Hepatitis A virus

Human hepatitis A virus (HAV) belongs to the family Picornaviridae and is the unique member of the genus Hepatovirus. HAV is a major cause of acute hepatitis (AH) worldwide that sometimes leads to fulminant hepatic (FH) failure, evolving in most countries on an endemo-epidemic mode. However, in some countries, notably in Europe, hygienic improvement led to a fall in HAV seroprevalence during last decades exposing populations to a risk of HAV outbreaks.

Only one serotype of HAV has been identified and a single infection confers lifelong immunity. However, genetic heterogeneity between HAV isolates from different parts of the world has enabled the classification of HAV strains into seven different genotypes, designated I to VII. Four of these have been associated with human disease, I, II, III, and VII. Most human HAV strains belong to genotypes I and III, with 80% of them being genotype I. Genotypes I and III are further divided into subtypes A and B. Genotypes II and VII are represented only by one human strain each, and genotypes IV, V, and VI include strains recovered from simians.

Genotype IA appears to be the agent responsible for the majority of hepatitis A cases worldwide and has been isolated from all parts of the world. Genotype IB appears to occur in the Mediterranean region, whereas genotype III viruses have been isolated from diverse sources such as Panamanian owl monkeys, drug abusers in Sweden and patients from India and Nepal. Single representatives of genotype II and VII were isolated from individual patients from Sierra Leone and France.

Several studies have indicated that HAV strains in North America mainly belong to subtype IA.

Hepatitis A virus (STRAIN HM-175)

Genotype IB.

The HM-175 strain was derived from a fecal sample collected in November 1976 from a 35-year old Australian male with serologically confirmed hepatitis A. The term HM175 has subsequently been used to designate strains of HAV which have been recovered from infected nonhuman primates and cell cultures inoculated with the original fecal extract and their progeny.

Attenuated mutants of HM175, CR326, and H2 are the best characterized candidates for live virus vaccines, but variants of strains GBM and MBB and chimeras between simian AGM27 and human HM175 strains also are being evaluated.

Hepatitis A virus (attenuated strain HM-175), cDNA to genomic RNA, clone HM-175/7MK-5.

Hepatitis A virus clone HM-175/7MK-5.

Genotype IB.

This virus was derived from wild-type HAV HM-175 after 32 passages in African green monkey kidney cells. The resultant cell culture-adapted virus is attenuated for chimpanzees.

Hepatitis A virus (STRAIN 18F)

Genotype IB.

HM175/18f virus is one of several cell culture-adapted HM175 variants which were rescued from persistently infected BS-C-1 cells and which have a rapid replication phenotype associated with cytopathic effects (rrlcpe+) in cultured monkey kidney cells. The nucleotide sequences of these viruses demonstrate the presence of numerous mutations from the sequence of the more slowly replicating noncytopathic (rrlcpe-) parent virus. The HM175/18f virus represents an independent isolate of the HM175 strain of HAV.

Hepatitis A virus (STRAIN 24A)

Genotype IB.

HAV clonal isolate (HM175/24a) was isolated from pHM175 virus stock by classical plaque purification techniques and propagated in FRhK-4 cells.

Hepatitis A virus (STRAIN 43C)

Genotype IB.

A cytopathic clonal variant (HM175/43c virus) was plaque purified from pHM175 virus harvest, and was selected for its ability to induce clearly visible plaques in FRhK-4 cells.

Hepatitis A virus (STRAIN CR326)

Genotype IA

CR326 was derived from a pool of sera collected from a 9-year old child during a prospective study of the epidemiology and the mode of transmission of viral hepatitis in semi-urban and rural areas of Alajuela, Costa Rica.

Hepatitis A virus (strain GA76)

Genotype IIIA.

Human isolates of hepatitis A (HAV) are a single serotype; however, recent genetic surveys using limited nucleotide sequencing have provided evidence that more than one genotype is responsible for HAV infection in different parts of the world. One of these genotypes was originally isolated from Panamanian owl monkeys (strain PA21), but has subsequently been found associated with human cases of HAV from Sweden in 1979 (H-122) and the United States of America in 1976 (GA76). HAV infected stool specimens from Nepal and northern India during 1989 and 1990 were found to contain virus whose genetic makeup was related to the PA21 and GA76 isolates. This genotype of HAV appears to be circulating in some parts of the world where HAV is hyperendemic, and is a potential cause of hepatitis A infection within a susceptible population.

Hepatitis A virus (STRAIN LA)

Genotype IA

Isolated from the stools of a hepatitis A patient collected during an epidemic outbreak in Los Angeles.

Hepatitis A virus (STRAIN LCDC-1)

Chinese strain of hepatitis A virus (HAV).

There is an 18 bp deletion in the capsid protein, VP1 gene, compared to HAV strains HM-175, MBB, and CR-326.

Hepatitis A virus (STRAIN MBB)

Genotype IB.

The first strain of HAV obtained directly from clinical material (MBB) was isolated by Frosner and his colleagues at the Pettenkoffer Institute in Munich, from a fecal specimen which had been collected from a patient 5 days prior to the onset of jaundice.

Hepatitis A virus isolate CF53/Berne

Genotype II.

The CF53/Berne is a cell-adapted isolate of HAV donated to the Berne laboratory. The original virus was derived in 1979 from the stool of a patient in Clermont-Ferrand, France, who had sporadic hepatitis A 3 days after the onset of jaundice. The CF53/Berne isolate sequence was compared to the complete available sequences of four representative HAV genotypes [genotype IA (GBM), genotype IB (HM-175), genotype III (NOR-21), genotype V (AGM27) and genotype VII (SLF88)] and shown to be related closest to the SLF88 strain. This close relationship was maintained when the three major protein-encoding region (P1, P2 and P3) were analyzed separately. Evaluation of the more conserved 5' UTR revealed that the CF53/Berne isolate had over 96% identity to human HAV genotype VII, about 92% identity to the human genotype IA and IB and approximately 83% identity to the simian HAV genotype V sequence.

Hepatitis A virus strain SLF88

Genotype VII .

It was previously identified as genotype VII, genotype: IIB.

Human HAV genotype VII, designated SLF88 was responsible for two epidemiologically linked fulminant hepatitis A cases and is the only identified strain from Sierra Leone. Within hyper-endemic regions, such as the Amazon basin in South America, most of Africa, the Middle East and Central Asia and the Indian subcontinent, the majority of infections occur during childhood. In these areas, distinct outbreaks occur rarely and clinical disease related to HAV infection is uncommon, as children generally experience asymptomatic infection. SLF88 is the only wild-type virus from this part of Africa for which we have a complete genome sequence.

Hepatitis A virus isolate DL3

Wild-Type Hepatitis A Virus isolate DL3 in China belonged to subgenotype IA

HAV (DL3) was isolated from a stool specimen collected from hepatitis A patient from Dalian, China. The sequence comparison and phylogenetic analysis revealed that DL3 is most similar to the isolates in Japan, suggesting the epidemiological link of hepatitis A happened in China and Japan.

Hepatitis A virus strain GBM

HAV strain GBM was recovered from a human fecal specimen, collected in the preicteric phase of the infection in Germany, and is named GBM wild type (GBM/WT) in this paper. The strain has been adapted for growth in HFS (human lung fibroblast cells) and/or FRhK-4 cells (fetal rhesus monkey kidney-derived cells) with a selection procedure for rapid growth and release of virus into cell culture supernatant. The comparison of the genome between the GBM wild type and HAV wild types HM175 and HAV-LA showed a 92 to 96.3% identity, whereas the identity was 99.3 to 99.6% between the GBM variants. Nucleotide differences between the wild-type and the cell culture-adapted variants, which were identical in both cell culture-adapted GBM variants, were localized in the 5' noncoding region; in 2B, 3B, and 3D; and in the 3' noncoding region.

The alignment of the genome sequence of the GBM wild type with other HAV wild-type sequences has shown a 92% (HM175) to 96.3% (HAV-LA) identity and classifies the GBM strain as subgenotype IA within the seven genotypes of human HAV isolated from different geographical regions. The comparison of the consensus sequence, a 168-nucleotide region encoding the putative VPI-2A junction, shows that wild-type HAV-LA is also a member of subgenotype IA but differs in comparison with the sequence of GBM/WT.

Hepatitis A virus substrain GMB/FRhK

Two GBM variants, GBM/HFS and GBM/FRhK, were attained after cell culture propagation. GBM/FRhK was isolated and propagated in FRhK-4 cells and after 63 passages exhibited a strict host range behavior. The two GBM cell culture-adapted variants, GBM/FRhK and GBM/HFS, differ in their biologic characteristics. While GBM/FRhK showed a strict host range for FRhK-4 cells, GBM/HFS replicated in both cell types.

Hepatitis A virus substrain GBM/HFS

Two GBM variants, GBM/HFS and GBM/FRhK, were attained after cell culture propagation. GBM/HFS was propagated eight times in human embryonic kidney cells and then passaged 23 times in HFS cells and is used as an inactivated vaccine. No replication was observed in HFS cells. The two GBM cell culture-adapted variants, GBM/FRhK and GBM/HFS, differ in their biologic characteristics. While GBM/FRhK showed a strict host range for FRhK-4 cells, GBM/HFS replicated in both cell types. Furthermore, GBM/HFS has been shown to be attenuated after inoculation into chimpanzees.

Hepatitis A virus isolate LY6

LY6, subgenotype IA was isolated from a sporadic self-limited Hepatitis A.

Complete sequences of the genomes of two wild type (wt) Human hepatitis A virus (HHAV) isolates, LU38 and LY6 from China were determined and compared with those of wt HHAV isolates AH1, AH2, AH3, FH1, FH2, FH3, GBM, HM175, LA and MBB. Sequence comparison showed that LY6 shared the highest identities of 97.4% for nt (196 differences) and 98.7% for aa (28 differences) with H1 and the lowest identities of 91.2% for nt (642 differences) with HM175 and 97.7% for as (51 differences) with GBM. The subgenotyping revealed that the LU38 and LY6 isolates are of IA subgenotype. The phylogenetic analysis showed that LU38 is closest to AH1 and the LY6 to FH3, suggesting that the epidemiological link of hepatitis A (HA) had developed in China and Japan.

Hepatitis A virus isolate LU38/WR

LU38, subgenotype IA was isolated from patient with fulminant hepatitis A virus infection.

Complete sequences of the genomes of two wild type (wt) Human hepatitis A virus (HHAV) isolates, LU38 and LY6 from China were determined and compared with those of wt HHAV isolates AH1, AH2, AH3, FH1, FH2, FH3, GBM, HM175, LA and MBB. Sequence comparison showed that LU38 shared the highest identities of 98.1% for nt (140 differences) and 99.2% for as (17 differences) with AH1, and the lowest identities of 91.4% for nt (741 differences) with HM175 and 98.1% for aa (43 differences) with GBM. The subgenotyping revealed that the LU38 and LY6 isolates are of IA subgenotype. The phylogenetic analysis showed that LU38 is closest to AH1 and the LY6 to FH3, suggesting that the epidemiological link of hepatitis A (HA) had developed in China and Japan.

Hepatitis A virus isolate HAF-203 [AF268396]

Brazilian strain (HAF-203) of hepatitis A virus (HAV).

It was isolated in 1992 (Brazil), and adapted in cell culture, after fourth passage.

Hepatitis A virus isolate AH1

Hepatitis A virus isolate AH2

Hepatitis A virus isolate AH3

Hepatitis A virus isolate AH1,

isolate AH2,

isolate AH3,

Genotype IA

Isolated from patients with self-limited acute hepatitis A virus in Japan. By comparing with genotype IA, wild-type HAV strain GBM, the analysis of whole genomes from six cases showed no specific substitutions between FH and AH. Identical nucleotide sequences were observed at the 3' non-translated region (NTR) in all six cases. In 5'NTR, few nucleotide substitutions were found in FH compared to AH, and in the non-structural protein 2B region, there were more amino acid substitutions in FH than in AH.

Hepatitis A virus isolate FH1

Hepatitis A virus isolate FH2

Hepatitis A virus isolate FH3

Hepatitis A virus isolate FH1,

isolate FH2,

isolate FH3,

Genotype IA.

Isolated from patients with fulminant hepatitis A virus in Japan. By comparing with genotype IA, wild-type HAV strain GBM, the analysis of whole genomes from six cases showed no specific substitutions between FH and AH. Identical nucleotide sequences were observed at the 3' non-translated region (NTR) in all six cases. In the 5'NTR, few nucleotide substitutions were found in FH compared to AH, and in the non-structural protein 2B region, there were more amino acid substitutions in FH than in AH.

Hepatitis A virus strain FG

An Italian cytopathic isolate (strain FG) of Hepatitis A. Sequence analysis revealed the presence of mutations common to either adapted or cytopathic variants of HAV. In particular, amino acid deletions in proteins VP1 and 3A were detected. Expression of protein 3A in E. coli showed that the N-terminal deletion renders this protein toxic to bacteria.

Hepatitis A virus (strain MSM1)

[AUTHORS : Stene-Johansen K , Tjon G, Schreier E, Bremer V, Bruisten S, Ngui SL, King M, Pinto RM, Aragones L, Mazick A, Jensen I P, Sundqvist L, Blystad H, Norder H, Skaug K. TITLE : Molecular epidemiological studies show that hepatitis A virus is endemic among MSM in Europe JOURNAL : Unpublished].

27-nm ribonucleic acid (RNA)

Available data as to the exact fate of virions immediately after oral intake are sketchy. In experimental infection of owl monkeys with human HAV, viral antigen was detectable by immunofluorescence in the stomach, small intestine, and large intestine not only after the initial oral inoculation but also later in the course of the disease. The ability to detect viral antigens in intestinal crypt cells using immunofluorescence suggests that viral replication can occur in the intestine. Virions presumably reach the liver in the portal blood (or after systemic circulation) and are taken up by hepatocytes. An attachment receptor for HAV in nonliver primate cells has been characterized; however, the relationship of this mucin-like class I integral membrane glycoprotein to hepatocyte uptake of virus is not clear. Once HAV has replicated in the liver and been released into bile, the enterohepatic cycle of gastrointestinal uptake and transfer to the liver could continue until neutralizing or other antibodies interrupted the cycle. REPLICATION: Current evidence indicates that HAV replication is probably exclusive to hepatocytes and gastrointestinal epithelial cells in vivo, although cell culture infection and replication in nonhepatocyte cell lines are well documented. Virus-encoded proteins replicate the RNA genome via a negative-strand intermediate and are themselves synthesized from the genomic positive strand. Intact virions contain the RNA genome, the covalently linked VPg protein, and a capsid of the coat proteins VP1, VP2, and VP3 with icosahedral symmetry. Virus particles appear in bile and blood, presumably being released across the apical hepatocyte membrane into the biliary canaliculus and across the basolateral membrane into the bloodstream. The mechanism of viral release and secretion is unknown but clearly is not dependent on cell destruction, since high viral titers are present in stool before there is any evidence of hepatocyte necrosis.

The HAV genome is a single-stranded, linear, 7.5 kb RNA (ORF, 6.7kb) molecule, with positive polarity.

The genome consists of a 5' non-translated region of about 735 to 740 nucleotides, which contains an internal ribosomal entry site, a coding region of 2,225 to 2,227 nucleotides consisting of the structural (P1) and non-structural protein-encoding regions (P2 and P3), and, finally, a 3' noncoding region of 40 to 80 nucleotides in length with a terminal poly(A) tract.

Although HAV was first successfully adapted to cell culture more than 20 years ago, its protein constituents have not been completely defined. Infected cells contain only low titers of virus, and consequently protein chemistry has been limited. The P1 region encodes the three major proteins of the viral capsid, VP1, VP2, and VP3. A fourth viral capsid protein (VP4), essential for virion formation, is not detected in mature viral particles. Each of the capsid proteins is cleaved from the precursor polyprotein by the viral protease 3C, encoded in the P3 region. The native conformation of the capsid proteins VP1 and VP3 forms a single, dominant, serologic epitope on the viral capsid and elicits a neutralizing antibody response. Nonstructural proteins encoded in the P2 and P3 regions are predicted to function in RNA synthesis and virion formation. VPg (virion protein, genome linked), also encoded in the P3 region, is covalently linked to the 5' genome terminus and involved in initiation of RNA synthesis.

The secondary structure of the 5' NCR is important in translation initiation. The Picornaviridae RNA genomes lack the cap assembly found at the 5' end of mRNA species that normally guides the ribosomal complex to the translation start site. An internal ribosome entry site formed by the 5' NCR functions to initiate translation in the picornaviruses, including HAV.

7,478 nt

The organization of the HAV genome is similar to that of the other picornaviruses.

The single open reading frame (ORF) of the piconoviruses is translated into one long precursor polypeptide, which is processed by a cascade of proteolytic cleavages to yield ultimately mature viral proteins.

Hepatitis A virus (HAV) has a world-wide distribution.

Approximately 1.5 million clinical cases of hepatitis A occur each year worldwide, and the prevalence of antibodies against hepatitis A in the general population can vary from 15% to almost 100% in some countries. Nordic countries show the lowest prevalence of infection, with an incidence of approximately 15%. In Australia, other parts of Europe, Japan, and the United States, the seroprevalence of antibodies to HAV is 40% to 70% in adults. In developing areas of the world, most adults show serologic evidence of past infection.

Worldwide, four major patterns of HAV infection can be described based on the age-specific prevalence of antibodies to HAV. These range from high endemicity, such as in Africa and parts of Asia and Latin America, where the majority of infections occur in early childhood, to low and very low endemicity, such as in North America and Western Europe, where few persons are infected in childhood, and the majority of the population remains susceptible throughout adulthood.

In developing countries, the incidence of disease in adults is relatively low because of exposure to the virus in childhood. Most individuals 18 and older demonstrate an immunity that provides lifelong protection against reinfection. In the US, the percentage of adults with immunity increases with age (10% for those 18-19 years of age to 65% for those over 50). The increased number of susceptible individuals allows common source epidemics to evolve rapidly.

In many Asian countries, improved hygiene standards and socio-economic conditions have led to a reduction in exposure to the hepatitis A virus (HAV) in childhood. However, the persistence of circulating HAV may lead to hepatitis A outbreaks, particularly in adolescents and adults. In other countries and specific areas, where socio-economic conditions have not improved as markedly, HAV endemicity remains medium-to-high.

In South-East Asia the causes and epidemiology of hepatitis A outbreaks vary according to the country, and there are often regional variations within a country. Outbreaks originate mostly from contaminated food and water, and commonly occur in institutions (e.g. schools, kindergartens, day care centres, colleges and hospitals) and/or food outlets (e.g. restaurants, grocery stores and street stalls). Outbreaks also occur in isolated communities of indigenous people. The epidemiology of outbreaks in developed countries is different to that of those in the developing world. In North America, hepatitis A outbreaks occur most commonly in the community as a whole, mainly affecting young adults and children in lower socio-economic classes. Outbreaks have also been reported among men who have sex with men and intravenous drug users, as well as in isolated communities. In regions of Europe where there is a low local prevalence of HAV, secondary transmission from HAV-infected migrants has sometimes been reported as a source of outbreaks.

Hepatitis A epidemiology in the United States has fundamentally changed with licensure of hepatitis A vaccine and implementation of national ACIP recommendations for its use. Before vaccine licensure during 1995--1996, hepatitis A incidence was primarily cyclic, with peaks occurring every 10--15 years. In the United States, during 1980--1995, approximately 22,000--36,000 hepatitis A cases were reported annually to CDC (rate: 9.0--14.5 cases per 100,000 population), but incidence models indicate that the number of infections was substantially higher. One such analysis estimated an average of 271,000 infections per year during 1980--1999, representing 10.4 times the reported number of cases. Each year in the United States, an estimated 100 persons died as a result of acute liver failure attributed to hepatitis A.

An appreciation of the relationship between the age at infection and the clinical expression of disease is central to understanding hepatitis A epidemiology. The likelihood of having symptoms with HAV infection increases with the age at which infection occurs. In children less than 6 years of age, most infections are asymptomatic, and if symptoms do occur, they are usually mild and non-specific. Among older children and adults, infection is usually symptomatic, with jaundice occurring in the majority of persons. The disease tends to be more severe among older persons; among reported hepatitis A cases in the USA, the case fatality ratio increased from 0.2% among children 5-14 years old to 1.8% among adults over 50 years old. There is considerable regional variation in hepatitis A rates, with incidence being consistently higher in the western and southwestern USA compared to other regions.

During the preceeding 2 decades, outbreaks have been reported with increasing frequency among users of injection and noninjection drugs in Australia, Europe, and North America. In the United States, outbreaks have frequently involved users of injected and noninjected methamphetamine, who have accounted for up to 48% of reported cases during outbreaks.

Asia: Large outbreaks have been documented in countries with transitional epidemiology. A classic example was the 1988 common source outbreak in Shanghai, Province, P.R. China, associated with consumption of contaminated raw shellfish, which affected over 300 000 persons. More recently, large outbreaks occurred in Central Asia in 1995-1997, with peak incidence rates of over 1000/100 000. In Tashkent, Uzbekistan, over 7000 cases were reported, resulting in overflowing hospitals and the closing of schools. Hepatitis A is reported to account for 50-60% of all acute viral hepatitis cases among children in Pakistan, and 232 children with fulminant hepatic failure secondary to hepatitis A were admitted to one tertiary care referral hospital in Karachi during a 9-year period. Hepatitis A was the etiology of the fulminant hepatitis of two-thirds of children presenting to two hospitals in Argentina during a 15-year period. In one of these hospitals performing liver transplantations, one-third of liver transplantations among children were for fulminant hepatitis A.

A territory-wide outbreak of hepatitis A occurred in Hong Kong in 1988. At least 17 separate groups of people developed the disease after sharing common meals of shellfish. The outbreak, which occurred in winter, may have been related to the popular hot pot method of cooking shellfish, in which cooking may be incomplete.

USA: In October 2003, the Associated Press reported that outbreaks of hepatitis A in Georgia and Tennessee had been linked to O'Charley's restaurants, and in November 2003, outbreaks of hepatitis A in western Pennsylvania were linked to a Chi-Chi's restaurant. The restaurants were the sources of infection for hundreds of patrons and their contacts, leading to a multistate Centers for Disease Control and Prevention (CDC) advisory and widespread vaccination efforts. The common thread that linked all of these outbreaks was green onions. A report on the Pennsylvania outbreak issued by the CDC in November 2003 noted that the hepatitis A virus (HAV) strains isolated from infected people in Georgia, North Carolina, Pennsylvania, and Tennessee shared very similar genetic sequences and that all had been linked epidemiologically to green onions. These sequences were in turn identical or very similar to sequences isolated from people infected with hepatitis A living along the United States-Mexico border and travelers returning from Mexico, leading eventually to definite links to produce from 3 firms in Mexico.

Pennsylvania, USA: The Pennsylvania Department of Health and CDC investigated an outbreak of hepatitis A among patrons of a restaurant in Monaca, Pennsylvania. Approximately 555 persons with hepatitis A have been identified, including at least 13 restaurant food service workers and 75 residents of six other states who dined at the restaurant. Three persons died. Preliminary sequence analysis of a 340 nucleotide region of viral RNA obtained from three patrons who had hepatitis A indicated that all three virus sequences were identical. Preliminary analysis of a case-control study implicated green onions as the source of the outbreak.

Ohio, USA: Forty-three cases of serologically confirmed hepatitis A occurred among individuals who ate at a restaurant in Ohio in 1998. Serum samples from all the restaurant employees who worked during the exposure period were negative for IgM antibodies to hepatitis A virus (HAV). A matched case-control study determined that foods containing green onions, which were eaten by 38 (95%) of 40 case patients compared with 30 (50%) of 60 control subjects, were associated with illness (matched odds ratio, 12.7; 95% confidence interval, 2.6-60.8).

Sumatra, Indonesia: A water-borne hepatitis A outbreak occurred in southern Sumatra, Indonesia, from May to August 2000. A case-control study was carried out, encompassing four of the ten villages affected by the outbreak. It was ascertained that HAV infection occurred mostly among children aged less than ten years. In addition, it was found that infected individuals were more likely to have consumed water from a public well, and more likely to have used a dry pit outside their house for human waste disposal, compared with the control group.

Malaysia: A recent outbreak in a Malaysian boarding school affected students aged 13-21 years. Of the 129 contacts of these students who were tested, nine (7%) were found to be seropositive.

Philippines: In September 2000, a regional surveillance unit in the Philippines contacted the National Epidemiology Center in Manila to report a potential hepatitis A outbreak in a large private school. Three days prior to the surveillance units report, students had been tested for HAV and 11 of 3994 were found to be infected. The source of infection was found to be an infected well, water from which was used to mix drinks in the canteen.

Vancouver, Canada: A hepatitis A outbreak, primarily affecting men who have sex with men, occurred in Vancouver, Canada, from 1997 to 1998. Outbreak control measures taken by Vancouver public health authorities included free vaccination, which was made available at community clinics and doctors offices. Extensive media coverage of the outbreak control programme led to 10,000 doses of vaccine being administered, representing approximately 50% coverage. Within three months the outbreak appeared to be over; however, in late 1999 new cases of hepatitis A began to appear among intravenous drug users. The vaccination campaign was broadened in December 1999 to include this population, and the number of new cases of hepatitis A in the region subsequently began to decline.

Slovakia: An epidemic occurred in two adjoining villages in northern Slovakia from December 1991 to March 1993 in which 121 cases of hepatitis A were reported. There had been no cases of hepatitis A infection in either village during the preceding 22 years.

Chiba City, Japan: A sequential outbreak occurred in an institution for the mentally handicapped people in Chiba City, Japan in the summer of 1995. Eight people were infected including 7 residents and one staff member.

Enteric (faecal-oral) transmission via person-to-person contact within the household is the predominant way of spreading the disease; sequential infections occur about one incubation period apart. The secondary attack of clinically apparent infection among household members may approach 20-50%. In nearly 40% of cases, however, no known risk factor can be found, although low socioeconomic status is a common feature in this group. Currently, in the USA, outbreaks across the community are thought to be the main source of HAV infection, affecting schoolchildren, adolescents, and young adults. Large families, household crowding, poor education, inadequate human-waste disposal systems, and mixing with other children in day-care centres are all linked with HAV endemicity and outbreaks. In communities experiencing recurrent hepatitis A outbreaks, children aged 3-5 years seem to be important transmitters of infection.

Because the majority of children have asymptomatic or unrecognized infections, they play a key role in HAV transmission and serve as a source of infection for others. In one study of adults without an identified source, 52% of their households included a child aged <6 years, and the presence of a young child was associated with HAV transmission in the household. In studies in which serologic testing of the household contacts of adults without an identified source of infection was performed, 25%--40% of contacts aged <6 years had serologic evidence of acute HAV infection (IgM anti-HAV).

: SPECIAL GROUPS :

: MSM : Oral-anal homosexual practices, digital rectal intercourse, and high numbers of sexual partners have been associated with an increased risk of HAV transmission.

DRUG USERS: Drug users who inject are also at increased risk, presumably through a combination of poor personal hygiene resulting in faecal contamination of the shared injection equipment, exposure to infected blood in shared needles, and possible contamination of the illicit injected drugs during transport in the intestine after swallowing or carriage in the rectum.

CHILD CARE CENTERS: Outbreaks among children attending child care centers and persons employed at these centers have been recognized since the 1970s, but their frequency has decreased as overall hepatitis A incidence among children has declined in recent years. Because infection among children is typically mild or asymptomatic, outbreaks often are identified only when adult contacts (typically parents) become ill. Poor hygiene among children who wear diapers and the handling and changing of diapers by staff contribute to the spread of HAV infection; outbreaks rarely occur in child care centers in which care is provided only to children who are toilet trained. Although child care centers might have been the source of outbreaks of hepatitis A in certain communities, disease in child care centers more commonly reflects extended transmission from the community.

HEALTH CARE INSTITUTIONS: Nosocomial HAV transmission is rare. Outbreaks have occasionally been observed in neonatal intensive-care units because of infants acquiring infection from transfused blood and subsequently transmitting hepatitis A to other infants and staff. Outbreaks of hepatitis A caused by transmission from adult patients to health-care workers are usually associated with fecal incontinence, although the majority of hospitalized patients who have hepatitis A are admitted after onset of jaundice, when they are beyond the point of peak infectivity.

Burn patients incubating HAV in hospital, and a patient who was immunodeficient and negative for HAV antibodies have all been sources of nosocomial infection. One example of nosocomial spread emphasizes the natural life cycle of the virus. A patient with an overdose and trauma from a motor vehicle accident had a T-tube draining bile during the incubation phase of hepatitis A. The bile was the only apparent source of infection in five cases of nosocomial hepatitis A.

On rare occasions, HAV infection has been transmitted by transfusion of blood or blood products collected from donors during the viremic phase of their infection. Since 2002, nucleic acid amplification tests such as polymerase chain reaction (PCR) have been applied to the screening of source plasma used for the manufacture of plasma-derived products.

FOODBORNE: HAV contamination of a food product can occur at any point during cultivation, harvesting, processing, distribution, or preparation.

Consumption of contaminated uncooked or undercooked food, such as bivalve molluscs, and, less commonly, foods that are contaminated after cooking by an infected food handler, has led to large numbers of outbreaks and, occasionally, outbreaks affecting hundreds of thousands of people.

The source of most reported foodborne hepatitis A outbreaks has been HAV-infected food handlers present at the point of sale (such as in a restaurant) or who prepare food for social events (such as a wedding). A single HAV-infected food handler can transmit HAV to dozens or even hundreds of persons and cause a substantial economic burden to public health. Common themes of these outbreaks include (1) the presence of an HAV-infected food handler who worked while potentially infectious (2 weeks before to 1 week after symptom onset) and had contact with uncooked food or food after it had been cooked, (2) secondary cases among other food handlers who ate food contaminated by the index case, and (3) relatively low attack rates among exposed patrons.

CONTAMINATED SHELLFISH: HAV-contaminated shellfish have been the source of foodborne outbreaks of hepatitis A, including several outbreaks involving many thousands of cases. Although reports of shellfish-related hepatitis A outbreaks continue to occur in some other countries, none have been reported recently in the United States.

NIGHT SOIL: The use of night-soil as a crop fertilizer is a likely risk factor in those countries where the practice is common.

Green onions require extensive handling during harvesting and preparation for packing. Contamination of green onions could occur 1) by contact with HAV-infected workers, especially children, working in the field during harvesting and preparation and 2) by contact with HAV-contaminated water during irrigation, rinsing, processing, cooling, and icing of the product. Green onions and other selected produce items (e.g., strawberries) might be more vulnerable to contamination because plant surfaces are particularly complex or adherent to viral or fecal particles. Outbreaks of other enteric pathogens linked to green onions have been reported.

WATERBORNE: The relative importance of waterborne transmission of HAV varies in the different areas of the world. The relative stability of HAV and its abundant shedding in feces suggest that indirect transmission via water is potentially very important. Waterborne transmission predominates in developing countries and no doubt is responsible for universal infection at an early age. Thus, it is responsible for endemicity rather than for clinically recognized outbreaks, which rarely occurs in these areas. In contrast, waterborne transmission probably accounts for a very small proportion of HAV infections in areas of the world with adequate water supply and waste disposal. In these areas hepatitis A is uncommon. Hepatitis A is no longer a childhood infection, and susceptible adults accumulate. Consequently, accidental contamination of water could result in extensive outbreaks. Such outbreaks are not very rare in many areas of the world.

Outbreaks in the context of floods or other natural disasters (e.g., hurricanes) have not been reported in the United States.

Outbreaks of hepatitis A among persons who use small private or community wells or swimming pools have been reported, and contamination by adjacent septic systems has been implicated as the source of contamination. Although the potential for hepatitis A outbreaks after flooding-related sewage contamination of potable water sources is recognized, no such incidents have been reported in the United States in several decades.

Occasional outbreaks have been linked to sources shared by large numbers of people or bathing areas. Workers in sewage and waste-water treatment plants are also potentially at risk.

Data from serologic studies among Scandinavian and English workers who had been exposed to sewage indicated a possible elevated risk for HAV infection; however, in these studies, the data were not controlled for other risk factors (e.g., socioeconomic status). Recently, two serologic surveys were conducted in the United States comparing the prevalence of anti-HAV among sewage workers to that among other municipal workers. Neither survey found a substantial increase in prevalence among sewage workers, although in one study the odds ratio of 2 was at the limit of statistical significance. No work-related instances of HAV transmission have been reported among sewage workers in the United States.

PRIMATE HANDLERS: Subclinical infections of nonhuman primates can serve as a link in the chain of infection of man, particularly among primate handlers, experimenters, and their families.

Outbreaks of hepatitis A have been reported among persons working with non-human primates that are susceptible to HAV infection, including several Old World and New World species. Primates that were infected were those that had been born in the wild, not those that had been born and raised in captivity.

Diseases in nonhuman primates resembles that in humans but is usually milder. After infecting these animals, HAV or viral antigen can usually be detected in the serum, liver, bile and feces. Other primate species are suceptible to infection but do not develop disease with human HAV strains; this limits their usefulness for studies of human strains.

In 1961 and 1963 Hillis reported an outbreak of infectious hepatitis among chimpanzee handlers and described the biochemical and histological abnormalities characteristic of human hepatitis in newly imported chimpanzees.

The reservoir is humans, and infected subjects remain contagious for two weeks before the onset of jaundice, and up to ten days after subsidence of symptoms. Approximately 1.4 million cases are reported each year throughout the world (incidence), with the actual figure being 3 to 10 times higher due to the number of non-apparent forms.

Humans; rarely captive chimpanzees; less frequently, certain other non-human primates

Increased resistance to unfavourable environmental conditions has been considered as the main mechanism for the maintenance and spread of the disease, especially in isolated communities. HAV in feces and blood is resistant to heating at 56 C for 30 min, to freezing and thawing, to exposure to acid, and to treatment with diethyl ether. HAV can be inactivated by ultraviolet light, and by many commonly used detergents containing formaldehyde or chlorine.

HAV is resistant to low pH (up to pH 1) and to heating, surviving 1 hr at 60 C. It appears to be extremely stable in the environment, with only a 100-fold decline in infectivity over 4 weeks at room temperature, and 3-10 months in water. HAV appears to be relatively resistant to free chlorine, especially when the virus is associated with organic matter.

Depending on conditions, HAV can be stable in the environment for months. Heating foods at temperatures greater than 185 F (85 C) for 1 minute or disinfecting surfaces with a 1:100 dilution of sodium hypochlorite (i.e., household bleach) in tap water is necessary to inactivate HAV.

Hepatitis A is a reportable disease in all states. The goals of hepatitis A surveillance at the national, state, and local levels include a) identifying contacts of case-patients who might require postexposure prophylaxis; b) detecting outbreaks; c) determining the effectiveness of hepatitis A vaccination; d) monitoring disease incidence by identifying acute, symptomatic infections in all age groups; e) determining the epidemiologic characteristics of infected persons, including the source of infection; and f) determining missed opportunities for vaccination. Cases of hepatitis A should be reported to local or state health departments (according to specific state requirements) so that appropriate control measures can be implemented, if indicated. Cases meeting specified criteria are reported by state health departments to CDC. Hepatitis A surveillance must be maintained at the local level so that the various recommended immunization strategies can be implemented and their outcome at the local, state, and national levels can be assessed. Laws requiring laboratories to promptly report all IgM anti-HAV positive results are likely to improve the completeness and timeliness of reporting.

Human

Homo sapiens

The host range of HAV is limited to humans and a few other primate species.

Although, man has been considered the only important host of HAV, the study of the existence of animal reservoirs is of great importance for attempting to explain the epidemiology of hepatitis A, to implement strategies for control, and especially to plan for the eradication of the disease.

The infectious dose is unknown but presumably is 10-100 virus particles.

HAV is excreted in feces of infected people and can produce clinical disease when susceptible individuals consume contaminated water or foods. Cold cuts and sandwiches, fruits and fruit juices, milk and milk products, vegetables, salads, shellfish, and iced drinks are commonly implicated in outbreaks. Water, shellfish, and salads are the most frequent sources. Contamination of foods by infected workers in food processing plants and restaurants is common.

In the prevaccine era, the majority of U.S. cases of hepatitis A resulted from person-to-person transmission of HAV during communitywide outbreaks. The most frequently reported source of infection (in 12%--26% of cases) was household or sexual contact with a person with hepatitis A. Cyclic outbreaks occurred among users of injection and noninjection drugs and among men who have sex with men (MSM), and up to 15% of nationally reported cases occurred among persons reporting one or more of these behaviors. Other potential sources of infection (e.g., international travel and recognized foodborne outbreaks) were reported among 3%--6% of cases.

Approximately 11%-16% of reported cases occur among children or employees in day care centers or among their contacts; however, this estimate might be too high because hepatitis A cases are attributed to day care center-related contact without requiring that the contact have hepatitis A or that a case of hepatitis A be identified in the day care center. For approximately 50% of persons with hepatitis A, no source was identified for their infection.

PERSONAL AND ENVIRONMENTAL HYGIENE: Personal hygiene is most important in preventing foodborne viral infection, and includes frequent handwashing and wearing gloves. This should apply for all points in the food chain where foodstuffs are handled manually. Foodborne outbreaks have occurred due to contaminated food sources that passed all microbiological assays. A common-sense guideline is to remove people with symptoms consistent with viral gastroenteritis from the production chain until at least 2 days after remission of the symptoms. A practical problem with this guideline is that an unknown proportion of viral infections will be subclinical, viral shedding may last longer, and, even in the incubation period, infected persons may shed sufficient amounts of virus to cause food contamination.

For prevention of foodborne transmission, it is also essential that food items are not grown or washed in fecally contaminated water.

For shellfish, strict control of the quality of growing waters can prevent contamination of shellfish. This includes control of waste disposal by commercial and recreational boats. Guidelines specifically aimed at reduction of viral contamination are needed, as it has become clear that the current indicators for water and shellfish quality are insufficient as predictors of viral contamination.

At the community level adequate chlorination of water and prevention of gross contamination of water supplies by sewerage will also help to prevent hepatitis A.

Passive immunisation with human immunoglobulin containing IgG anti-HAV had been the mainstay of prophylaxis for about 50 years, well before the protective antibody could be serologically identified and before HAV vaccines were available. Low blood concentrations of anti-HAV produced by intramuscular injection of immunoglobulin provide pre-exposure protection against clinical disease in a substantial proportion of recipients. Immunoglobulin for intramuscular administration, manufactured in the USA and western Europe, has a good safety record, but has been in short supply from time to time. Its use is declining now that HAV vaccine is being used more widely. Currently, in the USA, immunoglobulin is still recommended for protection from hepatitis A in children younger than 2 years, because residual anti-HAV passively acquired from the mother may interfere with vaccine immunogenicity. Immunoglobulin is ineffective in the control of hepatitis A in hyperendemic areas or for interrupting community-wide or common-source outbreaks.

In the USA, when a foodhandler is identified with hepatitis A, it is recommended that IG be given to other foodhandlers at the establishment, and, under limited circumstances, to patrons. Once cases are identified that are associated with a food service establishment, it is generally too late to administer IG to patrons, since the 2-week period during which IG is effective will have passed. This factor may explain some of the lack of success of IG treatment as outbreak interventions

Efficacy is greatest when IG is administered early in the incubation period; when administered later in the incubation period, IG often only attenuates the clinical expression of HAV infection.

Clinical trials conducted over the past 40 years using different batches of immune globulin have demonstrated the continued efficacy of this biological product in preventing clinical hepatitis when administered either prior to exposure or during the incubation period.

The duration of protection is dose-dependent and short; even large doses protect for no more than 4-6 months. Immunoglobulin is ineffective in the control of hepatitis A in hyperendemic areas or for interrupting community-wide or common-source outbreaks.

Serious adverse events from IGIM are rare. Anaphylaxis has been reported after repeated administration to persons who have known immunoglobulin A (IgA) deficiency; thus, IGIM should not be administered to these persons. Pregnancy or lactation is not a contraindication to IG administration.

IG can interfere with the response to other live, attenuated vaccines (e.g., measles, mumps, rubella vaccine [MMR] and varicella vaccine) when administered as either individual or combination vaccines. Administration of MMR should be delayed for at least 3 months, and varicella vaccine should be delayed for at least 5 months after administration of IG for hepatitis A prophylaxis. IG should not be administered within 2 weeks after the administration of MMR or within 3 weeks after varicella vaccine unless the benefits of IG administration exceed the benefits of vaccination.

Immunoglobulin is ineffective in the control of hepatitis A in hyperendemic areas or for interrupting community-wide or common-source outbreaks.

Vaccination of individuals most susceptible to HAV infection is the cornerstone of outbreak control. Long-term prevention of outbreaks will be achieved through a high vaccination rate in schools and day care centres.

Highly effective inactivated hepatitis A vaccines are available for use before exposure. To reduce the frequency with which foodhandlers with hepatitis A are identified, vaccination of foodhandlers has been advocated and implemented in some cities in the USA. However, such policies have not been shown to be cost effective and generally are not recommended in the USA or other developed countries.

Hepatitis A vaccine is recommended for persons at increased risk of hepatitis A (e.g., international travelers, men who have sex with men [MSM], injection-drug users [IDUs], and noninjection-drug users) and also for children in states and counties that have historically had consistently elevated rates of hepatitis A.

Inactivated and attenuated hepatitis A vaccines have been developed and evaluated in human clinical trials and in nonhuman primate models of HAV infection; however, only vaccines made from inactivated HAV have been evaluated for efficacy in controlled clinical trials. The vaccines containing HAV antigen that are currently licensed in the United States are the single-antigen vaccines HAVRIX (manufactured by GlaxoSmithKline, Rixensart, Belgium) and VAQTA (manufactured by Merck & Co., Inc., Whitehouse Station, New Jersey) and the combination vaccine TWINRIX (containing both HAV and HBV antigens; manufactured by GlaxoSmithKline). All are inactivated vaccines.

The first inactivated HAV vaccine (Havrix, SmithKline Beecham), became available in Europe in 1992 and was approved in the USA in 1995; the second killed vaccine came in 1996 (Vaqta, Merck). Both are whole-virus preparations, produced by growth of attenuated HAV strains in tissue culture and inactivated with formaldehyde. Another vaccine, developed in Switzerland and not yet widely available, incorporates immunogenic HAV particles, inactivated with formaldehyde, within reconstituted influenza virosomes. The HAV vaccines are stable and may be stored for 2 years at 4 C without an adverse effect on immunogenicity; all have been well tolerated.

An inexpensive, live, attenuated vaccine has been produced in China, and millions of Chinese may have been immunized. Little information is currently available about these preparations. The H2-strain vaccine does not induce seroconversion if given orally, but nearly all of the individuals given the vaccine subcutaneously developed antibodies.

The Chinese H2-strain vaccine gave 100% protective efficacy during a 4-year period at 11 primary schools. A large-scale vaccination programme among children aged 1-15 years reduced the number of cases.

The efficacy of HAVRIX was evaluated in a double-blind, controlled, randomized clinical trial conducted in Thailand among approximately 40,000 children 1-16 years of age living in villages that had high rates of hepatitis A. After two doses of vaccine (360 EL.U. per dose) administered 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval, 79%-99%). A double-blind, placebo-controlled, randomized clinical trial using VAQTA was conducted among approximately 1,000 children 2-16 years of age living in a New York community that had a high rate of hepatitis A. The protective efficacy against clinical hepatitis A was 100% (lower bound of the 95% confidence interval, 87%) after administration of one dose (25 U) of vaccine. In a small randomized trial, investigators found that hepatitis A vaccine was 79% efficacious in preventing IgM anti-HAV positivity after household exposure to hepatitis A when compared with no treatment.

In the United States, in 1999, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommended routine HAV vaccination of children in states, counties, and communities with rates greater or equal to 2 times the 1987-1999 national average (i.e., greater or equal to 20 cases per 100,000 persons) and recommended consideration of routine vaccination of children in areas with rates exceeding the national average (i.e., greater or equal to 10 to 19 cases per 100,000 persons). This expanded use of HAV vaccine has had a dramatic effect on the epidemiology of HAV in the United States. The rate of HAV infection is now at an all-time low of 2.6 cases per 100,000 persons. In Israel, which had reported HAV infection rates of 50.4 cases per 100,000 persons during 1993-1998, a 2-dose HAV vaccination program aimed at children 18-24 months of age (toddlers) resulted in a 95% reduction in the reported incidence of HAV infection in the total population, to 2.2-2.5 cases per 100,000 persons between 2002 and 2004. Of the 433 cases reported nationwide in 2002-2004 for which the patient's vaccination status could be ascertained, 424 patients (97.9%) had received no vaccine.

Long-term protection. Among adults who received three doses of HAVRIX (720 EL.U. per dose at 0-, 1-, and 6-month intervals), 100% of those persons had anti-HAV levels greater than 20 mIU/mL 8 years after the initial dose. Six years after vaccination, all but one of 313 adults administered two doses of 1,440 EL. U. of HAVRIX had anti-HAV levels greater than 20 mIU/mL. Protective levels of anti-HAV were still observed in 99% of 549 children evaluated 5-6 years after receiving VAQTA.

Estimates of antibody persistence derived from kinetic models of antibody decline indicate that protective levels of anti-HAV could be present for greater than or equal to 20 years. Surveillance data and population-based studies are being conducted to monitor the long-term protective efficacy of hepatitis A vaccine and to determine the possible need for a booster dose. In the longest such follow-up reported to date, no cases of hepatitis A have been detected among children followed for 7 years after vaccination.

Hepatitis A vaccine should not be administered to persons with a history of a severe reaction to a prior dose of hepatitis A vaccine or to a vaccine component (e.g., alum, 2-phenoxyethanol [in the case of HAVRIX]). The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk for hepatitis A in women who might be at high risk for exposure to HAV.

LOCAL REACTIONS: Approximately 50,000 persons were administered HAVRIX in prelicensure clinical studies. No serious adverse events were attributed definitively to hepatitis A vaccine. Among adults, the most frequently reported side effects occurring within 3 days after the 1,440 EL.U. dose were soreness at the injection site (56%), headache (14%), and malaise (7%). In clinical studies among children, the most frequently reported side effects were soreness at the injection site (15%), feeding problems (8%), headache (4%), and injection-site induration (4%). Approximately 9,200 persons were administered VAQTA in prelicensure clinical studies, with no serious adverse events reported among participants (156). Among adults, the most frequent side effects that occurred within 5 days following vaccination included tenderness (53%), pain (51%), and warmth (17%) at the injection site and headache (16%). Among children, the most common side effects reported were pain (19%), tenderness (17%), and warmth (9%) at the injection site.

SERIOUS ADVERSE EVENTS: An estimated 1.3 million persons in Europe and Asia were vaccinated with HAVRIX before the vaccine's licensure in the United States in 1995. Reports of serious adverse events, without regard to causality, received by the vaccine manufacturer included anaphylaxis, Guillain-Barre syndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis, encephalopathy, and erythema multiforme. Most of these events occurred among adults, and approximately one third occurred among persons receiving other vaccines concurrently.

In total, greater than 65 million doses of hepatitis A vaccine have been administered worldwide. Reviews of data from multiple sources for greater than 5 years regarding adverse events did not identify any serious adverse events among children or adults that could be definitively attributed to hepatitis A vaccine or an increase in serious adverse events among vaccinated persons above baseline rates.

HAV is most commonly contracted via ingestion; after that, the primary sites of virus replication are postulated to be the oropharynx and gastrointestinal tract. The virus is then transported to the major site of replication, the liver, where shedding into the bile occurs with subsequent passage to the intestines and feces. A brief viremia precedes the appearance of the virus in the stool and liver. For individuals infected with HAV, the concentration of virus excreted in the stool is highest during the 2-week period before the onset of jaundice, and then decreases once jaundice is apparent. Children and infants can continue to shed virus for 4 to 5 months after the onset of clinical illness. During the incubation period, HAV presumably replicates in hepatocytes, and in the absence of an immunologic response, liver injury and clinical symptoms do not occur.

The sequence of events that begins with entry via the gastrointestinal tract and ultimately results in hepatitis has not been completely resolved. Although the primary site of replication for HAV is the hepatocyte, the factor that determines this tissue tropism has not been elucidated. The host-cell receptor used in vivo has not been identified, but in vitro studies suggest it may be a class I glycoprotein. During the incubation period, viremia is observed at about the same time that fecal shedding of HAV is occurring. It is believed that HAV reaches the intestinal tract in the bile. Viremia terminates shortly after hepatitis develops, whereas feces may remain infectious for another 1 to 2 weeks. In some situations, HAV may circulate in the blood enclosed in lipid-associated membrane fragments that may transiently protect the virus from neutralizing antibody. In this regard, vesicular structures containing virus have been observed in cell cultures and in primate hepatocytes and Kupffer cells, where they appear to be released into the biliary system or the blood.

Virus-induced cytopathology may not be responsible for the pathologic changes seen in HAV infection as liver disease may result primarily from immune mechanisms. Antigen-specific T-lymphocytes are responsible for the destruction of infected hepatocytes. Increased levels of interferon have been detected in the serum of HAV-infected patients and are presumably responsible for the reduction in virus burden seen in patients following the onset of clinical disease and in their symptoms. Rarely, patients with acute viral hepatitis A develop features of cholestasis. Confluent hepatic necrosis may lead to fulminant hepatitis and death in 30 - 60% of cases. Death appears to be inevitable when necrosis involves more than 65 - 80% of the total hepatocyte fraction. In patients who survive an episode of acute fulminant hepatic failure, neither functional nor pathologic sequelae are common, despite the widespread necrosis. During the recovery stage, cell regeneration is prominent. The damaged hepatic tissue is usually restored within 8 to 12 weeks.

The incubation period of hepatitis A is 15-50 days, with a mean of about 30 days. HAV is excreted in the faeces for 1-2 weeks before the onset of illness, and for at least 1 week afterwards. Viral shedding is greatest at the onset of symptoms and then declines rapidly. Faecal excretion for several months has been reported in a few infected neonates and adults, measured by highly sensitive techniques, but the epidemiological importance of this finding remains uncertain. HAV RNA can also be detected in blood during the incubation period, acute phase, and 18-30 days after the onset of illness.

The incubation period for hepatitis A, is dependent upon the number of infectious particles consumed. Infection with very few particles results in longer incubation periods. The period of communicability extends from early in the incubation period to about a week after the development of jaundice. The greatest danger of spreading the disease to others occurs during the middle of the incubation period, well before the first presentation of symptoms.

The course of the disease is variable and appears to be affected by a number of factors such as age, gender, and the physical condition of the patient at the onset of disease. In childhood the disease is usually anicteric and frequently asymptomatic - infection being detected only by biochemical evidence of liver dysfunction or by serological tests. Increased severity is marked by a variety of vague complaints such as fatigue, malaise, anorexia, and nausea. These symptoms are usually short lived and followed by a complete recovery.

Many infections with HAV do not result in clinical disease, especially in children. When disease does occur, it is usually mild and recovery is complete in 1-2 weeks. Occasionally, the symptoms are severe and convalescence can take several months. Patients suffer from feeling chronically tired during convalescence, and their inability to work can cause financial loss. Less than 0.4% of the reported cases in the U.S. are fatal. These rare deaths usually occur in the elderly.

Patients progressing to grade 4 encephalopathy have a reasonably good prognosis compared to other aetiologies and survival rates of up to 67% have been obtained with medical management, despite the co-existence of such complications as cerebral oedema, renal and respiratory failure and the metabolic sequelae of acute liver failure.

Patients who develop jaundice are usually able to describe a short prodromal illness lasting from several days to a week or more which is characterized by increasing fatigue, malaise, loss of appetite, nausea, and vomiting. These symptoms are rarely severe enough to cause the patient to stay home from work or seek medical attention. The patient may complain of abdominal discomfort or tenderness over the liver.

In one study in which most of the subjects were children, the mean duration of the prodrome was 5 days; however in 14% of patients, symptoms were detected for 10 or more days prior to the onset of jaundice. Similarly, in a group of British soldiers with hepatitis, the prodromal period was usually less than a week, but exceeded this duration in 12% of patients.

Severe abdominal pain and protracted vomiting are unusual manifestations and should lead the clinician either to question the diagnosis or to suspect a more severe variant of the disease.

65%.

56%.

Arthralgia may occur although it is considerably less common than in patients with hepatitis B.

21%.

29%.

Occasionally, hepatitis A may present in an atypical manner either with diarrhea or fever, cough, or coryza. Such manifestations are more common among young children.

7%.

The icteric phase of hepatitis is ushered in by the appearance of dark, golden-brown urine due to bulirubinuria, followed 1 to several days later by pale stools and yellowish discoloration of the mucous membrane, conjunctivae, sclerae, and skin. The icteric phase begins within 10 days of the initial symptoms in more than 85% of HAV cases.

94%.

84%.

Occasionally, hepatitis A may present in an atypical manner either with diarrhea or fever, cough, or coryza. Such manifestations are more common among young children.

When it begins early in the incubation period, the diarrhea may be secondary to another enteric infection acquired from the same source.

25%.

26%.

49%.

43%.

Flu-like symptoms are common in the early stages of the illness; fever (37.5 to 38.5C) occurs in about three quarters of patients and may be accompanied by chills.

In hepatitis A, fever is a common occurrence, rarely becoming higher than 102F, and is probably only generally related to the intensity of the patient's illness. The fever may be accompanied by chills.

Fever, if present, usually subsides after the first few days of jaundice.

75%.

66%.

Headache may also occur during hepatitis A; this symptom is not generally associated with other forms of hepatitis.

Headache is common but usually mild.

70%.

17%.

Many patients develop itching, which can occasionally be severe enough to require antipruritics, but is usually mild and self limiting.

42%.

The clinical manifestations of HAV infection vary from an asymptomatic course to severe disease with jaundice occasionally culminating in fulminant hepatitis.

Jaundice becomes clinically apparent when the total bilirubin exceeds 2.0 to 4.0 mg.dL.

The recognition of jaundice depends on its intensity and the level of awareness of the patient and his family. Mild icterus may be unrecognized early in the course of the illness if the patient is not yet been examined by a physician. However, when a patient notes that he has dark urine, light-colored stools, or icteric skin or sclerae, he or she usually seeks medical attention. Actually, jaundice may be present at about the time of onset of fatigue and the loss of appetite or it may develop from 1 to 7 days later.

62%.

Among older children and adults, infection is usually symptomatic, with jaundice occurring in greater than 70% of patients.

Loss of appetite is a very common symptom, with the patient not only losing his appetite but often finding the sight or smell of food, especially fatty foods, nauseating.

90%.

54%.

A short prodromal or preicteric phase, varying from several days to more than a week, precedes the onset of jaundice. In more than half of the patients, the prodromal state usually is characterized by anorexia, fever (usually less than 103F), fatigue, malaise, myalgia, nausea, and vomiting. Many of these symptoms may be mediated by interferon induction.

67%.

Myalgia and pharyngitis have also been reported.

In more than half of the patients, the prodromal state usually is characterized by anorexia, fever (usually less than 103F), fatigue, malaise, myalgia, nausea, and vomiting. Many of these symptoms may be mediated by interferon induction.

52%.

20%.

The cause of nausea and vomiting is not known and has been attributed to inflammation of the mucosa of the stomach and duodenum which can be detected by gastroscopy and X-ray studies in both naturally acquired and experimentally infected infections. In addition patients with hepatitis often lose interest in cigarettes and find cigarette smoke offensive.

87%.

80%.

Paler than usual feces are observed in about half the patients during the first week or so of illness. The color usually returns in the second or third week and is a good marker of clinical improvement.

52%.

24%.

Myalgia and pharyngitis have also been reported.

20%.

14%.

Occasionally, hepatitis A may present in an atypical manner either with diarrhea or fever, cough, or coryza. Such manifestations are more common among young children.

14%.

Vomiting may occur but is usually neither severe nor protracted. The cause of nausea and vomiting is not known and has been attributed to inflammation of the mucosa of the stomach and duodenum which can be detected by gastroscopy and X-ray studies in both naturally acquired and experimentally infected infections.

71%.

80%.

77%.

(A) : Hepatitis A cannot be differentiated from other types of viral hepatitis on the basis of clinical or epidemiologic features alone. Serologic testing to detect immunoglobulin M (IgM) antibody to the capsid proteins of HAV (IgM anti-HAV) is required to confirm a diagnosis of acute HAV infection. Sensitive tests for IgM and immunoglobulin G (IgG) anti-HAV in saliva have been developed but are not licensed in the United States. In the majority of persons, serum IgM anti-HAV becomes detectable 5-10 days before onset of symptoms. IgG anti-HAV, which appears early in the course of infection, remains detectable for the person's lifetime and provides lifelong protection against the disease. Two serologic tests are licensed for the detection of antibodies to HAV: 1) IgM anti-HAV and 2) total anti-HAV (i.e., IgM and IgG anti-HAV, referred to in this report as anti-HAV). In the majority of patients, IgM anti-HAV declines to undetectable levels <6 months after infection. However, persons who test positive for IgM anti-HAV >1 year after infection have been reported, as have likely false-positive tests in persons without evidence of recent HAV infection. Total anti-HAV testing is used in epidemiologic studies to measure the prevalence of previous infection or by clinicians to determine whether a person with an indication for pre-exposure prophylaxis is already immune. HAV RNA can be detected in the blood and stool of the majority of persons during the acute phase of infection by using nucleic acid amplification methods, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates for epidemiologic investigations. However, only a limited number of research laboratories have the capacity to use these methods.

If laboratory tests are not available, epidemiologic evidence can help in establishing a diagnosis.

(B) : FULMINANT HEPATIC FAILURE: Fulminant hepatic failure is said to be an uncommon complication, occurring in only 0.14-0.35% of hospitalized cases. However, an increasing incidence has been documented in some northern European countries where up to 20% of cases of fulminant viral hepatitis is due to hepatitis A. The diagnosis is established with the onset of encephalopathy.

Postexposure prophylaxis with immunoglobulin is more than 85% effective in preventing hepatitis A if administered within 2 weeks after exposure to HAV, but the efficacy is highest when administered early in the incubation period. There are several specific circumstances in which the use of postexposure prophylaxis is indicated, including use for nonimmune persons who have had (1) household or sexual contact with an HAV-infected person during a time when the HAV-infected person was likely to be infectious (i.e., 2 weeks before to 1 week after onset of illness), and (2) whose last contact was within the previous 2 weeks.

People who have contact with individuals with hepatitis A should receive an intramuscular injection of immunoglobulin as soon as possible after recognition of infection in the index case. Immunoglobulin may not be effective if given more than 2 weeks after exposure. The duration of protection is dose-dependent and short; even large doses protect for no more than 4-6 months.

Serious adverse events from IGIM (Immunoglobulin Intramuscular) are rare. Anaphylaxis has been reported after repeated administration to persons who have known immunoglobulin A (IgA) deficiency; thus, IGIM should not be administered to these persons. Pregnancy or lactation is not a contraindication to IG (Immunoglobulin) administration.

Immunoglobulin is ineffective in the control of hepatitis A in hyperendemic areas or for interrupting community-wide or common-source outbreaks.

Preexposure Protection Against HAV Infection: The following recommendations for hepatitis A vaccination are intended to further reduce hepatitis A morbidity and mortality in the United States and make possible consideration of eventual elimination of HAV transmission. Hepatitis A vaccination is recommended routinely for children, for persons who are at increased risk for infection, and for any person wishing to obtain immunity. CHILDREN: (1) All children should receive hepatitis A vaccine at age 1 year (i.e., 12--23 months). Vaccination should be completed according to the licensed schedules and integrated into the routine childhood vaccination schedule. Children who are not vaccinated by age 2 years can be vaccinated at subsequent visits. (2) States, counties, and communities with existing hepatitis A vaccination programs for children aged 2--18 years are encouraged to maintain these programs. In these areas, new efforts focused on routine vaccination of children aged 1 year should enhance, not replace, ongoing programs directed at a broader population of children. (3) In areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children aged 2--18 years can be considered. Such programs might especially be warranted in the context of increasing incidence or ongoing outbreaks among children or adolescents.

The effectiveness of postexposure prophylaxis using hepatitis A vaccine has not been directly compared with immunoglobulin in a controlled clinical trial, and immunoglobulin remains the recommended choice for postexposure prophylaxis in the United States. Hepatitis A vaccine can be given at the same time (but in a different anatomic site) as immunoglobulin, and exposed persons who have an indication for vaccination should receive both.

The vaccine should be administered intramuscularly into the deltoid muscle. A needle length appropriate for the person's age and size should be used. VAQTA is licensed in two formulations, which differ according to the person's age. Persons aged 12 months--18 years should receive 25 U per dose in a 2-dose schedule; persons aged >18 years should receive 50 U per dose in a 2-dose schedule. HAVRIX is available in two formulations, which differ according to the person's age: for persons aged 12 months--18 years, 720 EL.U. per dose in a 2-dose schedule; and for persons aged >18 years, 1,440 EL.U. per dose in a 2-dose schedule. A pediatric formulation of 360 EL.U. per dose administered in a 3-dose schedule is no longer available. TWINRIX is licensed for use in persons aged 18 or >18 years. TWINRIX is a combined hepatitis A and hepatitis B vaccine containing 720 EL.U. of hepatitis A antigen (half of the HAVRIX adult dose) and 20 mcg of recombinant hepatitis B surface antigen protein (the same as the ENGERIX-B adult dose). Primary immunization consists of 3 doses, administered on a 0-, 1-, and 6-month schedule, the same schedule as that commonly used for single-antigen hepatitis B vaccine. TWINRIX contains aluminum phosphate and aluminum hydroxide as adjuvant and 2-phenoxyethanol as a preservative. After 3 doses of TWINRIX, antibody responses to both antigens are equivalent to responses seen after the single-antigen vaccines are administered separately on standard schedules.

Hepatitis A vaccine should not be administered to persons with a history of a severe allergic reaction to a previous dose of hepatitis A vaccine or to a vaccine component. The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretic risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk for hepatitis A in pregnant women who might be at high risk for exposure to HAV.

LOCAL REACTIONS: Approximately 50,000 persons were administered HAVRIX in prelicensure clinical studies. No serious adverse events were attributed definitively to hepatitis A vaccine. Among adults, the most frequently reported side effects occurring <3 days after the 1,440-EL.U. dose were soreness at the injection site (56%), headache (14%), and malaise (7%). In clinical studies among children, the most frequently reported side effects were soreness at the injection site (15%), feeding problems (8%), headache (4%), and injection-site induration (4%). The frequency of side effects after administration of TWINRIX was similar to those reported when the two single-antigen vaccines were administered. Approximately 10,000 persons were administered VAQTA in prelicensure clinical studies, and no serious adverse events were reported among participants. Among adults, the most frequent side effects that occurred <5 days after vaccination included tenderness (53%), pain (51%), and warmth (17%) at the injection site and headache (16%). Among children, the most common side effects reported were pain (19%), tenderness (17%), and warmth (9%) at the injection site.

SERIOUS ADVERSE EVENTS: An estimated 1.3 million persons in Europe and Asia were vaccinated with HAVRIX before the vaccine's licensure in the United States in 1995. Reports of serious adverse events, without regard to causality, received by the vaccine manufacturer included anaphylaxis, Guillain-Barre syndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis, encephalopathy, and erythema multiforme. The majority of these events occurred among adults, and approximately one third occurred among persons receiving other vaccines concurrently.

Since vaccine licensure in 1995, approximately 188 million doses of hepatitis A vaccine have been sold worldwide, including 50 million doses in the United States. During January 1995--October 2005, VAERS received 6,136 reports of adverse events among persons who received hepatitis A vaccine, with or without other vaccines. The most common events were fever, injection-site reactions, rash, and headache. The 871 reports of serious adverse events included reports of Guillain-Barre syndrome, transaminitis, and idiopathic thrombocytopenic purpura, which had been described previously in a published safety review, and seizures among children. The relation, if any, between the vaccine and reported serious events was not clear. In the original safety review, reported adverse events were similar for VAQTA and HAVRIX. The safety of the vaccine will continue to be assessed through ongoing monitoring of data from VAERS and other surveillance systems. Any adverse event suspected to be associated with hepatitis A vaccination should be reported to VAERS. Information on how to report adverse events is available at http://www.fda.gov/cber/vaers/vaers.htm; forms for this purpose can be obtained at telephone 800-822-7967.

EFFECTIVENES IN OUTBREAK SETTINGS: Several studies have examined the effectiveness of hepatitis A vaccine in controlling outbreaks in communities that have high rates of hepatitis A. Administration of hepatitis A vaccine to children aged 2-16 years during a clinical trial evaluating vaccine efficacy resulted in a substantial decrease in community hepatitis A rates, and ongoing vaccination of young children has prevented expected communitywide outbreaks in subsequent years. In several Alaskan villages in which hepatitis A outbreaks were occurring, vaccination of children and adolescents and of susceptible adults with one dose of hepatitis A vaccine resulted in a rapid decrease in the number of new cases. In addition, in several American Indian communities experiencing outbreaks, early and rapid implementation of childhood hepatitis A vaccination programs stopped the outbreaks.

Hepatitis A vaccine has been used in several communities that have intermediate rates of hepatitis A and were experiencing outbreaks. In Butte County, California, hepatitis A incidence decreased concurrently with the implementation of a program in which approximately 37% of children aged 2-12 years were administered one dose of hepatitis A vaccine. In Memphis, Tennessee, following a targeted vaccination program in which one dose of vaccine was administered to 52% of eligible children aged 2-9 years, hepatitis A rates decreased in this target population. In two villages in Slovakia, a communitywide outbreak ended 2 months after approximately two thirds of school-age children were administered two doses of vaccine.

Symptomatic viral hepatitis A usually only requires supportive therapy and the majority of cases are managed in the community.

As no specific treatment for hepatitis A has been shown to be effective, prevention is the most effective approach against the disease. Therapy should be supportive and aimed at maintaining adequate nutritional balance (1 g/kg protein, 30-35 cal/kg). There is no good evidence that restriction of fats has any beneficial effect on the course of the disease. Eggs, milk and butter may actually help provide a correct caloric intake. Hospitalization is usually not required.

FULMINANT HEPATIC FAILURE: Some patients require emergency liver transplantation. Transplantation is especially required in older patients (over 40 years) and those who are jaundiced for more than 7 days before the onset of encephalopathy. The serum bilirubin and the prothrombin time complement these parameters in the decision making process.

Autoantibodies directed against liver plasma membrane antigens have been described in patients with acute viral hepatitis, type A (AVH-A). The antibody against one such liver membrane antigen, liver specific membrane lipoprotein (LSP), was assayed in six marmosets orally inoculated with hepatitis A virus (HAV).

Guinea pigs

A study was undertaken to determine whether HAV can infect guinea pigs and whether they are useful as a model for studying aspects of HAV pathogenesis and for the evaluation of vaccines. HAV variants adapted to primate or guinea pig tissue culture were used to inoculate guinea pigs intraperitoneally and by the oral route. The animals were observed for clinical disease, shedding of HAV in stools, viremia, seroconversion, evidence for liver damage by biochemical liver function tests, virus presence in the liver, development of hepatic histopathological changes, and occurrence of HAV in extrahepatic organs. The animals developed an active, clinically inapparent infection with specific histopathological changes in the liver. Although virus replication occurred, as shown by RT-PCR and isolation of infectious virus from feces and serum, it seems unlikely that guinea pigs are suitable for studying the clinical features of hepatitis A, because the clinical and laboratory parameters remained normal. However, guinea pigs would be useful for studying some aspects of HAV pathogenesis and for testing the safety of vaccines.

A hepatitis A vaccine was prepared by formaldehyde inactivation of purified hepatitis A virus (HAV) LSH/S strain grown on human diploid MRC-5 cells. The vaccine was devoid of residual infectivity in vitro and failed to induce in marmoset monkeys any pathological features or variations of haematological and clinical chemistry values. Infectious HAV particles were not detected in faeces and sera of the vaccinated primates by ELISA or after passages in MRC-5 cells. The immunogenicity of the vaccine was evaluated by injecting guinea-pigs with 0.8, 0.2 or 0.05 micrograms of HAV antigen adsorbed onto 0.5 and 1 mg of Al (OH)3 or 0.3 mg of AlPO4. The antibody response, measured by a competitive radioimmunoassay, was dose- and adjuvant-dependent. One injection of 0.2 micrograms of AlPO4-adsorbed HAV antigen induced seroconversion in 100% of animals and high levels of specific and neutralizing serum antibodies. A further increase of antibody titres was observed after the second and third inoculations.

The development of spontaneous outbreak of hepatitis A (HA) among African green monkeys kept under strict isolation conditions was studied. It was shown that in the case of introduction of HAV the infection involved all the susceptible monkeys, running a course with and without any increase in the level of activity of serum alanine aminotransferase (ALT). After inoculation of commercial gamma-globulin only the infection without the ALT activity increase developed and some monkeys had no signs of HA at all. Experimental reinfection with HAV was produced in monkeys having anti-HAV titres of less than or equal to 1:3500.

A long-term complex observation of 8 African green monkeys (Cercopithecus aethiops) with spontaneous and experimental hepatitis A revealed two forms of the illness: acute and chronic. Some monkeys developed undulating chronic course of the disease consisting of 2-6 waves. Others developed relapses (1 to 3) which occurred within 2-4 or 6-11.5 months of the infection. The morphological changes in the liver persisted for 7-28 months. Alanine aminotransferase elevations in the blood and HAV shedding in feces were observed periodically for 7-20 months. Persisting HAV was shown to remain pathogenic for monkeys.

HA was induced in macaques as a result of infection with human hepatitis A virus (HAV-h). Disease similar to human HA was induced in cynomolgus macaques by HAV isolates from spontaneously sick rhesus (M. mulatta) and green monkeys. This experimental model of HA in macaques can be used for vaccine and anti-viral preparation testing.

Experimental hepatitis A (HA) models were obtained in macaca monkeys (15 M. fascicularis and 4 M. mulatta) by means of hepatitis A virus (HAV) isolated from the feces of a patient (HAV-H) and of spontaneously infected M. mulatta (HAV-MM) and green monkeys Cercopithecus aethiops (HAV-CA). Irrespective of the strains used all seronegative macaca monkeys developed HA after intravenous-oral inoculation with the following patterns: elevation of the serum alanine aminotransferase level, HAV shedding in feces, seroconversion with the appearance of anti-HAV IgM and morphological changes in the liver characteristic of acute hepatitis. HAV in fecal samples and elevation of alanine aminotransferase were periodically detected. Periods of their discovery varied from 5-22 to 15-47 days and those of morphological changes in the liver from 9-24 to 40-83 days. The results of the experiments show that experimental HA models in Macaca monkeys are no less adequate than the previous ones developed in chimpanzees (Pan troglodytes), marmosets (Saguinus mystax) and owl monkeys (Aotus trivirgatus), but they are more readily available. Both strain HAV-H and strains from monkeys can be used for HA modelling.

Hepatitis A infection characterized by virus excretion in feces, synthesis of specific IgM antibody, increased activity of alanine aminotransferase in the blood serum, and a complex of morphological lesions in the liver typical of acute hepatitis was reproduced in M. fascicularis (M. f.) and Macaca rhesus (M. r.) using 2 strains of hepatitis A virus (HAV) isolated from human patients. The incubation period varying from 9 to 23 (mean 16) days in M. f. and from 12 to 35 (mean 18) days in M. r. in primary infection shortened to 1-12 (mean 10) and 3-6 (mean 5) days in the process of virus passage from monkey to monkey. The disease was observed to run both manifest forms (except jaundice) typical of human HA and an inapparent form in which the level of enzymes remained within normal limits but HAV could be detected in feces, anti-HAV-IgM in the blood serum, and morphologically acute hepatitis in the liver.

The pathogenesis of hepatitis A virus (HAV) infection was studied in owl monkeys following oral administration of the wild-type HM-175 strain of HAV. Stools were collected daily and blood and pharyngeal swabs twice weekly for viral isolation, and animals were necropsied at various intervals after inoculation. Organs were examined for the presence of virus by isolation in cell culture and for viral antigens by immunofluorescence. Monkeys excreted HAV in the stools for 1-4 days after inoculation, presumably due to the residual unabsorbed inoculum. No virus was found in stools for the next 2-3 days. HAV re-appeared on days 4-7 and then persisted through day 39. Viremia occurred on the 10th day and continued until day 35. Virus was isolated occasionally from throat swabs 1 or 2 weeks after it was detected in stools and blood, and there was no evidence that HAV replicated in the pharyngeal tissues. Animals acquired anti-HAV antibody by the 4th week, and alanine aminotransferase (ALT) was elevated 5-5.5 weeks after inoculation. HAV was isolated from liver 5 days after inoculation; however, viral antigens were first detected in Kupffer cells of the liver at 14 days and in hepatocytes at 21 days. HAV antigen was detected in epithelial cells of the intestinal crypts and in the cells of the lamina propria of the small intestine 3 days postinoculation and thereafter until the 5th week.

Aotus sp. provides a useful animal model of human hepatitis A. 12 seronegative, colony-bred monkeys were inoculated intravenously with a fecal suspension containing either PA33 strain hepatitis A virus (a strain recovered from a naturally infected Aotus sp.) or HM-175 virus (recovered from a human). Viral antigen was detected by radioimmunoassay in the feces of six monkeys 6 to 17 days after inoculation with PA33 virus, and by 9 to 21 days serum aminotransferase activities were significantly elevated in each. Antibody to the virus developed in each monkey by 28 days after inoculation. Similar findings were noted in five of six monkeys inoculated with HM-175 virus, although the incubation period preceding aminotransferase elevations was somewhat longer (25 to 39 days). Liver biopsies obtained from the 11 infected monkeys demonstrated mild to moderate portal inflammation, as well as random areas of focal necrosis and inflammation extending outward from the portal region.

The susceptibility of chimpanzees to viral hepatitis type A was examined with immune electron microscopy. Of four seronegative infant chimpanzees, two were inoculated with a hepatitis A acute-phase stool filtrate rich in 27 nm virus-like hepatitis A antigen (HA Ag) particles, and two were inoculated with an HA Ag-negative preinfection stool filtrate. One of each pair of chimpanzees was inoculated intravenously, the other orally. One month later both chimpanzees that had received the HA Ag-positive filtrate developed biochemical, histologic, and clinical evidence of acute viral hepatitis. HA Ag particle (27 nm) were detected in their stools by immune electron microscopy; particle shedding followed a pattern similar to that in human volunteers. Immune electron microscopy also showed that antibody HA Ag had developed in the convalescent-phase sera of the infected chimpanzees. Control animals remained free of illness but later developed hepatitis three to five weeks after exposure to the two infected chimpanzee. The infectious inoculum was titrated in two additional seronegative chimpanzees.

The effect of hepatitis A vaccine in preventing infection following fecal-oral exposure was evaluated in a chimpanzee model of HAV infection. Two animals were vaccinated 1 and 3 days, respectively following inoculation and two inoculated animals served as unprotected controls. Of the two immunized animals, one had no evidence of HAV infection, while the other had an attenuated infection with no evidence of virus shedding.

Shedding of HAV in the feces of intravenously infected chimpanzees was first reported by Maynard et al. and Dienstag and his colleagues. In the first study, three animals were inoculated intravenously with a filtrate pool of feces collected from seven patients who had been involved in a common-source epidemic of hepatitis A. All of the animals developed biochemical hepatitis within 17 days of inoculation and examination of pooled fecal specimens collected just prior to and during the acute phase of the illness revealed the presence of HAV particles in two of three animals. A fecal filtrate from one of these animals transmitted hepatitis to another chimpanzee and the virus was also recovered from the feces of this animal. These findings were extended by Dienstag et al. who infected chimpanzees by inoculating them intravenously with 1ml of a 0.2% (w/v) filtrate of a human stool in which HAV had been detected by IEM. The animals developed biochemical and histological evidence of hepatitis 19 and 20 days after inoculation. HAV particles were detected, not only in the feces of these animals, but in aliquots of liver and bile collected during the acute phase of the illness.

Various species of macaque monkeys are reported to have naturally occurring antibodies to HAV and infection has apparently been transmitted and serially passaged in stump-tailed monkeys (Macaca speciosa) which developed histological and biochemical evidence of infection.

The newly-caught stump-tailed monkeys (Macaca speciosa) with negative antibody to hepatitis A were inoculated with human hepatitis A virus. The following findings were observed in the monkeys after inoculation: (i) the elevation of activities of the serum glutamic-pyruvic transaminase, lactate dehydrogenase and its isoenzyme (LDH5), (ii) the seroconversion of antibody to hepatitis A virus, and, (iii) the shedding of hepatitis A antigen in feces. These findings show that the stump-tailed monkey (Macaca speciosa) is susceptible to infection of human hepatitis A virus. The virus recovered from the feces of the infected monkey, named as Hang-zhou A-1A strain of hepatitis A virus, has experienced two generations of successful transmission in monkeys.

Grabow and Prozesky reported that a small African non-human primate, with a wide geographical distribution, the lesser bush baby (Galago senegalensis) may be susceptible to infection with hepatitis A virus.

A group of 38 bush babies (36 G. senegalensis moholi and 2 G. crassicaudatus), each of which was inoculated, with CR 326 or HAV-positive human or chimpanzee stools. The two G. crassicaudatus animals did not respond but in 31 G. senegalensis moholi animals serum transaminase levels increased, 22 developed anti-HAV, and HAV antigen was detected in stools of 3 animals. The pattern of disease resembled that seen in man, chimpanzees, and marmosets, but although lesser bush babies may be susceptible to HAV, they appear to be less so than chimpanzees or marmosets.

Primate

The host range of HAV is limited to humans and a few other primate species.

Bush baby

Galago sp.

Grabow and Prozesky reported that a small African non-human primate, with a wide geographical distribution, the lesser bushbaby (Galago senegalensis) may be susceptible to infection with hepatitis A virus.

Chimpanzee

Pan troglodytes

Hepatitis A infection has been reported to occur in captive non-human primates including the great apes (chimpanzee) as well as Old World (cynomolgus, African vervet, stump-tailed) and New World (aotus) monkeys. The presence of anti-HAV antibody in the sera of newly captured monkeys of these species shows that infection may also spread in their natural habitat.

The epidemiology of hepatitis A and B in the chimpanzee colony at the London Zoo between 1960 and 1978 was investigated. No evidence of hepatitis A infection was found in the colony. All chimpanzees with antibodies to hepatitis A had been caught in the wild.