Public health control of hepatitis A: memorandum from a WHO meeting.

Memoranda I Memorandums Public health control of hepatitis A: Memorandum from a WHO meeting* Hepatitis A virus infection is a significant cause of morbidity in many parts of the world, and hepatitis A vaccines will be important tools for its prevention and control. This Memorandum reviews the basic fea- tures of the disease and its epidemiology, and considers the measures which are available for control and prevention, including hepatitis A vaccine. The use of this vaccine should be adapted to specific epi- demiological circumstances existing within a geographical region, with special attention to the cost- effectiveness of immunization programmes. Although hepatitis A virus (HAV) infection is self- limited, with fulminant hepatitis and death occurring in only a small proportion of patients, it is a signifi- cant cause of morbidity-and consequently econo- mic losses-in many parts of the world. The virus is present globally, and rates of infection are inversely associated with levels of sanitation and personal hygiene. Improvements in sanitation and hygiene can reduce the transmission of HAV, but such improve- ments in countries with lower socioeconomic status result in an increase in the burden of clinical disease. This is because the peak rates of infection shift from early childhood, when infection is largely asympto- matic, to older age groups with symptomatic infec- * This Memorandum is based on the report of an Informal Consultation (unpublished document WHO/CDS/MIM/92.5) which was held in Geneva, Switzerland, on 5-6 October 1992. The participants at the meeting were Professor M.S. Balayan, Mos- cow, Russian Federation; Dr Supamit Chunsutiwat, Bangkok, Thailand; Professor B. Flehmig, Tiubingen, Germany; Dr A. Hall, London, England; Dr S.M. Lemon, Chapel Hill, NC, USA; Dr B. McMahon, Anchorage, AK, USA; Dr P. Ndumbe, Yaounde, Cameroon; Professor G. Papaevangelou, Athens, Greece (Chairman); Dr C. Shapiro, Atlanta, GA, USA; Professor A. Toukan, Amman, Jordan; and Dr Z.Y. Xu, Shanghai, People's Republic of China. WHO Secretariat Dr A.G. Andjaparidze, Dr R.B. Aylward, Dr D. Barakamfitiye, Dr J.C. Clements, Dr D. Fedson, Dr Y. Ghendon, Dr P. Gilbert-Miguet, Dr V.P. Gratchev, Dr M.A. Kane (Secretary), Dr P.-H. Lambert, Dr J. LeDuc, Dr D. Magrath, Dr N. Okabe, Dr F. Pinheiro, Mrs J. Rossel, Dr R.M. Scott, and Dr G. Torrigiani. Requests for reprints should be sent to Dr M. Kane, Global Programme for Vaccines and Immunization, World Health Orga- nization, 1211 Geneva 27, Switzerland. A French translation of this article will appear in a later issue of the Bulletin. Reprint No. 5562 tion. Passive immunoprophylaxis using immune globulin (IG) can prevent disease in individuals who are exposed to the virus; however, the protective effect is temporary, and IG is not effective in con- trolling hepatitis A on a population level. Within the past few years, several vaccines have been developed which provide active immunity and poten- tially long-lasting protection against hepatitis A. The development of these vaccines represents a major advance in the ability to control HAV infection and reduce the burden of disease. Clinical features and epidemiology The incubation period of hepatitis A, defined as the time between exposure to the virus and the onset of symptoms, averages 28 days (range, about 15 to 50 days). The acute infection ranges from an asympto- matic, anicteric infection to fulminant hepatitis and death. Early symptoms include fever, malaise, ano- rexia, nausea, diarrhoea, vomiting and right upper quadrant pain, which usually precede signs of liver damage such as jaundice and dark urine. Liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), rise and gen- erally peak about the time of onset of jaundice. The severity of the clinical illness is highly age-depen- dent; almost all children infected under age 2 do not develop specific signs or symptoms of hepatitis A, while most adults (>75%) over the age of 18 usually develop a characteristic illness with jaundice and dark urine. Infection is self-limited, and the duration of symptoms generally varies from two weeks to two months, although up to 15% of adults have symp- Bulletin of the World Health Organization, 1995, 73 (1): 15-20 © World Health Organization 1995 15 Memorandum toms for as long as 4 months. Mortality from hepati- tis A is rare and strongly age-related; fatal infections are more likely to occur in individuals aged over 40 years. Chronic hepatitis with persistence of HAV infection for more than 12 months has not been observed. Properties of hepatitis A virus Hepatitis A is caused by the hepatitis A virus (HAV), a non-enveloped, positive-stranded RNA virus classified within the genus hepatovirus of the picomavirus family. All human isolates of HAV, while having up to 20-25% variation in nucleic acid sequence, belong to one serotype. Epidemiological evidence in humans and studies in vitro and in vivo support the concept that anti-HAV antibodies in- duced by any isolate of the virus will protect against all viral strains. While HAV is inactivated by heat above 60-70 °C, it is resistant to drying for at least one month. It can readily survive freezing temperatures, and can persist in fresh or salt water for up to 12 months. The virus may remain infectious for several days or longer in contaminated food. HAV in fresh or salt water can be concentrated by molluscs, which can be an important source of infection in humans. Epidemiology In infected persons, HAV replicates in the liver and is excreted in large amounts in the stool. The only known site of replication is the liver. Substantial quantities of infectious virus circulate in the blood for up to 2 to 3 weeks, and it can also be found in saliva. In persons who develop clinically apparent hepatitis A, excretion of virus in stool at high titres begins two to three weeks prior to the onset of ill- ness, and may continue for several weeks in lower titres after jaundice occurs. The level of virus shed- ding does not correlate with the severity of liver disease. Some patients, especially infants, may inter- mittently excrete virus for up to six months in stool. The major route of transmission is faecal-oral. Person-to-person transmission commonly occurs be- tween family members and is also observed among children and staff in day care centres, and among persons in institutions. Nosocomial outbreaks of hepatitis A with transmission to health care workers have occurred but are rare. As HAV can survive for prolonged periods in the environment, contamination of water and food can result in common source out- breaks. Transmission due to transfusion of blood products does occur but is rare. Worldwide, geographical areas can be character- ized by HAV infection pattems of high, intermedi- ate and low endemicity. The level of endemicity correlates with the hygienic and sanitary conditions in each area (Table 1). Areas of high endemicity. HAV spreads readily in least developed countries with very poor sanitary and hygienic conditions, which include parts of Africa, Asia, and Central and South America. Most infected persons are young children, who are asymptomatic or do not show specific signs or symptoms of hepati- tis. Consequently, the reported disease rates in these areas are low and outbreaks of disease are rare. Areas of intermediate endemicity. Sanitary condi- tions are variable in developing countries, countries with transitional economies, and some regions of industrialized countries, and many children escape infection during early childhood. However, viral cir- culation remains high, and infection has often occur- red by adolescence or early adulthood. Since HAV infection often occurs in older age groups in these areas, compared with areas where HAV transmission is more highly endemic, the reported rates of clini- cally evident hepatitis A can be higher. Community- wide epidemics with extended person-to-person transmission account for a significant amount of disease in these areas. In certain populations, condi- tions are such that disease trends are cyclical. The virus spreads among children until the population is exhausted of susceptibles. After a period of several years, a new cohort of susceptible children emerges, allowing a return of high rates of viral transmission and clinical disease. Areas of low endemicity. In most industrialized countries, sanitation and hygienic conditions are good, and infection rates in children are generally low. However, community-wide outbreaks continue to occur in some countries, and contribute signifi- Table 1: Epidemiological features of hepatitis A virus infection worldwide HAV Usual age of Risk groups for endemicity infection clinical disease High <5 years Children Intermediate 5-15 years Many Low >20 years Contacts of cases, travellers, drug users, homosexually Outbreaks Rare Common: community-wide, foodborne, waterborne, shellfish Occasional: day-care centres, foodborne, waterborne, shellfish, active men community-wide WHO Bulletin OMS. Vol 73 199516 Public health control of hepatitis A cantly to the burden of disease. In some countries, day-care centres are also important settings for HAV transmission. Common-source epidemics due to con- taminated food or water also occur, but contribute less to the overall disease burden. In some countries with very low prevalence (e.g., in northern and west- ern Europe), the rates of HAV infection are very low in all age groups, and the disease tends to occur more commonly among specific risk groups, such as travel- lers, homosexually active males, and intravenous drug users. Recent investigations of the molecular epidemiology of HAV support these impressions gained from classical epidemiological studies. Preventive measures and prophylaxis General measures for hepatitis A prevention include hygienic and sanitary measures to prevent transmis- sion of any enteric illness. In household settings, good personal hygiene, including good hand-washing practices, and attention to proper food preparation are important in reducing the.risk of transmission. At the community level, provision of safe drinking- water and proper disposal of sanitary waste will reduce the incidence of hepatitis A. Good hand- washing practices and personal hygiene among food handlers, as well as good food-handling techniques, are important in preventing foodborne outbreaks of hepatitis A. Prevention of hepatitis A outbreaks associated with uncooked shellfish relies upon sur- veillance of water beds where shellfish are harvested to ensure that there is no evidence of faecal contami- nation, and control of the commercial distribution of shellfish from unsupervised areas. Immune globulin IG is a preparation of antibodies made from pooled human plasma using the Cohn-Oncley cold ethanol fractionation procedure or other techniques, and is administered intramuscularly to prevent hepatitis A. If given before exposure or within two weeks after exposure to the virus, IG is more than 85% effective in preventing symptomatic hepatitis A. Protection is conferred by passive transfer of anti-HAV antibody. In Japan and certain European countries, as the hepa- titis A incidence (and consequently the anti-HAV prevalence among plasma donors) has decreased over time, titres of anti-HAV in IG have also de- clined. In some European countries, specific high- titre anti-HAV IG is available for prevention of hepa- titis A. IG for intramuscular use made under good manufacturing practices with the Cohn-Oncley pro- cedure has never been shown to transmit hepatitis B virus (HBV), hepatitis C virus, HIV, or other blood- borne agents. Hepatitis A vaccines The isolation and propagation of HAV in cell culture were critical steps necessary for the successful devel- opment of hepatitis A vaccines. Several HAV iso- lates have been propagated in tissue culture and have been used to make both inactivated and attenuated vaccines. The use of any hepatitis A vaccine should be subject to approval by the appropriate national control authorities. (a) Live attenuated hepatitis A vaccines Several live attenuated hepatitis A vaccines are cur- rently under development and two are now licensed in China. Some investigators believe that attenuated vaccines may have substantial advantages over inac- tivated vaccines in that they may require smaller quantities of virus and only a single dose of vaccine, resulting in much lower costs, and possibly a longer duration of immunity. For these reasons, develop- ment of these vaccines should be encouraged. How- ever, several aspects of attenuated vaccines must be assessed in greater detail, including possible rever- sion to wild type, the significance of transient and mild elevations of liver enzymes after administra- tion, and possible transmission of vaccine virus to contacts. Additional controlled trials with attenuated vaccines are needed for a better assessment of both safety and efficacy. (b) Inactivated hepatitis A vaccines Inactivated hepatitis A vaccines are generally pre- pared by purification of virus propagated in cell cul- ture, followed by formalin inactivation and possib- ly adjuvanting with aluminum hydroxide. Similar methods of propagation, inactivation and adjuvanting are used to prepare inactivated poliovirus vaccines. No serious adverse reactions have occurred in phase II and phase III clinical trials with several of these vaccines. As the virus in the vaccine is inactivated, immunodeficiency or HIV infection does not contraindicate its administration. Immunogenicity studies have shown that 70-90% of persons develop anti-HAV antibody following a single dose, and nearly 100% of persons following two doses of vac- cines prepared by several different manufacturers. Antibody levels obtained after a single dose of vac- cine are often higher than those obtained after a single dose of IG, and substantial levels of anti-HAV neutralizing antibody are present in the majority of recipients of a complete immunization series. One immunogenicity study has suggested that simulta- neous administration of large doses of IG with the first vaccine dose may lower the active antibody re- sponse. However, the diminution in antibody titre does not appear great enough to expect an impact on the protective effect of the vaccine. WHO Bulletin OMS. Vol 73 1995 17 Memorandum Animal challenge studies have shown that inac- tivated hepatitis A vaccines may confer protection against disease. Recent field efficacy trials in chil- dren with two separate HAV vaccines produced from different strains have demonstrated 94-100% effica- cy in preventing clinical hepatitis A. The duration of protection after vaccination is unknown. However, antibody decay studies suggest that measurable anti- body will persist for many years. Continued observa- tion of immunized groups will be required to deter- mine the need for additional late booster doses of vaccine. Two inactivated hepatitis A vaccines are now commercially available and several different vaccines are expected to be widely available in the near future. (c) Use of the inactivated hepatitis A vaccine Route and schedule. The recommended route and schedule for administration of inactivated hepatitis A vaccines may vary according to the manufacturer and the national control authority. However, these vaccines are likely to require two or three doses for long-lasting protection. Prevaccination testing for susceptibility and postvac- cination testing for serological response. HAV infection induces lifelong immunity, therefore per- sons who have anti-HAV antibody from prior infec- tion do not need to be vaccinated with hepatitis A vaccine but if immunized, they do not react adverse- ly. Screening for anti-HAV prior to vaccination may or may not be cost-effective depending upon several factors, including the expected prevalence of anti- HAV in the population, the cost of the screening test, and the cost of the vaccine. For example, anti-HAV prevalence is generally greater than 50% among per- sons born in developing countries and persons born in industrialized countries prior to 1945. Prior testing in these persons may be cost-effective. Anti-HAV prevalence among persons born in industrialized countries after 1945 is generally lower than 25%. Therefore, vaccination without prescreening is usual- ly cost-effective in these persons. Due to the high immunogenicity observed with inactivated hepatitis A vaccines, postvaccination test- ing for serological response is not generally indicated. Use of immune globulin and hepatitis A vaccine in specific geographical areas Appropriate public health use of hepatitis A vaccine requires up-to-date epidemiological information. Surveillance of acute hepatitis, with differentiation of hepatitis A and B as a minimum, is an essential element of this epidemiological picture and should be a target for countries in which it does not current- ly exist. Areas of high endemicity. In these parts of the world, the vast majority of persons become infected prior to 5 years of age without evidence of hepatitis, and develop lifelong immunity. However, occasional mortality from fulminant hepatitis A does occur. While most clinical cases of hepatitis A are seen in children, adults who escape childhood infection remain susceptible to infection which presents as more serious clinical hepatitis. With socioeconomic development, infection will shift to older ages, thus increasing the disease load in adults. Despite the high prevalence of antibody in the population, the virus perpetuates in the region owing to its high physical stability. In highly endemic areas, it is difficult and impractical to identify risk groups for transmission of hepatitis A and any intervention strategy must take into account that children below 5 years are the single most important risk group for infection in this setting. However, taking into consideration the rela- tively small disease burden from hepatitis A, the present expense of the vaccine, and the uncertain duration of immunity from HAV vaccination, the cost-benefit of an infant mass immunization pro- gramme may be too low for most developing coun- tries in the light of other pressing health problems. As vaccine costs decrease, and more data become available concerning the duration of immunity, these cost-benefit considerations should be reassessed. The increased hepatitis disease burden with increas- ing age of infection should also lead to a reassess- ment of the cost-benefit of a mass immunization programme, and those developing countries in this situation may wish to formulate a programme at an earlier stage. It should also be noted that socioeconomic devel- opment in these areas is usually an uneven process so that improvement in parameters affecting the risk of hepatitis A infection in some households may out- pace that of the community as a whole. As a result, individuals in such households are less likely to be exposed to HAV at an early age. However, as sus- ceptible adults, they become exposed to infection when they interact with the environment outside their own homes. In such individuals, hepatitis A vaccination may be considered while still in school (before employment) or while attending institutions of higher education. It is strongly emphasized that efforts to improve water supplies and sanitation levels should continue to have a high priority in order to reduce the infec- tion rate with hepatitis A. Areas of intermediate endemicity. HAV infection occurs in high rates in older children and adults and can result in significant morbidity. In these areas WHO Bulletin OMS. Vol 73 199518 Public health control of hepatitis A hepatitis A occurs endemically and in large commu- nity-wide epidemics. In considering the potential use of vaccine, each country must determine the relative public health importance of hepatitis A vaccination based upon the disease burden, other health priori- ties, and the available resources. A variety of strat- egies of hepatitis vaccination in these areas could be formulated depending on the specific disease situa- tion. Ideally, when vaccine cost and availability per- mit, the ultimate aim should be large-scale (mass) vaccination. Initially, however, priority groups should be defined based on the local situation. For example, public health authorities may select persons in institutions, preschool children, municipal workers and/or army recruits for priority immunization. Community-wide epidemics. Community-wide epi- demics of hepatitis A contribute to a substantial amount of the hepatitis A burden in areas of inter- mediate and low endemicity. These outbreaks are often large, with highest rates in children and young adults, and in households which are larger in size and with lower socioeconomic status. IG has been ineffective in sustained control of HAV trans- mission in affected communities. Hepatitis A vaccine should be strongly considered for this purpose. Vac- cination strategies may vary from community to community. Further studies are required to define the optimal immunization strategies. Areas of low endemicity. In industrialized countries, most children escape HAV infection, and viral circu- lation is low in the general population. However, hepatitis A continues to occur within certain groups such as travellers, homosexually active men, and illi- cit drug users. Day-care centres, and communities with lower socioeconomic level are important set- tings for the transmission of HAV. If administered to travellers, IG is highly effective in preventing hepati- tis A for travel-related exposure of less than 3 months; for longer periods, repeated injections are necessary. Studies have also shown that appropriate administration of IG in day-care centres where cases of hepatitis A are identified can control outbreaks and prevent further transmission. Administration of IG generally has not been effective in preventing community-wide outbreaks of hepatitis A since continued circulation of virus outlasts the duration of IG protection. Hepatitis A vaccine, by affording protection of longer duration than IG, may offer great advantages in preventing and controlling hepatitis A in these groups and settings. If the vaccine is shown to be protective when administered after exposure to HAV, then prevention strategies using hepatitis A vaccine instead of IG can be considered in the post- exposure setting. Studies are needed on whether the vaccine protects when first administered after expo- sure. While the vaccine has been shown to be effica- cious in controlled trials, data are needed on the comparative programme effectiveness of using hepa- titis A vaccine instead of IG to prevent disease in a community-wide setting. Economic analyses are needed to evaluate whether vaccination in these groups and settings should be considered. Until data are available, few definite recommendations can be made. Some of the possible uses of hepatitis A vaccine are discussed below. Travellers. Persons from areas of low endemicity who travel to areas of intermediate or high endemici- ty are at risk for acquiring hepatitis A. In general, travellers to the USA, Canada, Westem Europe, Japan, Australia and New Zealand do not have a significantly increased risk of hepatitis A and, there- fore, IG prophylaxis or vaccination is not warranted. Travellers to other areas should receive hepatitis A vaccine prior to their departure, especially for travel of long duration, and for those who travel repeatedly. The issue of prescreening of travellers for anti-HAV antibody prior to vaccination has been discussed above. Day-care centre children and staff. Outbreaks have been recognized among children and employees in day-care centres, and in some instances these out- breaks may be the source of larger community epi- demics. Outbreaks have been predominantly recog- nized in centres with children who are not toilet- trained, where clinical disease occurs in staff, parents and older siblings of day-care centre children. The use of IG has been well documented to control outbreaks of disease in these settings. Although this has not yet been studied, the available data from hepa- titis A vaccine efficacy studies suggest that the vac- cine may be able to replace IG in control of day-care centre outbreaks. Studies should be carried out to evaluate the effectiveness of vaccine in controlling recognized outbreaks and preventing further transmis- sion. Vaccines have the additional benefit of prov- iding long-lasting protection. The cost-effective- ness of pre-exposure vaccine administration to staff and children in day-care centres should be evaluated. Persons in residential institutions. Historically, hepatitis A outbreaks in institutions for the develop- mentally disabled are frequent. As conditions within institutions have improved over the past decades, the incidence and prevalence of the disease have decrea- sed, although large outbreaks can occur if the virus is introduced. Outbreaks in these institutions may be controlled with IG. As with day-care centres, the role of vaccine in replacing or supplementing IG in controlling or preventing outbreaks need to be stud- ied. These considerations also apply to the potential WHO Bulletin OMS. Vol 73 1995 19 Memorandum use of vaccine to control and prevent outbreaks in other residential institutions, such as prisons. Homosexually active men. Extensive outbreaks among homosexual men have been recognized in urban areas in the USA, England and Australia. Thus, homosexually active men should be considered for vaccination with hepatitis A vaccine. Users of illicit injectable drugs. Within the past decade, hepatitis A outbreaks have been reported with increasing frequency among injecting drug users, both in the USA and in Europe. As these indi- viduals may have underlying liver disease due to chronic infection with other hepatotropic viruses, they may be at higher risk for severe complications from hepatitis A. Consideration should be given to vaccination of these drug users. Food handlers. Food handlers, if infected with HAV, can be the source of foodbome epidemics. When a food handler is recognized with HAV infection, and especially when outbreaks are recognized, it is often too late to provide prophylaxis to patrons of the food establishment. However, in this situation IG is recom- mended in some countries for other food handlers in the establishment. If it is determined that vaccine pro- vides post-exposure protection, consideration should be given to use of vaccine in this situation. Economic analyses are needed to determine whether pre-expo- sure vaccination of food handlers is indicated. Health care workers. Nosocomial outbreaks from infected patients to health care workers are rare. There is no convincing epidemiological evidence that health care workers in general are at increased risk for hepatitis A. Thus, additional studies are required to determine whether routine hepatitis A vaccination of health care workers is indicated. Persons with chronic liver disease. Since clinical hepatitis A may be more severe in persons with chronic liver disease due to hepatitis viruses or other etiologies, use of inactivated hepatitis A vac- cine in these persons should be considered. Other groups. Data regarding risk to sewage treat- ment plant workers are limited, and no outbreaks have been observed among this group. Although at present the available data are insufficient to recom- mend routine vaccination of sewage treatment plant workers, further studies for a more accurate quantifi- cation of the risk are needed. Future considerations The epidemiological characteristics of hepatitis A strongly suggest that effective control of hepatitis A in populations with high and intermediate levels of endemicity could only be achieved by universal immunization. As groups at high risk for hepatitis A in low endemicity areas may be difficult to reach with vaccine programmes, universal immunization may be required in these areas as well. The high cost of inactivated HAV vaccines is the major factor res- tricting the use of such vaccines to reduce the dis- ease burden. Since attenuated HAV vaccine, or potentially recombinant, live-vectored hepatitis A vaccines may offer substantial advantages in terms of costs, production and administration, their develop- ment should be strongly encouraged. Several important questions remain regarding inactivated hepatitis A vaccine, including whether such vaccines may provide protection when given shortly after exposure, and the relative merits of IG and vaccine in this setting; the duration of protection and the extent of immunological memory provided by the vaccine in pre-exposure immunization; the effect of simultaneous administration of IG and vac- cine on immunogenicity; and the cost-effectiveness of various strategies of hepatitis A vaccine use. Studies addressing these questions should be en- couraged, and their results will greatly influence the decisions on how hepatitis A vaccine can be used to prevent and control HAV infection. The development of vaccines combining inacti- vated hepatitis A vaccine with other vaccine antigens in a single formulation would have significant advantages such as fewer injections, lower cost, simplicity of administration, and greater acceptance by parents and physicians. Research in combining hepatitis A vaccine with other vaccines (hepatitis B or DPT) should therefore be encouraged. WHO Bulletin OMS. Vol 73 199520