hygiene. Hence, the global seroepidemiology of hepatitis A is changing in many developing nations giving rise to unique nonimmune adolescent and adult populations emerging in endemic regions, thereby conferring a risk of developing severe hepatitis A. Abstracts, articles, and cross references were examined in search engines including PubMed and chapters from standard textbooks and monographs. This narrative review of some relevant recent information on this shifting seroepidemiology in endemic areas discusses changes in national and regional vaccination strategies with public health implications.
Keywords: Hepatitis A, seroepidemiology, seroprevalence, vaccine
|How to cite this article:|
Das AK. Changing seroepidemiology of hepatitis A infection and its prevention in endemic regions. Int J Health Allied Sci 2016;5:75-80
|How to cite this URL:|
Das AK. Changing seroepidemiology of hepatitis A infection and its prevention in endemic regions. Int J Health Allied Sci [serial online] 2016 [cited 2020 Jan 18];5:75-80. Available from: http://www.ijhas.in/text.asp?2016/5/2/75/180427
| Introduction|| |
Hepatitis A virus (HAV) is a small nonenveloped, single-stranded RNA virus (a member of the hepatovirus genus of the family Picornaviridae) and is the most common cause of acute viral hepatitis worldwide. It is thermostable and acid resistant. HAV is acquired by the fecal-oral route and person-to-person contact and classically causes an enterically transmitted disease. After infection, it replicates in hepatocytes and incites immune-mediated hepatitis. Following entry into the liver, viral RNA is uncoated, and host ribosomes bind to form polysomes. Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase. Then, the assembled virus particles are shed into the biliary tree and excreted through feces.
Destruction of infected hepatocytes and hepatocellular damage is mediated by human leukocyte antigen-restricted, HAV-specific CD8+ T-lymphocytes, and natural killer cells. Mortalities and morbidities increase with advancing age and in patients with chronic hepatitis C , while in children below age 5, it is mostly asymptomatic.
In the USA, the direct medical cost has been reported $2800 and $700 for hospitalized and nonhospitalized cases of HAV infection, respectively, and a loss of $2600 in wages by each infected adult. Hence, it has additional health-economic implications apart from being a common disease.
While compiling this narrative review, different search engines, textbooks, printed articles, and monographs were examined to get basic comprehensive information on the topic. PubMed and other search engines were searched. A total of 104 articles, abstracts, chapters, and monographs were examined which were published in the last 20 years.
| Epidemiological Considerations and Factors Influencing it|| |
Globally, the HAV prevalence in the population is directly related to the improved socioeconomic and sanitation levels worldwide; data indicate that HAV seroprevalence is proportional to the age of infected population. The younger the infected population, more endemic is the disease in that region or country. However, it shows a wide geographical variation, even in the same country including hyperendemic countries such as India.
The seroepidemiology of hepatitis A has been described based on the distribution of anti-HAV IgG, IgM, and total anti-HAV antibodies, either singly or in combination across the age groups in a given population. Areas of the world can be characterized as having high, intermediate, and low endemicity, also sometimes referred to as Type A, B, and C seroprevalence patterns, respectively. Developed countries such as Australia, North America, Western Europe, and Japan have good sanitation and hygienic conditions, and therefore, the infection rates in children are usually low. Hence, in less-developed countries such as Africa, Asia, and Central and South America with very poor sanitary and hygienic conditions, HAV infection is highly endemic. In these countries, most persons acquire HAV infection in early childhood. This is due to the fact that children in these regions have less hygienic behavior compared to adults, and the infection generally remains clinically inapparent in more than 50% cases. The reported rates of the disease in these areas are also relatively low in contrast to developed countries where reporting of cases is good. In underdeveloped countries, outbreaks are uncommon because asymptomatic HAV infections acquired during childhood confer immunity in the adult population which is not the case in developed countries. Hence, outbreaks in the latter are usually well identified, reported, and recorded.
Several factors are responsible for the propagation of the virus among young children in endemic or hyperendemic countries. They include household crowding, lower social background, poor levels of sanitation, and inadequate/unsafe water supplies.,, There are differences in seroprevalence between urban and rural settings also (in the same country, endemicity is high), being lower in school children residing in urban areas, which is a contributing factor to local pockets with variable seroprevalence pattern. The significant increase in the seroprevalence with older age and lower social class is exemplified in a study in which 296 Egyptian children aged 2.5–18 years of different social classes were tested to evaluate whether to give HAV vaccine early in life or to leave these children to acquire natural immunity. Overall, 61.4% of them were seropositive, and anti-HAV was detected in 27.3% of high and 81% of low social class children aged <6 years. A comparatively high HAV seroprevalence also exists among children with noneducated parents too, reflecting the relationship of the disease to low social background. Reports from Brazil, Argentina, Venezuela, and Mexico, all endemic for HAV, also showed that HAV seroprevalence is significantly lower in people living in medium and high socioeconomic conditions.,
| The Changing Patterns of Hepatitis a Virus Seroepidemiology|| |
In many Asian countries, HAV infection is still highly endemic. Studies from Pakistan in the 1980s, 1990s, and 2000s indicate that more than half of preschool children acquire immunity and almost all adolescents and adults are immune. Between the 1980s and 1990s in Nepal, nearly all adolescents were immune by age 15. In Bangladesh, more than half of 5 years olds and nearly all adolescents and adults are immune.
In hypoendemic countries, sporadic outbreaks occur abruptly affecting a large population usually due to introduction of infection from outside the country,,, mostly by person-to-person contact. This type of outbreaks is difficult to contain. A cyclical pattern of disease is observed in some countries classified as having intermediate endemicity such as Mauritius and Thailand, which are going through a transition phase into improving economy. It is also characterized by sporadic outbreaks of symptomatic disease in an older population.
These cyclical outbreaks generally result in high HAV seroprevalence in the affected population following these outbreaks often with considerable morbidity or mortality, but very low seroprevalence in those who are born after the outbreaks are over. HAV is then transmitted in these community-wide outbreaks until the region is exhausted of susceptible persons, after which there is a lapse of several years until a new cohort of susceptible children reaches the age when clinical disease is more frequent.,
In spite of a changing pattern of epidemiology of HAV seroprevalence in previously intermediate or hyperendemic areas with improvements in economic growth and sanitation, potential foci of source of HAV virus will still remain in some high-risk population. This group includes intravenous drug users, inmates of institutions, frequent international travelers, and homosexual males. The implication of an evolving epidemiological shift along with existence of foci of high-risk individuals may therefore translate into a transition from endemic subclinical transmission of infection (with high seroprevalence) to an epidemic pattern. A classical example is the Shanghai outbreak in adults. This sort of outbreak usually is frequently associated with more symptoms, morbidity, and mortality, and more importantly, in those with other associated chronic liver disease, irrespective of age., An analysis of HAV epidemiological data from Centers for Disease Control and Prevention (USA) during 1983–1988 estimated a case fatality rate of 11.7% in hepatitis B surface antigen carriers and 4.6% in those with other chronic liver disease. These rates were 58- and 23-fold higher, respectively, than for patients without preexisting liver disease. All these data emphasize the importance of recognizing any shifting of epidemiological disease pattern in endemic countries where adults with liver diseases in particular are supposed to be immune to the disease.
Therefore, instead of being content with a fixed notion of a strictly defined epidemiological HAV endemicity across the world, workers have begun to look if there has been a gradual shift in the age of acquiring the infection from early childhood to adulthood in different parts of the world over the last two decades. Recent studies in several South American countries, such as Argentina, Bolivia, Brazil, Venezuela, Chile, and Uruguay, revealed that there has been a shift from high to intermediate endemicity, with a decreasing prevalence of anti-HAV attributable to the improvements in public health programs and sanitary conditions., Similarly, in Taiwan, the prevalence has decreased markedly in the last several years. In the 1970s, the prevalence of anti-HAV in adults was >90% while subsequent studies showed that in Taipei, the prevalence was nearly 0% and in the rural areas, very few adolescents and young adults had anti-HAV.
In countries of intermediate endemicity such as Korea, Indonesia, Thailand, Sri Lanka, and Malaysia, the available literature indicates that the incidence is decreasing in urban areas, with the age at infection increasing from very childhood to late adolescence resulting in increased the risk of outbreaks, morbidity, and complications in younger population.,,
In older Iranian studies, the seroprevalence of HAV infection has been reported to be over 95%. Between 2006 and 2007, a cross-sectional population-based study from Tehran, Iran, in 551 subjects showed an overall seroprevalence rate of anti-HAV IgG of 90% and concluded that the seroprevalence of HAV still was too high for recommending routine vaccination in the general population. The seroprevalence was greater among men than women and increased with age. However, there was no significant relationship between age and gender.
Interestingly, during 2006 itself in another study, 1869 (18–65 years) subjects from the general population of three Iranian provinces (Tehran, Golestan, and Hormozgan) showed a seroprevalence of HAV being 85%, 99%, and 96%, respectively. The overall seroprevalence was 86% and did not differ between the two genders. The prevalence in younger subjects and urban populations was under 70%. In multivariate analysis, older age, being married, and level of the father's education were associated with seropositivity. The authors concluded that the trend pointed toward a lower prevalence in younger age groups and people from urban areas pointed toward the possible benefit of vaccination in these subgroups. These two studies done around the same time in a hyperendemic region illustrate the ground realities of variable endemicity in the same geographical area.
Viral hepatitis remains a major public health problem in India which is hyperendemic for HAV and 90–100% of the population becomes immune by adolescence. However, when it affects older children, it causes more complications  while infection in children below 5 years of age still remains mostly asymptomatic. It is reported that >75% of children above 6 years of age and young adults will have clinically significant disease., Another aspect, i.e., dual infection, of HEV and HAV (both enterically transmitted) in 13.4% of children and 4.4% of adults with acute viral hepatitis from India has been reported indicating that it may not be rare in adults., In developing countries, where hepatitis A and E infections are endemic, severe complications can arise in the case of mixed infection.
In India, which has undergone a very rapid socioeconomic development in the last years, many high endemicity pockets for HAV infection exist, making a transition to a moderately increased disease incidence akin to Western industrialized countries with coexistence of heterogeneous pockets of susceptible and exposed individuals in different regions and cities, mainly across different social classes.,, Even in highly endemic areas, the virus can survive due to its high physical stability as mentioned earlier. HAV can also exploit all known mechanisms of genetic variation to ensure survival, including mutation and genetic recombination. Further, the level and pace of development in developing nations may be uneven in the same country that may lead to infections in some pockets which can outpace that of the community as a whole. Over the last several years, several studies from India have reported an increase in acute HAV infections among older populations, confirming an epidemiological shift.,,,,
Hence, there may be a question whether or not India, like in some other countries, should be categorized as hyperendemic for HAV because of this evolution into a heterogeneous nature of endemicity over the last several years. This shift in age of infection will increase the proportion of cases with clinical disease with increasing case-fatality rate. The economic burden of annual medical costs to treat HAV cases worldwide is more than $3 billion if the annual number of cases globally is taken as 1.5 million, but there is agreement that this figure is possibly 10 times higher as many cases are under-reported in endemic countries as outbreaks are not common there.
Hence, a fresh look at prevention issues, especially vaccination in developing world, is required.
| Prevention of Hepatitis a Virus Infection|| |
The prevention and prophylaxis of HAV infection include good hygiene, clean water systems, avoidance of food contamination, vaccination, and immune globulin. Good hand washing practices, attention to proper food preparation, proper disposable of sanitary waste, provision of safe drinking water, food handling, and personal hygiene of food handlers are important measures to prevent infection, propagation, and outbreaks both in household and community levels. In addition, surveillance of water beds to prevent fecal contamination is also important, especially in those regions where shellfish are harvested. These measures which do not involve vaccination are critical in reducing disease transmission.
Recommendations for the use of the hepatitis A vaccine vary considerably among countries. Hepatitis A vaccine has been available since 1992, but initially questions remained about the durability of that vaccine-related protective immunity. A mathematical modeling suggests those who seroconvert to the vaccine will be protected for at least 20 years or even 25 years. A study of 306 persons vaccinated in 1996 with three doses of the combined HAV and hepatitis B virus vaccine demonstrated that all had anti-HAV titers >15 mIU/ml 15 years later. Postvaccination testing for antibody titer is not indicated as the response is good and no commercial kits are available for the same. The booster dose seems to induce an anamnestic antibody response; hence, some argue that even if the absolute antibody titer falls below protective levels in future after completed vaccination with seroconversion, still protection may continue in them. There are experimental data to suggest this. Additional studies are needed to establish the role of booster dose in long-term prophylaxis.
The inactivated vaccine is highly immunogenic although seroconversion rate varies with the dose and schedule and also the age of the individual vaccinated. Its safety in pregnancy has not been established and is contraindicated in the presence of allergy or hypersensitivity. On an average, 95–100% will develop adequate protective antibodies, whose absolute lower limit is still to be determined. A booster after 6–8 months later increases the antibody response, but final antibody concentration is never equal to that acquired by natural infection, being 10–100-fold less. The booster dose probably gives a long-term protection in healthy population. In those with chronic liver disease who need vaccination, the seroprotection rates equal that found in healthy adults, but final antibody titer seems to be comparatively lower. Those who are >40 years old also show a similar pattern. HIV infection leads to reduced immunogenicity as also the presence of passively transferred maternal antibody to infants born whose mothers were previously infected with HAV.
Out of a total of 11 countries that have implemented universal immunization, studies from some, for example, Israel, Italy (Puglia), Spain (Catalonia), and the United States, have demonstrated a reduction of up to 90% reduction in the incidence of hepatitis A. The data for the United States, where HAV became reportable from 1966, are particularly striking, reporting ~ 66% decreased hospitalization and markedly lower medical expenses between 1996 and 2004. Targeted policies, especially for healthy travelers, have also been shown to be effective and are adopted by several countries and vaccination is included as postexposure prophylaxis of contacts. Immune serum globulin (ISG) at a dose of 0.02 ml/kg is used for passive prophylaxis in susceptible travelers although rarely it may fail to protect. Concomitant administration with ISG leads to a lower antibody level compared to receiving the vaccine alone although not clinically significant. A single-dose HAV vaccine may be equally or more effective than ISG for immunoprophylaxis in healthy travelers to endemic regions. ISG will be appropriate if the person is allergic to HAV vaccine and affords protection for 3–5 months depending on dose (0.02 ml/kg or 0.06 ml/kg).
For postexposure prophylaxis of household contacts, the Advisory Committee on Immunization Policies has however continued to recommend that ISG (within 14 days of exposure) should be reserved for those < 1 or > 40 year age, immune-deficient, or with chronic liver disease while active vaccination should be used in healthy contacts between 1 and 40 years of age. A live attenuated vaccine based on H2 strain has been used in China extensively and also tested in India and has shown good immunogenicity, with negligible side effects.
| Issues in Global Vaccination Strategies|| |
The efficacy and usefulness of universal active HAV vaccination of all newborn children are confirmed by data from the USA in the mid-90's when the number of acute HAV drastically came down in the few years after implementation of the program. This implies that HAV vaccines do have health benefits and indirectly also confers a substantial economic benefit by cutting down on the medical cost of treatment as mentioned earlier. However, vaccination policies range from being part of national universal immunization programs for children to targeting at-risk groups across the world. Several factors govern the impact of effective vaccination in the population, most important being the epidemiological pattern, sanitation, and hygiene. It is to be noted that international travel and food-related exposures remain two of the most frequent causes of HAV infection, especially in industrialized countries. In the changing global scenario, these cannot remain static, especially in developing countries, although the recommendations for the use of the hepatitis A vaccine vary considerably among countries. More data should be generated to define pockets of declining HAV seropositivity in endemic regions so that policies to identify high-risk population can be undertaken with resultant targeted intervention to reduce disease outbreaks and mortality. Experience in this aspect is insufficient at present. Case reporting should be streamlined to specially focus on identifying geographical areas with consistently high disease rates. In these areas, routine vaccination for children can be considered. With increasing number of various chronic liver disease cases in developing world including India, screening them for vaccination may be justified. These measures will be important in countries such as India or China which are undergoing a transition in HAV epidemiology with an increasing, older, vulnerable population. Cost-effectiveness of vaccination is a core consideration in these countries to assist national policy making and prevention programs as well as their sustainability. In some middle-income countries, studies have confirmed that it is cost-effective or even cost-saving under certain conditions. Therefore, the most influential parameters are vaccine price, medical costs, incidence, and discount rate on sensitivity analyses. Still, however, taking the present vaccine cost into account, in countries such as India, if the reported/estimated prevalence of HAV antibody in a particular age group and region is > 50%, it is better to screen the individuals before recommending vaccination. However, if the probability of an individual having been exposed to HAV is < 50%, suggesting “very low” endemicity, vaccination may be offered without antibody screening. More of such cost–benefit studies need to be done. Since universal vaccination in resource-limited countries may not be cost-effective, single-dose vaccination of vulnerable high-risk population following targeted screening may be an alternative but practical option, given the huge economic burden of treating HAV infection worldwide. Present data are insufficient to show a consistent decline in childhood HAV seroprevalence rates and increased susceptibility to HAV in young adults in Asian countries. However, HAV will continue to challenge us with disease burden and health care expenses in future. Seroprevalence studies with proper data monitoring should be emphasized, streamlined, and an ongoing process.
| Conclusion|| |
Seroprevalence surveillance for changes in national as well as regional disease burden should continue in developing countries, concentrating on the factors which modify it. Monitoring high-risk population/regions will help generate information on clusters of susceptible adolescents and adults. Relevant guidelines can then be formulated for targeted vaccination of these susceptible groups after their appropriate characterization.
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