1558 SECTION 17  Viral Infections
168  Hepatitis A Virus
Yen H. Pham • Daniel H. Leung
HISTORY
Hepatitis A has been recognized as a clinical entity for centuries, notably
as large epidemics of jaundice among military camps in both ancient
and modern times. During the past several decades, epidemiologic and
clinical studies have defined the infectious nature of the disease, leading
to the differentiation of “infectious hepatitis,” now known as hepatitis
A.206 In the 1970s, isolation of hepatitis A virus (HAV) and identification
by immune electron microscopy among stool samples of patients
with HAV133 led to understanding of the fecal-oral route of transmission,
the clinical course of infection, and the efficacy of immunoglobulin
in preventing disease.206,207,423 This hastened the development of
serologic tests that differentiate acute and resolved infections, definitions
of pathogenic events during infection, and further epidemiologic
study of HAV infection. Following propagation of HAV in cell
culture,88,304,404,406 the evolution and licensure of highly effective vaccines
have dramatically changed the landscape of HAV infection, though
certainly not eradicated it.61,264,408
PROPERTIES
Classification
HAV is a 27-nm, nonenveloped, positive-sense RNA virus belonging
to the family Picornaviridae. Although HAV initially was classified in
the genus Enterovirus, nucleotide analysis indicates that HAV is distinct
from all other picornaviruses. 222,225,395,416 In contrast to other enteroviruses,
HAV has essentially no nucleotide or amino acid homology, does not
have an intestinal replication phase, replicates slowly in cell culture,
rarely produces a cytopathic effect, and is relatively resistant to inactiva-
tion by heating.87 For these reasons, HAV has been reclassified in a
separate genus designated Hepatovirus.257,416
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Genomic Organization and Genetic Variation
Hepatitis A is composed of an icosahedral capsid that contains a positive-
sense, single-stranded RNA genome of approximately 7.5 kb in length
with a single open reading frame flanked by 5′ and 3′ untranslated
regions (UTR). The 5′ UTR is the most conserved region of the genome
and contains an internal ribosome entry site. The open reading frame
encodes a polyprotein organized into three functional regions: P1, P2,
and P3. P1 is secondarily cleaved into four capsid proteins, VP1 to VP4,
whereas P2 and P3 proteins encode nonstructural proteins associated
with replication.222,225,363,405,406,416
HAV exists as a single serotype. The neutralization site appears to
be conformational and derived from epitopes located on VP1 and VP3,
as identified by neutralizing monoclonal antibodies.268,299 A high degree
of nucleotide conservation exists among geographically diverse human
HAV isolates. However, enough genetic diversity exists to define several
HAV genotypes and subgenotypes. The entire nucleic acid sequences
of several HAV strains have been determined by molecular cloning,
and a large number of HAV isolates have been characterized by sequenc-
ing of short genome segments.270
The genomic regions most commonly used to define HAV genotypes
include (1) the C terminus of the VP3 region, (2) the N terminus of
the VP1 region, (3) the junction of the VP1 and P2A regions, and (4)
the VP1-P2B regions and the entire VP1 region (Fig. 168.1).81,270
Six genotypes (I to VI) are now defined based on analysis of the
900 nucleotides of the complete VP1 protein. Only genotypes I, II, and
III, divided into subtypes A and B, infect humans. The other three (IV,
V, and VI) appear to be restricted in their primary replication to Old
World monkeys.269,376
The worldwide geographic distribution of HAV serotypes has been
well described.81,270,315 Genotype I is the most prevalent worldwide,
particularly genotype IA, which dominates in North, Central, and South
 CHAPTER 168  Hepatitis A Virus 1559

Structural proteins Non-structural proteins

V Pg 5’ UTR VP4 VP3 VP2 VP1 2A 2B 2C 3A 3B 3C 3D 3’ UTR poly(A)

900 nucleotides

VP3 VP1 2A

VP3 C terminus VP1 N terminus VP1–2A junction

(206 nucleotides) (171 nucleotides) (168 nucleotides)
Fig. 168.1  Genomic organization of hepatitis A virus.

America; China; Japan; Thailand; and Europe.48,177,184,315 Subgenotype Transmission of Hepatitis A

IB is reported mainly from the Mediterranean region and South Africa
and is the most prevalent in Turkey.278 Subgenotype IIIA is the most
prevalent in India, Nepal, and Korea.170,348,421 In low-endemicity areas,
such as the United States and Western Europe, subgenotype IA dominates,
although all genotypes have been reported.82,270 Of note, subgenotypes A person acquires
IIA, IIB, and IIIB rarely have been reported.102 hepatitis A virus by
ingesting contaminated
The analysis of the other genomic regions (i.e., the N terminus of
food or water
the VP1, VP1-2B regions, the entire VP, and the C terminus of VP3)
allows better strain discrimination. Growing sequence databases allow
for the identification of the geographic origin of a given subgenotype.
This genetic variation has proved useful in identifying clusters and
linking apparently sporadic cases.10,101,167,172,267,313
Genotype does not appear to influence the clinical presentation or
outcome of infection,2,144,170 although outbreaks in Korea suggest that
genotypes might account for differences in disease severity. Report of
a national hepatitis A outbreak in Korea from 2006 to 2008 indicated
that genotype IIIA infection demonstrated significantly higher trans-
aminase levels, prothrombin time, and leukocyte count, with more severe
symptoms including fever and dark urine on admission compared to
genotype IA infection.421 Similarly, another Korean study found genotype The virus multiplies
IIIA to be associated with higher alanine transaminase (ALT) levels and in liver cells, enters
longer hospitalization among adolescents and young adults in a multivari- the bloodstream,
ate logistic regression model.419 Raw sewage can and travels to the
spread hepatitis A digestive tract
Virulence to food and to
HAV is known to produce disease in humans and nonhuman primates. drinking water
HAV replicates more slowly in cell culture than other picornaviruses,
and wild-type viruses may require many weeks of adaptation or serial
passages before infectious foci or HAV antigen is detected.33,219,222,284,342
With increasing passage in cell culture, the virus adapts to growth in
vitro with more rapid production of viral antigen and increasing virus The virus exits
titers. HAV produces a high ratio of defective to complete (infectious) the body in the stool
virus both in cell culture and during infection.43,416 Cell culture adaptation
FIG. 168.2  Transmission of hepatitis A.
is associated with mutations in nonstructural proteins and the 5′
nontranslated region.121,123 Mutations in the VP1/2A and 2C genes are
associated with loss of virulence, but virulence can be restored if genes
from the wild-type virus are reintroduced.122 Cell culture-adapted HAV
rarely produces a cytopathic effect, although cytopathic strains have
been isolated and serve as a useful model for laboratory studies.88,272 only partially at 60°C (140°F) for 1 hour.87 Temperatures of 85° to 95°C
The HAV virion appears to be extremely stable, although the (185°F–203°F) for 1 minute are required for complete inactivation of
molecular determinants of this characteristic are not known. HAV is HAV in foods such as shellfish.87,257 HAV is also completely inactivated
stable in the environment, with only a 100-fold decline in infectivity by formalin (0.02% at 37°C [98.6°F] for 72 hours) but appears to be
when it is stored for longer than 4 weeks at room temperature.87,246,247,294 relatively resistant to free chlorine, especially when the virus is associated
The virus retains infectivity even when treated with nonionic detergents, with organic matter.235,339 For general-purpose disinfection, a 1 : 100
organic solvents, and low pH at 38°C (100.4°F) for 90 minutes.87,256 dilution of 5% sodium hypochlorite (i.e., household bleach) in tap
HAV is more resistant than poliovirus to heat in that it is inactivated water inactivates HAV in most situations.61,130,131

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1560 SECTION 17  Viral Infections
EPIDEMIOLOGY
Routes of Transmission
Routes of HAV transmission are determined by the timing and location
of virus replication, circulation, and excretion during infection. HAV
replicates in the liver, is excreted in bile, and is found in highest concentra-
tion in stool (up to 108 infectious particles per milliliter).363 The highest
concentration in stool occurs during the 2-week period before jaundice
develops or liver enzymes become elevated, followed by a rapid decline
after jaundice appears (Fig. 168.2).133,346,363 Children and infants may
shed HAV for longer periods than adults. Through the use of polymerase
chain reaction (PCR) platforms to amplify viral nucleic acid, HAV RNA
has been detected in the stool of infected neonates for as long as 6
months after infection, and some studies have shown excretion in older
children and adults 1 to 3 months after the onset of clinical illness.176,318,420
Chronic shedding of HAV does not occur, although virus may be
detectable in stool during relapsing illness (see the section on relapsing
hepatitis A).345 Viremia occurs during the prodromal stage of infection
and extends through the period of liver transaminase elevation
(Fig. 168.3), with serum viral load several orders of magnitude lower
than those in stool.42,76,208,222,225 In experimentally infected animals, HAV
can be detected in saliva during periods of peak excretion in stool.76
HAV also has been detected in the saliva of infected humans with
concurrent HAV viremia through HAV RNA with identical serum and
saliva sequences.233 This method is recommended for investigation of
outbreaks.6,7 The saliva as an extrahepatic site of early HAV replication
could create a potential risk for saliva-transmitted infection.5
Detection of HAV antigen in stool by enzyme immunoassay or
detection of HAV RNA in serum or stool by PCR does not demon-
strate that an infected person is infectious, because these assays may
detect defective as well as infectious viral particles. HAV RNA may be
detected in stool for months, beyond the period of infectivity. Data
from epidemiologic studies suggest that peak infectivity occurs during
the 2 weeks before the onset of symptoms until 1 to 2 weeks after the
onset of jaundice. Fecal excretion of HAV may persist longer in children
and in immunocompromised persons than in otherwise healthy adults.
The development of the nucleic acid amplification by immunocapture
reverse transcription PCR (RT-PCR) allowed for determination of viral
infectivity by direct RT-PCR on virus captured by monoclonal antibody
in the reaction tube.45,191 Immunocapture RT-PCR is useful to assess the
infectivity of human enteric viral pathogens in the environment to aid in
monitoring of water and food quality and for treatment processes.184,316
Not surprisingly, HAV transmission occurs primarily by the fecal-oral
route, usually by person-to-person transmission in households and
extended-family settings and between sexual contacts.352 Person-to-person
transmission results in high rates of infection in young children in
developing countries and has been the predominant mode of transmission
Clinical illness
Infection ALT
IgG
IgM
Response
Viremia
HAV in stool
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Week
FIG. 168.3  Immunologic, virologic, and biochemical events during the
course of a typical hepatitis A virus (HAV) infection. ALT, Alanine
transaminase; IgG, immunoglobulin G; IgM, immunoglobulin M.
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in the United States, particularly during community-wide outbreaks,
as well as in outbreaks in childcare centers.25,27,37 HAV in feces has been
shown to be infectious even after being dried and stored for 1 month,
and extremely stable in the environment as previously dis-
cussed.247,87,246,247,294 Fecal contamination of food or water can result in
common-source outbreaks. HAV has been transmitted by transfusion,
but such transmission occurs rarely because the blood donation must
occur during the early prodromal stage of the disease or from an
asymptomatic person who is viremic.221,224 In the United States, PCR
is applied to screening of source plasma used for the manufacture of
plasma-derived products. These assays are sufficiently sensitive to remove
most units that have HAV, and serosurveillance for HAV infections
among recipients receiving blood products in the United States indicates
that HAV infections are now rare.50,57
The risk for transmission to newborns by pregnant women with
HAV appears to be low, although data are scarce.71,310, Most infants born
to mothers with HAV infection were not affected and had normal
antibody and transaminase levels.262,327,371 A couple case reports have
described vertical HAV transmission associated with jaundice and raised
liver enzymes during the first weeks of life with uneventful improve-
ment.124,310 Newborns who acquire HAV infection perinatally or from
a transfusion usually are asymptomatic, and the infection is detected
by the development of hepatitis A in hospital staff or other persons
having contact with the infant.318,400 Two published case reports have
described intrauterine transmission of HAV during the first trimester
that resulted in fetal meconium peritonitis.218,248 After delivery, both
infants were found to have a perforated ileum. Another study in Korea
of 12 pregnant women with HAV included 1 case of fetal ascites and
intraabdominal calcification suggestive of meconium peritonitis which
spontaneously resolved in serial sonographic imaging, and 1 case of
confirmed vertical transmission in 2009.71
Although mothers infected with HAV can have anti-HAV immu-
noglobulin (Ig)M and IgG antibodies and HAV RNA in their breast
milk,90,96 transmission by breast milk has not been demonstrated.96
Patterns of Disease Worldwide
Worldwide, the endemicity of HAV infection differs markedly among
and within countries (Fig. 168.4).182 Patterns of HAV infection can be
differentiated, each being characterized by distinct age-specific profiles
of prevalence of antibody to HAV (anti-HAV), incidence of hepatitis
A, and prevailing environmental (hygienic and sanitary) and socioeco-
nomic conditions.23,27,157,159,181,182
In areas with a high endemic pattern of infection, represented by
the least developed countries (i.e., parts of Africa, Asia, and Central
and South America), poor socioeconomic conditions allow HAV to
spread readily (see Fig. 168.4). Most persons are infected as young
children, and essentially the entire population is infected before reaching
adolescence, as demonstrated by the age-specific prevalence of anti-HAV
(Fig. 168.5).22,84,181,333,377 Because virtually all HAV infections occur in
age groups in which asymptomatic infection predominates, reported
disease rates may be low and outbreaks rare.
In areas of intermediate endemicity, HAV is not transmitted as readily
because of better sanitary and living conditions, and the predominant
age at infection is older than that in highly endemic areas.73,181 Paradoxi-
cally, the overall incidence and average age of reported cases often increase
because high levels of virus circulate in a population that includes many
susceptible older children, adolescents, and young adults, in whom
symptoms are likely to develop with HAV infection.155 Large common-
source outbreaks also can occur because of the relatively high rate of
virus transmission and the large number of susceptible persons, especially
among those of higher socioeconomic levels. Such an outbreak occurred
in Shanghai in the late 1980s, with more than 300,000 cases associated
with the consumption of contaminated clams.160 Nonetheless, person-
to-person transmission in community-wide epidemics continues to
account for much of the disease in these countries.391
Considerable hepatitis A-related morbidity and associated costs can
occur. A study at a tertiary care referral hospital in Karachi, Pakistan,
identified 2735 patients younger than 15 years with confirmed hepatitis
A during a 9-year period (1991–98). Of the 2735 patients, 232 were
 CHAPTER 168  Hepatitis A Virus 1561

Pacific
Atlantic
Ocean
Ocean

Indian
Ocean
Estimated
Hepatitis A
Virus Prevalence
High
Intermediate
Low
Very low

FIG. 168.4  Estimated geographic distribution of patterns of endemicity of hepatitis A virus infection.

Europe, and the Middle East) demonstrated a mix of intermediate and

Prevalence of anti-HAV (%)

100
90
80
70
60
50
40
30
20
10
0 in 2009.264 In 2010, 1670 cases were reported to the Centers for Disease
5 10 15 20 25 30
Age (Years)
FIG. 168.5  Distinct age-specific profiles of prevalence of antibody to
hepatitis A virus (anti-HAV).
admitted to the hospital, and 30 patients (1%) developed progressive
hepatic dysfunction and liver failure.329 In one Korean hospital, 304
patients older than 18 years were admitted from 2009 to 2011 with acute
hepatitis A. Of those 304 patients, 18 (5.9%) progressed to acute liver
failure, eight (2.6%) of whom died or underwent liver transplantation.340
In most areas of North America and Western Europe, sanitary and
hygienic conditions are such that the endemicity of HAV infection is
low. Relatively fewer children are infected, and disease often occurs in
the context of community-wide and childcare-center outbreaks and
occasionally as common-source outbreaks.26,27,149,302,330,331,366 In some
regions (e.g., Scandinavia), the endemicity of HAV infection is very
low and disease occurs almost exclusively in defined risk groups, such
as travelers returning from areas where HAV infection is endemic or
illicit drug users.40
Changes have occurred in the epidemiologic trends and patterns
of hepatitis A infection around the world related to vaccine A imple-
mentation, socioeconomic progress, and improvement in hygiene
measures.182,196,210,216,214,260,378
Systematic review and meta-analysis of published data using IgG
anti-HAV seroprevalence data between 1990 and 2005 from different
world regions indicated that high-income regions (i.e., Western Europe,
Australia, New Zealand, Canada, the United States, Japan, the Republic
of Korea, and Singapore) remain as having very low HAV endemicity
levels and a high proportion of susceptible adults. The low-income
regions (i.e., sub-Saharan Africa and parts of South Asia) still present
high endemicity levels and almost no susceptible adolescents and adults,
and most middle-income regions (i.e., Asia, Latina America, Eastern
High
low endemicity levels.182
Intermediate Patterns of Disease in the United States
The epidemiology of hepatitis A in the United States has been altered
profoundly by the introduction of hepatitis A vaccines, with a significant
Low
reduction as a vaccine-preventable infectious disease (Fig. 168.6A). Rates
Very low have declined sharply since the mid-1990s. The rate of HAV disease
was less than one case per 100,000 population in all age groups starting
35 40 45 50+ Control and Prevention (CDC), representing a 94% decline in contrast
to rates from 1990 to 1997 and significantly lower than previous incidence
nadirs.64,65,67,68 Numbers of acute cases reported to CDC further decreased
to 1239 in 2014. However, national surveillance systems collect data on
symptomatic cases, and incidence models indicate that most infections
are not symptomatic. One such analysis estimated that an average of
271,000 infections occurred per year during 1980 to 1999—10.4 times
the reported number of symptomatic cases.12 With use of similar
modeling methodology, an estimated 17,000 infections occurred in
2010 (see Fig. 168.6B).55,66
Variation by Age and Race or Ethnicity
Historically, the highest hepatitis A rates were reported among children
5 to 14 years of age, with approximately one third of cases occurring
in children younger than 15 years.62 Because many young children have
unrecognized or asymptomatic infection, they also are likely to represent
a major reservoir for HAV transmission. Incidence models indicated
that during the 1980s and 1990s, more than half of HAV infections
occurred among children younger than 10 years, most of whom were
younger than 4 years.12 Since the mid-1990s, decreases in rates among
children have been greater than among adults, and the proportion of
cases among children dropped from 35% in the prevaccine era to 19%
in 2003.399
From 2002 to 2010, rates were similar and low among persons in
all age groups (<1.0 cases/100,000 population). In 2010, the range was
from 0.23 to 0.74 cases per 100,000 population.64,65,67,68 The highest
rates were for persons 15 to 24 years of age (0.74 cases per 100,000
population) and the lowest rates were among children younger than 9
years (0.3 cases/100,000 population).64,67 Since then, the percentage of
patients with acute hepatitis A in the United States who were 0 to 19
years of age has steadily decreased to 11.10% in 2013, with the highest
percentage continuing to be the 20- to 59-year age group (65.26%).230,231
Before the use of hepatitis A vaccine, rates among Native Americans
and Alaska Natives were more than 10 times higher than other racial
and ethnic groups, and rates among Hispanics were approximately three

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1562 SECTION 17  Viral Infections

16,000 to 2003–06, which may reflect lower rates of infection secondary to

14,000 higher rates of immunization among younger age groups.253 The decrease
in seroprevalence in the adult population reflects the replacement of
Number of cases

12,000
adults who were exposed naturally to HAV in the past by an adult
10,000 population who were neither vaccinated nor previously exposed.167
8,000
6,000 Geographic Variation
4,000 Analyses of national surveillance data collected during the 1980s and
2,000
1990s showed striking regional variation in the incidence of hepatitis
A. The national average incidence was approximately 10 cases per 100,000
0 persons per year during 1987 to 1997, with the highest rates and almost
2000 2002 2004 2006 2008 2010 all cases consistently occurring in a limited number of states and counties
Year concentrated in the western and southwestern United States.54,63
A Source: National Notifiable Diseases Surveillance System Approximately two thirds of cases were reported from the 17 states
(NNDSS) with the highest rates, even though only one third of US residents lived
in these states. With the implementation of routine vaccination of
Incidence of Hepatitis A, by year children in these states in 1999, rates equalized across the country,399
United States, 1980-2010 with significantly greater reductions in incidence in areas where vac-
cination was recommended.264,105,322,399
180,000 HAV infection rates are now the lowest ever reported and similar
Reported acute cases
160,000 Estimated acute cases
in all regions. The rate of acute hepatitis A declined from 1.5 cases per
140,000
100,000 population to 0.54 per 100,000 population from 2005 to 2010.64,67
In 2010, the case rate ranged from 0.1 case per 100,000 population
Number of cases

120,000 (Arkansas, Mississippi, and South Dakota) to 1.0 case per 100,000
100,000 population (Arizona).65,68
80,000 Potential Sources of Infection
60,000 The distribution of potential HAV exposures among cases for which
40,000
information regarding exposures is available has changed in the vaccina-
tion era. The proportion of cases attributable to household or sexual
20,000 contact with a person who has hepatitis A has declined as routine
0 hepatitis A vaccination of children has increased, from 15% to 25% to
5.6% to 7.3% of reported cases in 2009 and 2010.56-58,60,64,65,67,68 The
94
96

20 8
00

20 2
04
06

20 8
80

19 2
84
86

19 8
90

19 2

10
9

0
8

number of international travel–associated cases has remained approxi-

19
19

19

19
19

20

20
20
19
19

Year
B Source: http://www.cdc.gov/hepatitis/HAV/HAVfaq.htm
FIG. 168.6  (A) Reported number of hepatitis A cases, United States,
2000–10. (B) Hepatitis A incidence rates (per 100,000 population) based
on cases reported to the Centers for Disease Control and Prevention
(1980–2010). (A, Courtesy National Notifiable Diseases Surveillance
System (NNDSS) of the Centers for Disease Control and Prevention.
Available at: https://www.cdc.gov/hepatitis/statistics/2010surveillance/
slide2.1.htm.)
times higher than among non-Hispanics. These disparities have lessened
or disappeared in the era of routine childhood vaccination, with
rates among Hispanics in 2003 dropping to approximately twice
those among non-Hispanics (86% decline in contrast to 1990–97); rates
among Native Americans and Alaska Natives were the same as or
lower than those among other ethnic groups.399 In 2010, the rate for
hepatitis A among Hispanics was 0.7 cases per 100,000 population,
the lowest rate ever reported for this group.264 Rates among Native
Americans and Alaska Natives in 2010 were the lowest ever recorded
(0.2/100,000 population) and the same as or lower than other ethnic
groups.64,67
Seroprevalence of antibody to HAV (anti-HAV) in the population
reflects immunity to either previous infection or vaccination. As
determined by the National Health and Nutrition Examination Survey
(NHANES), the overall seroprevalence of anti-HAV in the United States
was 34.9% from 1999 to 2006.199,201 HAV seroprevalence among children
has increased from 8% in 1988–94 to 35.3% in 2007–08, reflecting
increased immunization of children and others.253 For US-born children
6 to 19 years of age, the strongest factor associated with seroprevalence
was residence in vaccinating states. Among US-born adults aged older
than 19 years, the overall age-adjusted seroprevalence of anti-HAV was
29.9% during 1999–2006, which was not significantly different from
the seroprevalence during 1988–94.199,201 Among US-born adults 40
years of age and older, HAV antibody prevalence decreased from 1988–94
mately the same, but as overall incidence declined, the proportion of
cases attributable to this exposure has risen to 14% to 15% reported
in 2009–10.64,65,67,68 In sites conducting enhanced hepatitis surveillance
during 2005–07 as part of the Emerging Infection Program of the CDC,
the most frequent (46%) potential source of infection among persons
reported with HAV disease was travel outside of the United States and
Canada. These cases mostly reflected persons who traveled, but also
included some who were exposed to a traveler but did not travel
themselves.200 As in previous years, most travel-related cases (85%) were
associated with travel to Mexico, Central America, and South America.200,333
Recognized foodborne outbreaks account for a small proportion of
cases in most years (3–5%), but large outbreaks such as those associated
with contaminated green onions in 2003 have increased the proportion
of cases associated with food in some years to as high as 16%.10,56-58,60,404,406
In 2010, the linkage to an outbreak could be determined in only 10%
of the reported cases for which this information was available.65,68
Cyclic outbreaks occur among men who have sex with men (MSM)
and users of injecting and noninjecting drugs; during outbreak years,
this exposure can account for 10% to 15% of nationally reported
cases.58,60,83,142,162,171,323
In 2010, only 5% of the case reports with information available
about sexual practices indicated sex with another man and only 2%
reported use of injection drugs.65,68 Nearly 50% of patients with hepatitis
A do not have a recognized source of infection.57,58,60,64,65,67,68
Community-Wide Epidemic
Historically, most cases of hepatitis A in the United States occurred in
the context of community-wide epidemics, during which infection is
transmitted from person to person in households and extended-family
settings.26 Once initiated, these epidemics often persisted for several
years and proved difficult to control289,336,337 even when attempts were
made to vaccinate some portion of the population rapidly.16,86 Children
played an important role in HAV transmission during these epidemics.
During community-wide outbreaks, serologic studies of members of
households with an adult case and no identified source found that 25%
to 40% of contacts younger than 6 years had serologic evidence of

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having had recent HAV infection.313,352 In one of these studies, 52% of
households of adults without an identified source of infection included
a child younger than 6 years, and the presence of a young child was
associated with household transmission of HAV.352 In this study, transmis-
sion chains were identified involving as many as six generations and
more than 20 cases. With the advent of routine vaccination of children,
community-wide outbreaks have largely ceased. Community-wide
outbreaks that have been sustained by transmission among adults in
high-risk groups continue to be identified, and novel strategies to provide
vaccination in settings such as jails have had some success.56,58,267,279,368,395
Epidemiology of Hepatitis A in Specific Settings
Childcare Centers
The role of children with asymptomatic infection has been recognized
in outbreaks in childcare centers since the 1970s.330-332 Because infection
in children usually is mild or asymptomatic, these outbreaks often are
not recognized until adult contacts (usually parents) become ill.158,159
Outbreaks rarely occur in centers that do not have children in diapers
and occur more commonly in larger centers.158,159 Both poor hygiene
in these children and the need for staff to handle and change diapers
contribute to spread. Despite the occurrence of outbreaks when HAV
is introduced into a childcare center, studies of childcare center employees
do not show a significantly increased prevalence of HAV infection in
contrast to control populations.140,180 On occasion, outbreaks in childcare
centers can be the source of more extensive transmission within a
community.104,157,158,387 Hepatitis A outbreaks within childcare centers
have become unusual events in recent years, as routine vaccination of
all young children is the standard.
Other Groups and Settings
Hepatitis A cases in school-age children usually reflect disease that has
been acquired in the community. However, multiple cases among children
within a school may indicate a common-source outbreak.172 Historically,
HAV infection was endemic in institutions for the developmentally
disabled; however, with smaller facilities and improved conditions, the
incidence and prevalence of infection have decreased, and outbreaks
rarely are reported in the United States.357
During the past 2 decades, outbreaks have been reported with
increasing frequency in illicit drug users in North America, Australia,
and Europe.52,162,171,173,279,323,337,368,395 In the United States, these frequently
involve users of injected and noninjected methamphetamine, who may
account for as many as 30% of reported cases in these communities
during outbreaks.26,171,173,267,395 Cross-sectional serologic surveys have
demonstrated that injection drug users have a higher prevalence of
anti-HAV than the general US population.178,393 More recent survey of
520 injection drug users age 18 to 40 years in San Diego from 2009 to 2010
found that 63% had no detectable anti-HAV antibodies,78 suggesting
that more aggressive implementation of the hepatitis A vaccine program
is needed in this high-risk group.
Transmission among injection drug users probably occurs through
both percutaneous and fecal-oral routes.173
Hepatitis A outbreaks in MSM have been reported frequently, most
recently in urban areas in the United States, Canada, Europe, and
Australia.38,50,83,142,328,355,373,374 These outbreaks may occur in the context
of an outbreak in the larger community.26 Some studies conducted
during outbreaks and seroprevalence surveys among MSM identified
specific sex practices associated with illness, whereas others have not
demonstrated such associations.30,83,85,165,192,393
Transfusion-related hepatitis A rarely occurs because HAV does not
result in chronic infection and blood donors are screened for elevated
transaminase levels. Currently, nucleic acid amplification tests also are
used to screen source plasma used in the manufacture of plasma-derived
products. However, during the mid-1990s, outbreaks were reported in
Europe and the United States in patients who received factor VIII and
factor IX concentrates prepared by solvent-detergent treatment to
inactivate lipid-containing viruses.238,349 HAV is resistant to solvent-
detergent treatment, and contamination presumably occurred from
plasma donors with hepatitis A who donated during the incubation
period. The risk for acquiring infection in patients with hemophilia is
not known, although data from one serologic survey of hemophiliac
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CHAPTER 168  Hepatitis A Virus 1563
patients suggested that they might be at increased risk for acquisition
of HAV infection.234 However, no HAV infections attributed to blood
products were identified in an analysis of serosurveillance data collected
from 140 hemophilia treatment centers in the United States between
1998 and 2002, suggesting that improved viral inactivation procedures,
donor screening, and increased hepatitis A vaccine coverage among
clotting factor recipients can reduce the risk for transmission of HAV
to recipients of clotting factors.50,57 Transmission related to blood
transfusions has resulted in nosocomial outbreaks in neonatal intensive
care units.198,277,318 Hepatitis A has been reported in adult cancer patients
treated with lymphocytes that apparently were incubated in serum from
a donor with HAV infection, although the patient source was not
identified.402
Nosocomial transmission from adult patients to health care workers
has often been associated with fecal incontinence of the patient.153,287,288
Such transmission is a rare event, however, because most patients with
hepatitis A are hospitalized after the onset of jaundice, when infectivity
is low.130,131,346 Health care workers have not been found to have an
increased prevalence of anti-HAV in contrast to control populations
in serologic surveys conducted in the United States.148
Persons from developed countries who travel to developing countries
with a high, transitional, or intermediate endemicity of HAV infection
are at substantial risk for acquiring hepatitis A (see Fig. 168.4).182,333,354
Hepatitis A infection is one of the most common vaccine-preventable
infections acquired during travel.333 A more recent study of Swiss travelers
estimated the risk to be six to 30 cases per 100,000 person-months of
stay in developing countries among persons who did not receive
immunoglobulin or vaccine before departure.266 The risk is higher among
travelers staying in areas with poor hygienic conditions,211 it varies
according to the region and the length of stay, and it appears to be
increased even among travelers who reported staying in urban areas
or luxury hotels.333,354 In some European countries, returning international
travelers with hepatitis A account for a substantial proportion of reported
cases (16–40%).72,410 In the United States, the proportion of cases
attributed to recent international travel has increased from 5% to
15%.64,65,67,68
The potential for new foodborne outbreaks around the world has
been enhanced with the world globalization by importation of food
products from countries where hepatitis A remains endemic to countries
with low endemicity. This has been nicely demonstrated during recent
outbreak investigations of hepatitis A infection, including the multistate
outbreak associated with semidried tomatoes in Australia during 2009113
and similar outbreaks in the Netherlands296,297 and France during 2010.146
Foodborne hepatitis A outbreaks are now recognized relatively
infrequently in the United States and are associated most commonly
with contamination of food during preparation by a food handler with
HAV infection. However, persons who work as food handlers are not
at increased risk for acquiring hepatitis A because of their occupation.
Food contaminated before retail distribution, such as lettuce or fruits
contaminated at the growing or processing stage, has been recognized
as the source of hepatitis A outbreaks.10,101,103,172,275,309,317,406 Outbreaks
related to contaminated shellfish, commonly noted in the past,103,108,282,301
have become increasingly uncommon.31 After the large multistate
outbreaks linked to oysters in 2005,31,101,404,406 another large outbreak of
occurred United States in 2013 associated with frozen pomegranate
arils imported from Turkey. A total of 165 people from 10 states became
ill with hepatitis A genotype IB, 69 (42%) of whom required hospitaliza-
tion, but no deaths were reported.79 Waterborne transmission of HAV
is now rare in the United States; earlier outbreaks were linked to sewage
contamination or inadequate treatment of water.29,36,41,46,98,143,235,398 In
2014, 13 (2.6%) of 500 case reports linked to an outbreak indicated
exposure that may have been linked to a common-source foodborne
or waterborne outbreak.66,69,264
Control of food outbreaks usually requires intensive public health
effort.93 HAV foodborne disease investigation with direct food testing
through HAV RNA molecular techniques has made the recovery of
implicated food faster and more efficient.31 Molecular epidemiology
through sequencing of outbreak strains has been demonstrated to be
an excellent tool for the investigation of HAV infection outbreaks within
the United States and European countries.31,113,146,167,296,374
1564 SECTION 17  Viral Infections
PATHOLOGY AND PATHOGENESIS
Pathology
The light microscopic findings in acute hepatitis A, which include
inflammatory cell infiltration, hepatocellular necrosis, and liver cell
regeneration, are common to all forms of acute viral hepatitis. These
histologic findings vary with the stage and severity of hepatitis. Early
biopsy specimens generally show portal infiltration by lymphocytes,
plasma cells, and macrophages positive for periodic acid–Schiff.109,365
Spotty or focal necrosis, as evidenced by balloon degeneration, shrinkage,
and fragmentation of hepatocytes, is seen commonly.109 HAV antigen
is found primarily in the cytoplasm of hepatocytes, but it also can be
found in liver macrophages. However, because HAV infection is self-
limited and does not result in chronic liver disease, liver biopsy rarely
is indicated (see the discussion on treatment).
Differences have been noted in light microscopic findings of
hepatitis A and other forms of viral hepatitis, particularly hepatitis
B. In addition to degeneration of hepatocytes in the perivenular area,
periportal inflammation and destruction of hepatocytes adjacent to
the portal area may be more pronounced than in hepatitis B.1,283,365
Findings in some patients, including extension of the inflammatory
infiltration from the periportal area into the hepatic parenchyma and
disruption of the limiting plate, may be difficult to distinguish from
those of chronic hepatitis.1,109 Cholestasis can be more prominent than in
hepatitis B.324
The histologic findings in fulminant hepatitis A are indistinguishable
from those in other forms of fulminant viral hepatitis. Examination of
pathologic specimens shows massive hepatic necrosis, abnormal
architecture of surviving hepatocytes, and a diffuse inflammatory
response.203,204 Viral antigen can be found in pathologic specimens.
Pathogenesis
The mechanism by which HAV crosses gastrointestinal epithelium and
infects liver cells has not been completely established. Previous studies
have shown that HAV-IgA complex can translocate across epithelial
cells and that HAV-IgA complexes are taken up by hepatocytes through
the asialoglycoprotein receptor.114,115 In this model of HAV infection,
virus would first infect gastrointestinal cells and then be transported
into the enterohepatic circulation as part of an HAV-IgA complex, with
subsequent selective uptake by hepatocytes. HAV is able to bind to
human cells through a specific cellular receptor inserted into the plasma
membrane, and DNA that encodes this receptor (huhavcr-1) has been
identified in many human tissues.132 HAVCR-1 was first discovered as
the cellular receptor for HAV (HAVcr-1) in African green monkeys in
1996.190 This cellular receptor is a member of the T-cell immunoglobulin
mucin (TIM, also known as TIM-1) gene family. It appears to regulate
the size and effector functions of T cells and also might play a role in
the development of atopy.249 The relationship of TIM1 and atopy with
HAV exposure is important, and various epidemiologic studies around
the world have shown lower prevalence of allergy and asthma among
the HAV-seropositive individuals in contrast to HAV-seronegative
individuals.244,245 Immunoglobulin (Ig)A is a natural ligand of HAVCR-1,
and the association of IgA with HAVCR1 enhances virus receptor activity
with synergistic effect in virus-receptor interactions.361
HOST INNATE AND ADAPTIVE
IMMUNE RESPONSES
Cellular Immune Response
Unlike other picornaviruses, infection of cultured cells with wild-type
HAV has no cytopathic effect.396 The general assumption is that HAV
infection also is noncytopathic in vivo, and therefore the cytopathic
changes in the liver associated with hepatitis A are immune medi-
ated. HAV is able to suppress interferon (IFN)-β gene expression in
the initial stages of infection, which might facilitate prolonged viral
production and infection of neighboring cells.134 This could be explained
in part by a disruption in the signaling through the toll-like receptor 3
pathway.242,306 A recent research study demonstrated that the interaction
between HAV and its receptor HAVCR1 inhibits CD4 T-cell regulatory
cell function, resulting in an immune imbalance allowing viral expansion
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with limited hepatocellular damage during the early phase of infection,
which is characteristic of HAV infection.237 Symptoms and biochemical
evidence of liver injury do not occur at the time of maximum virus
replication and fecal shedding (during the late incubation period).
Rather, liver injury is associated closely with viral clearance. CD8+,
class 1-dependent, cytotoxic, and virus-specific T cells that are capable
of producing IFN-γ are present in the circulation and the liver.139,380
Additional inflammatory cells, recruited to the site of infection by
IFN-γ and other cytokines secreted by CD8+ cells, may be responsible
for much of the liver injury. Complement has been shown to bind
to HAV capsid proteins, and serum complement levels drop during
infection, but whether complement-mediated cellular injury occurs
is unclear.241 The mechanism by which infection is resolved remains
uncertain.
Humoral Immune Response
Unlike hepatitis C, the adaptive immune response to HAV is robust
and extremely effective in eliminating the virus. Neutralizing antibodies
to the virus (anti-HAV) generally appear in the serum concurrent with
the earliest evidence of serum transaminase elevation and hepatocellular
injury.
Antibodies directed against conformational epitopes displayed on
intact virions as well as empty viral capsids are produced during the
later stages of infection (see the earlier section on genomic organization
and genetic variation). Virus-specific IgM and IgG and IgA antibodies
are present in serum; IgM anti-HAV generally can be detected at the
onset of symptoms (see Fig. 168.3).242
CLINICAL MANIFESTATIONS
Similar to other forms of viral hepatitis, the clinical manifestations of
HAV infection are variable and range from asymptomatic anicteric
infection to symptoms of acute hepatitis, including fever, malaise,
anorexia, nausea, vomiting, right upper quadrant pain, and jaundice.
The likelihood of having symptomatic HAV infection and the severity
of the illness are related to the age of the patient. In early childhood,
infection usually is asymptomatic, whereas infection in adulthood
generally is accompanied by symptoms. The diagnosis of hepatitis A
must be confirmed by serologic testing because no constellation of
symptoms is pathognomonic of the disease.
Incubation Period
The average incubation period is 28 to 30 days but can range from 15
to 50 days.206 The average incubation period has been reported to be
shorter in patients who acquired HAV infection by parenteral transmis-
sion from contaminated blood products and in chimpanzees infected
parenterally than in those infected orogastrically.241,338
Spectrum of Illness
HAV infection, confirmed by the detection of IgM anti-HAV in serum,
can be inapparent (asymptomatic, with no elevation in serum trans-
aminase levels), subclinical (asymptomatic, with elevation of serum
transaminase levels), or clinically evident (with symptoms). Specific
symptoms of liver dysfunction include jaundice and dark urine caused
by hyperbilirubinemia. However, symptomatic hepatitis A without
jaundice (anicteric) does occur. Nonspecific symptoms of acute hepatitis
A can include fever, myalgia, anorexia, nausea, right upper quadrant
pain or discomfort, diarrhea, and pruritus.
Many acute HAV infections, particularly subclinical and anicteric
infection, are not recognized 352,418 The frequency of symptoms with
acute infection is influenced strongly by age. Children are less likely
than adults to have symptomatic infection, and jaundice rarely occurs
in children younger than 6 years.151 In one report describing outbreaks
in several daycare centers, the proportion of infected children without
symptoms was 84% in children younger than 3 years, 50% in children 3
to 4 years of age, and 20% in children 5 years or older.158,159 Symptoms
develop in most adults with acute infection. In a study of two outbreaks
among young adult US military personnel, symptoms developed
in 76% to 97% of infected persons, and approximately 55% were
icteric.213

CLINICAL SIGNS AND SYMPTOMS
In an individual patient, the clinical symptoms of acute hepatitis A are
indistinguishable from those caused by other forms of viral hepatitis.
Particularly in older children and adults, the onset of illness often is
quite abrupt and may consist of fever, myalgia, anorexia, malaise, nausea,
intermittent dull abdominal pain, and vomiting. Fever (temperature
rarely higher than 38.9°C [102°F]) and headache occur more frequently
than in other forms of acute viral hepatitis.358 Pediatric patients may
have diarrhea or, less commonly, upper respiratory tract symptoms
such as cough, sore throat, and runny nose, and the diagnosis of hepatitis
A might not be considered in children with predominantly respiratory
or gastrointestinal symptoms and transient fever without the typical
malaise, fatigue, and anorexia.138,219,225 Dark urine followed by jaundice
and light-colored stool, if present, will appear within a few days to a
week after onset of the prodromal symptoms.28,156,213,219,225 When this
icteric phase begins, symptoms often resolve and appetite returns in
young children, but older children and adult patients may experience
a transient worsening in the prodromal symptoms of anorexia, malaise,
and weakness.205,263
In addition to jaundice and scleral icterus, physical findings may
include mild hepatomegaly and tenderness, but severe tenderness suggests
other diagnoses. The spleen may be palpable in 10% to 20% of patients,
and posterior cervical adenopathy may be present.75,213,372 Pleural effusions
have been reported to occur, do not appear to be associated with more
severe disease, and resolve spontaneously.4 Ascites, peripheral edema,
and findings indicative of hepatic encephalopathy suggest the presence
of a more severe form of hepatitis but are rare (see the discussion on
atypical clinical manifestations and complications of hepatitis A).
Ultrasonographic findings in children with uncomplicated hepatitis A
have included edema or thickening of the gallbladder wall, abdominal
lymphadenopathy, and, less commonly, transient ascites and pancreatic
abnormalities.75,197
The symptoms of hepatitis A last for several weeks on average and
usually not longer than 2 months.203,204 Prolonged or relapsing hepatitis
A can occur (see the discussion on relapsing hepatitis A) and, in the
case of prolonged hepatitis A, may be associated with genetic markers
for autoimmune hepatitis.128
Laboratory Abnormalities
As in other forms of viral hepatitis, during HAV infection, inflammation
of the liver is accompanied by abnormalities in serum hepatic enzymes,
with increases in serum aspartate transaminase (AST), alkaline phos-
phatase, and γ-glutamyltranspeptidase (GGTP) levels. Elevations of
serum ALT and AST occur most consistently and may precede the
appearance of symptoms by a week or more (see Fig. 168.3). Peak levels
generally occur 3 to 10 days after the onset of symptoms and are between
200 and 5000 IU but can reach as high as 20,000 IU. The level of ALT
usually is higher than that of AST because the inflammatory response
is destructive, particularly to the plasma membrane, in acute viral
hepatitis. ALT is found in the cytosol of the plasma membrane, whereas
AST is located mainly in cell mitochondria.156
Serum bilirubin levels, although frequently elevated, usually remain
below 10 mg/dL and peak 1 to 2 weeks after illness begins. Higher levels
can be seen in some patients, especially when HAV infection is com-
plicated by cholestasis (see the section on cholestatic hepatitis A). Alkaline
phosphatase is usually only mildly elevated, rarely reaching more than
2 or 3 times the normal level. GGTP levels generally are 3 to 10 times
the upper limit of normal. Serum immunoglobulin levels often are
elevated, and IgM levels frequently are higher than those in acute hepatitis
B and non-A, non-B hepatitis, but not diagnostic.422 Coagulopathy or
elevated prothrombin time (PT)/ international normalized ratio (INR)
are rare. A prolongation of these labs are generally associated with
severe liver damage and a prognostic indicator for the development of
fulminant hepatitis.414
Patients with acute HAV infection usually have a mild lymphocytosis
with occasional atypical mononuclear cells.263
Apart from patients who have relapsing or cholestatic hepatitis
A (see the section on atypical clinical manifestations and complica-
tions of hepatitis A), serum bilirubin and transaminase levels usually
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CHAPTER 168  Hepatitis A Virus 1565
return to normal by 2 to 3 months after the onset of illness in most
patients.203,204
Diagnostic Tests
Because the pattern and magnitude of symptoms and the hepatic enzyme
abnormalities of hepatitis A are not distinctive for hepatitis A, the
diagnosis requires serologic detection of IgM anti-HAV along with
demonstration of an acute onset of signs and symptoms of hepatitis
and jaundice or elevated transaminase levels. Persons with signs and
symptoms of hepatitis and an epidemiologic link to other confirmed
cases are likely to have hepatitis A, even if no laboratory confirmation
is available. Sensitive and specific radioimmunoassays or enzyme
immunoassays show that virtually all patients have detectable IgM
anti-HAV during the acute or early convalescent phase of HAV infection
(see Fig. 168.3).227 A small proportion (3%) of patients tested within
3 days of the onset of symptoms may be IgM anti-HAV negative but
become IgM anti-HAV positive within the initial 2 weeks of illness.227
During the first 4 to 8 weeks after the onset of symptoms, the titer of
IgM anti-HAV in serum is high.163 Antibody generally disappears within
6 months, although rarely it can be detected for 2 years or longer.111,163,202,227
False-positive IgM anti-HAV test results among persons who have
no other evidence of recent infection have been reported, suggesting a
low positive predictive value when it is used to test asymptomatic persons
with no known recent HAV exposures.54,58,59,63 IgM anti-HAV may be
detectable for a longer time in patients with symptomatic illness than
in those with asymptomatic infection.163,189,347
IgG anti-HAV is present in low titer at or shortly after the onset of
acute HAV infection, and the titer rises during the course of several
weeks as the IgM anti-HAV titer falls (see Fig. 168.3). IgG anti-HAV
remains detectable in serum for the lifetime of the individual and confers
lasting protection against disease. Secretory IgA antibodies are detected
in a minority of humans or primates with acute HAV infection but are
unlikely to provide any significant protection against HAV infection.353
IgG anti-HAV is transferred passively across the placenta and declines
to undetectable levels in most infants by the time they reach 12 to 15
months of age.25,26,228,229
Commercially available enzyme immunoassays either detect total
(IgG and IgM) antibody against HAV capsid proteins by using a competi-
tive inhibition (blocking) format or detect IgM antibody to capsid
proteins by using an IgM capture format.220,223 These assays do not
measure the neutralizing antibodies responsible for biologic activity
against HAV, but detection of total anti-HAV by conventional assays is
correlated with the appearance of neutralizing antibodies.205,220,223
Neutralizing antibody can be detected by assays that measure inhibition
of HAV in cell culture (i.e., radioimmunofocus inhibition test or plaque
assay).11,88,220,223 Neutralizing antibodies elicited against one strain of
HAV have been shown to have biologic activity against other HAV
strains.220,223
When tested in parallel with a World Health Organization anti-HAV
reference reagent, the lower limit of detection of most commercially
available assays is approximately 100 mIU/mL of anti-HAV.147,220,223
Although antibody concentrations achieved by passive or active immu-
nization are known to provide protection against HAV infection, they
are generally 10- to 100-fold lower than those produced after natural
infection.220,223
The lower limit of antibody necessary to provide protection against
HAV infection is unknown. In vitro studies with cell culture–derived
virus suggest that low levels of antibody (e.g., <20 mIU/mL) are neutral-
izing.220,223 Clinical trials that evaluated vaccine efficacy have not provided
an estimate of the minimum protective antibody level because vaccine-
induced levels of antibody have been very high and few infections have
occurred in vaccines. Experimental studies in chimpanzees indicate
that very low levels of passively transferred antibody (<10 mIU/mL)
obtained from immunized individuals do not protect against infection
but prevent clinical hepatitis and shedding of virus.305
PCR techniques using serum specimens have been useful in some
clinical, epidemiologic, or environmental studies. Although HAV
concentrations in stool decline quickly after illness onset, HAV RNA
can be detected in most serum specimens that are collected within 4
to 6 weeks after onset of illness.42
1566 SECTION 17  Viral Infections
BOX 168.1  Atypical Clinical Manifestations and
Complications of Hepatitis A Virus Infection
Relapsing hepatitis A152,325,370
Fulminant hepatitis A243,280,308,369
Cholestatic hepatitis A154,370
Hepatitis A triggering autoimmune hepatitis370,388
Extrahepatic manifestations
Transient rash or arthralgias150,370
Papular acrodermatitis of childhood305
Cutaneous vasculitis94,174,175
Cryoglobulinemia174,175,325
Guillain-Barré acute syndrome359
Other neurologic syndromes (e.g., myeloradiculopathy, mononeuritis, vertigo,
meningoencephalitis)19,39,359
Renal syndromes (acute renal failure, nephritic syndrome, acute
glomerulonephritis)17,100,183
Pancreatitis259
Aplastic anemia and thrombocytopenia125,236
Atypical Clinical Manifestations and Complications of
Hepatitis A
Box 168.1 lists the atypical clinical manifestations and complications
of hepatitis A.
Relapsing Hepatitis A
Relapsing hepatitis is a relatively common manifestation of hepatitis
A that occurs in approximately 10% of patients.325 One to 4 months
after having the initial episode of acute hepatitis, these patients have a
second episode; more than one relapse rarely occurs.152,325,370 Patients
with relapsing hepatitis A have no distinctive clinical features of their
first disease episode. After the first episode, most patients experience a
significant improvement in symptoms and biochemical abnormalities.
However, the frequency with which serum transaminase levels completely
normalize during this period has been variable; in one report, normaliza-
tion occurred in only one of seven patients with relapsing hepatitis
A.370 The relapse episode of hepatitis rarely is more severe than the
initial episode and is accompanied by elevated serum transaminase
levels (typically to >1000 U/L) and persistence of IgM anti-HAV.
Molecular studies have demonstrated the presence of HAV in stool and
HAV RNA in serum during relapse, but whether patients are infectious
is unknown.152 The illness usually lasts a total of 16 to 40 weeks and
results in full recovery.152,325 Although the pathogenesis of relapsing
hepatitis is unknown, it probably is immunologically mediated.325
Persistent HAV infection with a relapsing clinical course has been reported
in patients after they have undergone liver transplantation for fulminant
hepatitis A; HAV-specific genomic sequences have been identified in
the grafts of these patients.127,414
The IgA has been postulated as a carrier supporting hepatotropic
transport of HAV, which may contribute to different clinical outcomes.116
Over a period of several weeks after infection, anti-HAV IgA is able to
promote an enterohepatic cycling of HAV, resulting in continuous
endogenous reinfection of the liver. A mouse model demonstrated that
highly avid IgG antibodies, which are present in later times of the
infection, can terminate the reinfection. The endogenous reinfections
in the presence of a developing neutralizing immunity might contribute
to prolonged, as well as relapsing, courses of HAV infections, and the
IgA may act as a protracting factor.116
Fulminant Hepatitis A
In the United States, a relatively small proportion of all fulminant
hepatitis is caused by hepatitis A.243,285,308,326,369 A prospective multicenter
study conducted among 348 children with acute liver failure in the
United States, Canada, and the United Kingdom found that only three
cases (1%) could be attributed to hepatitis A.351 However, 26% to 60%
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of children with acute liver failure had hepatitis A in tertiary care
center–based studies conducted in Turkey, India, Argentina, and Paki-
stan.15,18,21,329 In one Korean hospital, 304 patients more than 18 years
of age were admitted from 2009 to 2011 with acute hepatitis A. Of
those 304 patients, 18 (5.9%) progressed to liver failure, and of these,
eight (2.6%) died or underwent liver transplantation.340 Between 1998
and 2005, 29 adults with HAV IgM-positive acute liver failure were
enrolled in the Acute Liver Failure Study Group (ALFSG) in the United
States. Acute HAV accounted for 3.1% of the patients enrolled. At 3
weeks of follow-up, 16 had spontaneously recovered (55%), nine
underwent transplantation (31%), and four had died (14%). The propor-
tion of HAV cases enrolled in the ALFSG significantly decreased from
5% to 0.8% between 1988 and 2005 (P < .007).364
Among patients hospitalized with hepatitis A, the case-fatality rate
has been estimated to be 0.14%.252 In the 1988 Shanghai epidemic that
involved primarily adolescents and young adults, 47 deaths (0.015%)
were recorded among the 310,746 diagnosed cases.80 A national cohort
study in Taiwan looking at hospital admissions related to HAV from
1997 to 2011 showed an overall mortality rate of 16.8 per 1000 hospi-
talizations. Male sex, age over 40 years, cirrhotic liver, and long length
of stay are significant factors associated with death in HAV-hospitalized
cases.70 On the basis of national surveillance data in the United States,
death occurs in 0.3% to 0.6% of persons with symptomatic hepatitis
A, reaching 1.8% among those over 50 years of age.333 In 2013, nine
(0.9%) cases of deaths related to HAV were reported to the CDC. None
were reported in 2014.65,68,69
Host factors reported to be associated with an increased risk for
development of fulminant hepatitis include older age44,209,252,394,417 and
underlying chronic liver disease.3,95,193,224,389,394,415,417 Reported findings
among persons with fulminant disease include nucleotide or amino
acid substitutions in the 5′ untranslated region,145 P2 region, and P3
region of the HAV genome.270 Viral factors such as substitution rate in
the entire genome were not associated with acute liver failure in the 29
patients identified with HAV liver failure in the adult ALFSG from 1998
to 2004; however, a negative PCR (undetectable or very low viral load)
was the single factor that correlated more significantly with more severity
and worse outcomes.2 This finding has been previously described in
the literature and suggests that the excessive host response maybe a
determining factor in the development of fulminant hepatitis A.311 An
in-depth analysis conducted in India for a 5-year period concluded
that higher CD8 T cells and coinfection with other viral hepatitis
infections were more commonly associated with fulminant hepatitis;
and, contrary to previous findings, higher viral load was also an important
contributing factor.170
Fulminant hepatitis A has no distinctive clinical features that dis-
tinguish it from fulminant hepatic failure of other causes. Within
approximately 8 weeks of the onset of illness, symptoms of hepatic
encephalopathy and marked prolongation of PT are noted in patients
with no history of previous liver disease.281 Complications can include
cerebral edema, sepsis, gastrointestinal bleeding, and hypoglycemia. The
prognosis of fulminant hepatitis A without transplantation is better
than that of fulminant disease related to other viral causes, and 40%
to 70% of patients can be expected to recover.150,280,326,369 In one hospital
series, more rapid onset to liver failure after onset of jaundice was
associated with improved outcome, and higher bilirubin concentration
and more prolonged prothrombin time were associated with poor
outcomes.99
Extrahepatic Manifestations
During acute hepatitis A, transient rash and arthralgias occur in as
many as 14% and 19% of patients, respectively, particularly during the
prodromal period.150,370 Urticaria has been reported but occurs less
frequently than in acute hepatitis B.110 Papular acrodermatitis of child-
hood, the Gianotti-Crosti syndrome, rarely occurs in the United States
but has been reported elsewhere in association with HAV infection.320
The cutaneous lesions, which consist of nonpruritic, symmetric flat
papules on the face, extremities, and buttocks, may persist for several
weeks before spontaneously resolving.117
Other extrahepatic manifestations that occur chiefly in association
with cholestatic or relapsing hepatitis A include cutaneous vasculitis

and cryoglobulinemia.94,174,175 The vasculitis, manifested as erythematous
maculopapular lesions often affecting the lower extremities and buttocks
and typically associated with purpura, appears as leukocytoclastic
vasculitis and granular deposits of IgM anti-HAV and complement in
blood vessel walls in skin biopsy specimens. Cryoglobulinemia includes
cryoglobulins composed of IgG and IgM and IgM anti-HAV antibod-
ies.94,174,175,325 These manifestations resolve spontaneously with resolution
of the hepatitis.
In the absence of fulminant disease, neurologic syndromes have
been observed only rarely in association with hepatitis A. Guillain-Barré
syndrome has been reported to occur 3 days to 2 weeks after the onset
of hepatitis A, as have myeloradiculopathy, vertigo, mononeuritis (cranial
or peripheral nerve), meningoencephalitis, and exacerbation of multiple
sclerosis.19,39,291,292,359 Renal complications, including acute renal failure,
nephrotic syndrome, and acute glomerulonephritis, also rarely have
been reported in children who did not have fulminant disease.17,100,183
Self-limited, mild pancreatitis likewise appears to occur.259 Reported
hematologic complications include aplastic anemia and severe throm-
bocytopenia.125,236 Gestational complications, including premature rupture
of membranes and placental separation, have been reported among
pregnant women with acute hepatitis A, but infants born to these women
were healthy otherwise.119,319
Cholestatic Hepatitis A
Cholestatic hepatitis occurs in a small percentage of patients with hepatitis
A. These patients are deeply icteric and may have pruritus, fatigue,
fever, loose stools, anorexia, dark urine, and weight loss. In two reports
of 10 patients with cholestatic hepatitis A, peak serum bilirubin levels
generally were higher than 10 mg/dL, with some as high as 38 mg/dL,
and remained elevated for 12 to 16 weeks.154,370 Serum transaminase
levels declined but remained elevated during the period of cholestasis.
In one of these reports, five patients had prolonged prothrombin times
that normalized with the administration of vitamin K.154
Cholestatic hepatitis A can be distinguished from obstructive jaundice
by normal abdominal ultrasound findings. Conducting further invasive
diagnostic procedures, such as liver biopsy or endoscopic retrograde
cholangiopancreatography (ERCP), is not necessary in most cases.325
Hepatitis A Triggering Autoimmune Hepatitis
Several reports have described patients in whom hepatitis A is followed
by type 1 autoimmune chronic hepatitis.307,370,388 Laboratory studies
demonstrated a T-cell defect in these patients, suggesting a genetic
predisposition to the development of autoimmune hepatitis that is
“triggered” by HAV infection. These patients have required corticosteroid
therapy, sometimes for long periods.
TREATMENT
Hepatitis A has no specific therapy, and because HAV infection is
self limited and does not result in chronic infection or chronic liver
disease, treatment generally is supportive with hydration and good
nutrition. Hospitalization may be necessary for patients who are
dehydrated from nausea and vomiting or who have fulminant hepatic
failure. Because no conclusive data indicate that bed rest or inactivity
influences the course of illness, no restriction of activity is necessary.
Similarly, no specific diet is indicated, although many patients may
have an intolerance to fatty foods during their illness. Medications,
particularly those that have the potential to cause hepatic damage
and those that are metabolized by the liver, including acetaminophen,
should be used with caution. The half-life of these medications may be
prolonged.
No evidence exists that exchange transfusions, plasmapheresis, or
corticosteroids are effective.126,156 Liver transplantation is successful in
the few who require it.164,343,369,393 Persistent HAV infection has been
demonstrated in some transplant recipients, but whether it affects survival
is unknown.118,127 Because survival rates of adult and pediatric patients
are relatively high without transplantation and no single factor is predic-
tive of a poor outcome, establishment of criteria for choosing candidates
for transplantation has been difficult.150,281,369,386 Reported survival rates
after transplantation in patients with fulminant hepatitis from all viral
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CHAPTER 168  Hepatitis A Virus 1567
causes range from 40% to 89%, depending on the severity of liver
failure and other factors.215,217,369
Investigators are exploring direct-acting antivirals (DAAs) as a
treatment option for the treatment of acute hepatitis infections, including
HAV 3C cysteine protease inhibitors and HAV-specific siRNAs. HAV
3C proteinases play an important role in the processing of the HAV
polyprotein, and inhibitors of HAV 3C can result in the suppression
of HAV replication.188 Studies revealed that siRNAs against the HAV
2C- and 3D-coding regions inhibited HAV 2C and HAV 3D expression
and that the combination of 2C-siRNAs and 3D-siRNAs strongly inhibited
HAV replication.187,186 Exploration of DAAs for the treatment of HAV
remains in the early stages of investigation in vitro and cell cultures.
Human studies have yet to be performed.
PREVENTION
In addition to general measures of good personal hygiene, particularly
handwashing; provision of safe drinking water; and proper disposal of
sanitary waste, preexposure or postexposure immunization primarily
with hepatitis A vaccine or with immunoglobulin can prevent the
acquisition of hepatitis A.
Immunoglobulin
Immunoglobulin is a sterile solution of antibodies prepared by a serial
cold ethanol precipitation procedure from pooled human plasma that
has tested negative for hepatitis B surface antigen, antibody to human
immunodeficiency virus (HIV), and antibody to hepatitis C virus.77
When it is administered before exposure or within 2 weeks after exposure,
immunoglobulin is more than 85% effective in preventing hepatitis A
by passive transfer of anti-HAV.202,261,355 Whether immunoglobulin
completely prevents infection or leads to asymptomatic infection and
the development of persistent anti-HAV (passive-active immunity)
probably is related to the amount of time that has elapsed between
exposure and administration of immunoglobulin.219,225,355 Although in
recent years immunoglobulin lots have had slightly lower titers of
anti-HAV, probably because of a decreasing prevalence of previous HAV
infection in plasma donors, no clinical or epidemiologic evidence of
decreased efficacy has been reported.362
Hepatitis A immunoglobulin (IG) may be given instead of or in
addition to hepatitis A vaccine to certain groups who are traveling to
countries with high, transitional, or intermediate endemicity of HAV
infection (see Fig. 168.4).54,63 Travelers who are at increased risk of
severe or fatal hepatitis A infection, including adults older than 40 years
of age (particularly adults 75 years and older), persons with chronic
liver disease, those who are immunocompromised, and those who are
planning to depart in 2 weeks or less should receive IG (0.02 mL/kg)
at a separate anatomic injection site in addition to the standard initial
dose of vaccine. IG is also indicated for travelers who are allergic to a
vaccine component or who elect not to receive the vaccine, as well as
for travelers younger than 12 months, as hepatitis A vaccine is not
licensed in the United States for children in this age group (see the
section on vaccines).54,63 Although hepatitis A often is asymptomatic
in infants and young children, preexposure prophylaxis is indicated to
prevent the rare severe cases and transmission to others after return
from abroad.
For preexposure prophylaxis of travelers, the dose of IG is 0.02 mL/
kg body weight if travel will be for less than 3 months. Because of the
decay of passive immunity during the course of time, a dose of 0.06 mL/
kg is necessary for persons who will be abroad for 3 to 5 months, and
readministration every 5 months is necessary for extended trips. Hepatitis
A vaccine, if it is not contraindicated, is a better choice for such persons
and can be administered at any time prior to departure in healthy
persons.
Aggressive use of vaccine immunoprophylaxis is indicated to control
hepatitis A outbreaks409,300 in childcare centers in which hepatitis A is
diagnosed in a child or employee54,61,63,330,331 and in other settings (e.g.,
hospitals and facilities for developmentally disabled persons) when
outbreaks occur.55,60 When a food handler is identified with hepatitis
A, postexposure prophylaxis should be administered to other food
handlers at the establishment and, under limited circumstances, to
patrons.49,54,63,135,136 Once cases are identified that are associated with a
1568 SECTION 17  Viral Infections
food service establishment, it generally is too late to administer post-
exposure prophylaxis to patrons because the 2-week postexposure period
during which prophylaxis is effective will have passed.
Previously unvaccinated household or sexual contacts of patients
with hepatitis A should receive postexposure prophylaxis. In the absence
of postexposure prophylaxis, secondary attack rates of 15% to 30%
have been reported in households, with higher rates of transmission
occurring from infected young children than from infected adolescents
and adults. Attack rates in food handlers are generally lower.201
IG is usually used for postexposure prophylaxis in susceptible persons
who are either children younger than 12 months or persons older than
40 years, immunocompromised persons, and persons with chronic liver
disease.201
For postexposure prophylaxis, 0.02 mL/kg body weight of IG is
administered intramuscularly. For infants and young children, the
injection can be administered in the anterolateral aspect of the thigh
or the deltoid muscles; for older children and adolescents, the injection
should be administered in the deltoid or gluteus muscles, into which
a large volume of IG can be injected.51,56 If the IG is administered in
the gluteus, the injection should be given in the superolateral aspect to
avoid injury to the sciatic nerve.51,56
Vaccine is recommended as postexposure prophylaxis in healthy
persons 12 months through 40 years of age as of 2007, because it induces
active immunity providing longer protection, has higher acceptability
and availability, and is easy to administer.54,55,63,66,201
IG does not interfere with the immune response to oral poliovirus
vaccine, to yellow fever vaccine, or, in general, to inactivated vaccines.
However, IG can interfere with the immune response to some live
attenuated vaccines (e.g., measles-mumps-rubella vaccine [MMR] and
varicella vaccine). Administration of MMR and varicella vaccines should
be delayed for at least 3 months and at least 5 months, respectively,
after the administration of immunoglobulin. Immunoglobulin should
not be given within 2 weeks after the administration of MMR or within
3 weeks of the administration of varicella vaccine, unless the benefits
of immunoglobulin administration are greater than the benefits of
vaccination.51,56 For travelers younger than 1 year of age in whom the
use of immunoglobulin may interfere with the administration of other
needed vaccines (e.g., MMR and varicella), the use of inactivated hepatitis
A vaccine could be considered (see the discussion on inactivated
vaccines).
Serious adverse events from IG rarely occur. Because anaphylaxis
has been reported after repeated administration to persons with IgA
deficiency, these persons should not receive IG.120 Pregnancy or lactation
is not a contraindication to the administration of IG. For infants and
pregnant women, a preparation that does not include thimerosal is
preferable.
Hepatitis A Vaccine
The ability to propagate HAV in cell culture allowed the development
of hepatitis A vaccines. Both inactivated and live attenuated hepatitis
A vaccines have been developed by use of defined isolates from infected
cell lines.106,239,240,255,303,344 Available data indicate that both inactivated
and live attenuated hepatitis vaccine are capable of providing long-term
protection, but only inactivated vaccines are licensed in the United
States.232,286,176,403
Vaccine Preparation and Performance
Inactivated hepatitis A vaccines are prepared by a method similar to
that used to prepare inactivated poliovirus vaccine, by propagation of
cell culture–adapted virus in human fibroblasts, purification by ultrafiltra-
tion or other methods, formalin inactivation, and adsorption to an
aluminum hydroxide adjuvant.14,74 Inactivated vaccines using the HM175
strain (HAVRIX, GlaxoSmithKline) and the CR326F′ strain (VAQTA,
Merck) have been licensed in pediatric and adult formulations for
intramuscular administration and are available in the United States for
persons 12 months of age and older (Table 168.1). One of these vaccines
(HM175 strain) is formulated with 2-phenoxyethanol as a preservative,
whereas the other is formulated without a preservative.290 The antigen
content of one vaccine (CR326F′ strain) is expressed as units of HAV
antigen as defined by a standard; the antigen content of the other vaccine
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TABLE 168.1  Recommended Doses and
Schedules for Inactivated Hepatitis A Vaccines
Available in the United States
Age Volume No. of Scheduleb
(y) Vaccinea Dose (mL) Doses (mo)
1–18 HAVRIX 720 ELU 0.5 2 0, 6–12
VAQTA 25 U 0.5 2 0, 6–18
≥19 HAVRIX 1440 ELU 1.0 2 0, 6–12
VAQTA 50 U 1.0 2 0, 6–18
>18 TWINRIX 720 ELU 1.0 3 0, 1, 6c
ELU, Enzyme-linked immunosorbent assay units.
a
HAVRIX is manufactured from HAV strain HM175 by GlaxoSmithKline; VAQTA is
manufactured from HAV strain CR326F′ by Merck & Co, Inc.; TWINRIX is a combined
hepatitis A and hepatitis B vaccine that also contains 20 µg per dose recombinant hepatitis
B surface antigen protein.
b
Zero months indicates initial dose; subsequent numbers represent months after the initial
dose.
c
An alternative four-dose schedule, given on days 0, 7, 21–30, followed by a dose at month
12, also is licensed in the United States. This schedule is used prior to planned exposure
with short notice.
From Centers for Disease Control and Prevention. Prevention of hepatitis A through active
or passive immunization: recommendation from the advisory Committee on Immunization
Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2006;55(RR-7):1–23.
(HM175 strain) is determined by reactivity in a quantitative immunoassay
for HAV antigen and is expressed as enzyme-linked immunosorbent
assay units (ELU).
Two other inactivated hepatitis A vaccines are manufactured and
available in Europe and other parts of the world.175,212,293,392 In addition,
a combination inactivated hepatitis A and recombinant hepatitis B
vaccine is available in the United States for persons 18 years and older,61
and a pediatric formulation is available in Europe, Canada, and other
parts of the world.107
In extensive studies in children and adults, the inactivated hepatitis
A vaccines available in the United States have been found to be highly
immunogenic. In general, after one dose of vaccine, 95% to 100% of
children 1 year or older and adults respond with concentrations of
antibody considered to be protective; a second dose given 6 to 18 months
later results in a boost in antibody concentration and probably is
important for long-term protection.20,25,74,169,251,271 Persons whose second
dose is delayed as long as 3 to 8 years after the first dose have responses
to vaccination similar to the responses of those who receive the vaccine
on licensed schedules.24,179,413 Studies conducted among infants and
children younger than 18 months have demonstrated that simultaneous
administration of hepatitis A vaccine with diphtheria-tetanus-acellular
pertussis (DTaP), Haemophilus influenzae type b, hepatitis B, MMR,
and inactivated poliovirus vaccines does not affect the immunogenicity
and reactogenicity of these vaccines.25,26,34,91,254,295,379 IgM anti-HAV
occasionally can be detected by standard assays, primarily if it is measured
soon (i.e., 2 to 3 weeks) after vaccination.341,390
Conditions that may result in reduced immunogenicity include HIV
infection, chronic liver disease, and older age. Among adults with HIV
infection, 61% to 87% had protective antibody concentrations after
completing the vaccination series.166,195,274,397 Higher CD4+ T-lymphocyte
count at baseline was associated with response to vaccination.13,166,195,312,397
However, HIV-infected persons with normal or near-normal CD4+
T-lymphocyte counts have response rates that exceed 95%.401 A retrospec-
tive study in adult patients with HIV who received two doses of HAV
vaccine demonstrated a durable seropositive response for up to 6 to 10
years after HAV vaccination. Suppressed HIV RNA levels were associated
with durable HAV responses.89 Awareness of hepatitis susceptibility and
hepatitis coinfection status in HIV-infected patients is essential for
optimal clinical management. Despite recommendations for hepatitis
screening and vaccination of HIV-infected MSM, rates for screening
and vaccination remained suboptimal in the United States from 2004
to 2007.168 HIV-infected patients have an elevated risk for HAV coinfec-
tion, which is significant considering the elevated prevalence of liver

disease in this population. Furthermore, HIV-infected persons may
experience prolonged HAV viremia, which has important public health
implications for transmission within the community.89 Among persons
with chronic liver disease, seroprotection rates were similar to those
observed among healthy adults, but the final antibody concentrations
were substantially lower.193,194,215,217
Most infants born to anti-HAV–positive mothers have lost detectable
antibody by the time they reach 12 to 15 months of age, and both
pediatric hepatitis A vaccines are now licensed for use in children as
young as 12 months.141,230,231 Studies in children younger than 1 year
of age indicate that the vaccine is safe and immunogenic for those who
do not have passively transferred antibody from previous maternal
HAV infection.26,226,298,375 However, there are concerns that the presence
of passively acquired maternal anti-HAV may substantially reduce
hepatitis A vaccine immuogenicity. A study following 183 children over
a 15-year period showed a 90% to 100% seropositivity at 10 years of
age. However, there was a decrease through ages 15 to 16 years in children
in whom vaccination began at age 6 months (50–75%) when compared
to infants in whom vaccination began at 12 to 15 months of age.350 In
studies of infants who received hepatitis A vaccine according to several
different schedules, those with passively transferred maternal antibody
at the time of vaccination responded, but final antibody concentrations
were approximately one third to one tenth those of infants who did
not have passively transferred antibody and were vaccinated according
to the same schedule.26,92,226,228,298,375
The clinical significance, if any, of these lower antibody concentra-
tions is unknown. One study found that all infants vaccinated in the
presence of passively transferred maternal antibody responded to a
booster dose given 6 months later with an anamnestic response, sug-
gesting that they had been primed by the primary series.92 However,
in another small study, two of six children who had lost detectable
antibody did not have an anamnestic response to a booster dose
administered approximately 6 years after they had received the primary
vaccine series in infancy in the presence of passively transferred
antibody.135,136
Inactivated hepatitis A vaccine has been shown to be highly efficacious
in preventing clinically apparent disease. In a study of approximately
40,000 Thai children 1 to 16 years of age, the efficacy of inactivated
vaccine (HM175 strain) was 94% (95% confidence interval [CI], 79%,
99%) after two doses (360 ELU per dose) administered 1 month apart.176
In a study of another inactivated vaccine (CR326F strain) involving
approximately 1000 children 2 to 16 years of age in a New York com-
munity with high hepatitis A rates, efficacy was 100% (lower bound of
the 95% CI, 87%) starting 17 days after the administration of one dose
(25 U).403
Since hepatitis A vaccines became available in the United States in
1995, studies, demonstration projects, and surveillance data have evalu-
ated their effectiveness in controlling and preventing the development
of hepatitis A in communities. In areas with the highest hepatitis A
rates, such as Native American and Alaska Native communities, vaccina-
tion of the majority of children—and in some cases adolescents and
young adults—resulted in a rapid decline in the incidence of disease,
and with ongoing routine vaccination of children, the reduction in
incidence of disease has been sustained.32,52,54,250 In larger, more hetero-
geneous communities with lower but consistently elevated hepatitis A
rates, interruption of ongoing community-wide epidemics by vaccination
of children proved more difficult.86 In contrast, sustained routine vac-
cination of children can reduce hepatitis A incidence markedly during
the course of time (see discussion on vaccine recommendations and
use).16,91,112 Examination of time trends of hospitalization for hepatitis
A at a tertiary pediatric hospital in Athens in 1999 to 2013 shows that
hospitalization rates significantly decreased after implementation of
the universal vaccination program in 2008 (from 50.5 to 20.8 per 1000
hospitalizations).287,288
Hepatitis A vaccine also is effective when it is used to prevent infection
after exposure. Hepatitis A vaccine administered soon after exposure
prevented infection in a chimpanzee model.314 Hepatitis A vaccine was
found to be 79% efficacious in preventing infection in contrast to no
treatment in a small randomized trial conducted in Italy.321 In a random-
ized controlled trial conducted in Kazakhstan, among persons aged 2
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CHAPTER 168  Hepatitis A Virus 1569
to 40 years who were contacts of hepatitis A cases, the efficacy of hepatitis
A vaccine administered within 14 days after exposure to HAV was shown
to be similar to that of IG in healthy children and adults younger than
40 years of age.390 Based on their results and because the vaccine offers
advantages over IG, the Advisory Committee on Immunization Practices
(ACIP) of the US Public Health Service currently recommends the
hepatitis A vaccine in preference to IG for postexposure prophylaxis of
healthy persons from the ages of 12 months to 40 years.54,63 Advisory
groups or expert panels in some other countries also have recommended
that hepatitis A vaccine be used as the primary means of preventing
hepatitis A after exposure.273,360
Experience to date indicates that the incidence of adverse events
after vaccination is comparable to that after the administration of other
widely used vaccines. In prelicensure clinical studies in children, the
side effects reported most frequently included soreness, tenderness,
warmth, or induration at the injection site (4–19%); feeding problems
(8%); and headache (4%).34,61,254 Through 2005, more than 188 million
doses have been sold worldwide, including more than 50 million doses
in the United States.61 No serious adverse events in children or adults
have been identified that could be definitively ascribed to hepatitis A
vaccine.35,61 The Vaccine Adverse Events Reporting System (maintained
by the US Food and Drug Administration and the CDC) has received
approximately 6000 reports of adverse events occurring after receipt
of hepatitis A vaccine. The most common events were minor and of
brief duration, such as fever, injection-site reactions, rash, and headache.
The 871 serious adverse events included Guillain-Barré syndrome,
elevated transaminases, idiopathic thrombocytopenic purpura, and
seizures among children.61,276 Rare adverse events reported after marketing
include syncope, jaundice, erythema multiforme, anaphylaxis, brachial
plexus neuropathy, transverse myelitis, encephalopathy, and others. For
events for which incidence rates are available, such as Guillain-Barré
syndrome, reported rates were not higher than reported background
rates.61
Anti-HAV persists at protective levels in vaccinated adults for at
least 10 to 12 years after vaccination,381,385,384 and more recent
publications have demonstrated protective levels up to 15 and 17 years
after vaccination383,382 and in children for at least 5 to 10 years after
vaccination.129,161,381 Available data indicate that both inactivated and live
attenuated hepatitis A vaccine are capable of providing long-term protec-
tion for up to 15 years in both children and adults.286 Recent studies using
mathematical models predict that 84% to 95% of children and adults
who receive the hepatitis A vaccination would remain seropositive for
30 years.350,367
In one follow-up study, two thirds of infants who did not have
passively transferred maternal antibody at the time of vaccination had
detectable anti-HAV 6 years later, and all who had lost antibody had
an anamnestic response to a booster dose.135,136 Estimates based on
kinetic models of decline in antibody suggest that the duration of
protection could be 15 to 25 years or longer.381,411,412 A study randomized
by maternal anti-HAV status included 197 children younger than 2
years of age who received different schedules of HAV vaccine and
demonstrated that the seropositivity induced by hepatitis A vaccine
can persists for at least 10 years regardless of presence of maternal
anti-HAV.334
In some settings, performing prevaccination serologic testing may
be considered in an attempt to reduce cost by not vaccinating persons
with previous immunity.47 Testing of children is not indicated because
of their expected low prevalence of infection and the lower cost of
vaccine for this age group. Testing may be considered for older adolescents
and adults in certain population groups with a high prevalence of
infection (e.g., Native Americans and Alaska Natives), persons who
either were born in or lived for extensive periods in geographic areas
that have high endemicity of HAV infection (e.g., Central and South
America, Africa, and Asia), and adults 40 years of age and older. However,
the cost of testing, the vaccine cost, and the likelihood that the person
will return for vaccination should be taken into account. Postvaccination
testing is not indicated because of the high rate of response to the
vaccine. Furthermore, most anti-HAV testing methods licensed for use
in the United States cannot reliably detect the low anti-HAV concentra-
tions generated by immunization.55,66
1570 SECTION 17  Viral Infections

the United States. Rates declined most dramatically among children in

TABLE 168.2  Advisory Committee on parts of the country where routine vaccination of children was recom-
Immunization Practices Recommendations for mended and where the estimated coverage was highest.399
Routine Preexposure Use of Hepatitis A Vaccine Since 2001, incidence rates in each successive year have been historic
lows, with the 2010 rate of 0.54 cases per 100,000 population demonstrat-
Group Comments
ing a 94% decline in contrast to previous lows observed in the early
All children at age 12–23 monthsa Integrate into routine childhood 1990s.64,67
vaccination schedule; children who Vaccine coverage data are limited but indicate that declines in
are not vaccinated by age 2 years incidence have occurred with modest levels of coverage, suggesting a
can be vaccinated at subsequent strong herd immunity effect.9,94,105,322, Modeling studies suggested that
visits 39% of potential cases were averted in 2001 because of the direct effects
Children age 2–18 years Maintain existing programb; can be of immunization and herd immunity.322 Similar observations have been
considered in areas without made in Israel and Spain. The incidence of hepatitis A declined by 95%
existing programs in Israel within 3 years after initiation of an immunization program
International travelers Except persons traveling to Canada, among children 18 to 24 months old, even though no catch-up vaccina-
Western Europe, Japan, Australia, tion of other age groups was attempted.92 Routine vaccination of
or New Zealand, who are at no 12-year-old children in Catalonia, Spain, was followed by a 58% reduction
greater risk than in the United in overall incidence.112 Hepatitis A incidence is cyclic, and data from
States additional years are needed to verify that low rates are sustained and
Infants <12 months of age traveling attributable to vaccination and to provide a definitive determination
to endemic area should receive of the overall impact of this strategy of routine childhood vaccination.
immunoglobulin prophylaxis However, the consistency and strength of these data render alternative
Men who have sex with men Includes adolescents explanations unlikely.
Illicit drug users Includes adolescents Vaccination of successive cohorts of children eventually should result
Persons with chronic liver disease Increased risk of fulminant hepatitis in a sustained reduction in the incidence of disease nationwide and
A with HAV infection thus provide the opportunity to eliminate HAV transmission. To achieve
Persons receiving clotting factor this goal, implementation of recent ACIP recommendations for vaccina-
concentrates tion of young children nationwide will be needed. Pediatric combination
vaccines that include hepatitis A vaccine would facilitate this effort.
Persons who work with HAV in
Vaccination of persons at increased risk for acquiring hepatitis A,
research settings
including travelers to countries where hepatitis A is endemic, adolescent
Anyone wishing to obtain immunity and adult MSM, persons who use illegal drugs, those who work with
HAV, Hepatitis A virus. HAV in research settings, and persons who have clotting factor disorders,
a
Hepatitis A vaccine is not licensed for children younger than 12 months. also is recommended.61,271,258 Persons with chronic liver disease who
b
States covered by 1999 ACIP recommendations (Alabama, Alaska, Arizona, California, acquire hepatitis A have been reported to have a high case-fatality rate
Colorado, Idaho, Minnesota, Missouri, Nevada, New Mexico, Oklahoma, Oregon, South and are also recommended for vaccination.61
Dakota, Texas, Utah, Washington, Wyoming, and selected areas in other states).55,60 In 2009, ACIP recommended hepatitis A vaccination for all previously
From Centers for Disease Control and Prevention: Prevention of hepatitis A through active unvaccinated persons who anticipate close personal contact (e.g.,
or passive immunization. Recommendations of the Advisory Committee on Immunization household contact or regular babysitting) with an international adoptee
Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1–23.
from a country of high or intermediate endemicity during the first 60
days after arrival of the adoptee in the United States. The first dose of
the two-dose hepatitis A vaccine series should be administered as soon
as adoption is planned, ideally within 2 weeks before the arrival of the
Vaccine Recommendations and Use adoptee.63,65
Recommendations for the use of hepatitis A vaccine were issued first ACIP considered the likelihood that a child adopted by parents in
by the ACIP (Table 168.2), the American Academy of Pediatrics, and the United States may be actively infected with hepatitis A and shedding
other groups in 1996 and updated in 1999 and 2006.8,51,55,59-61 As part virus at the time of the adoption. During 1998 to 2008, approximately
of an incremental strategy aimed at achieving widespread routine 18,000 children were adopted from foreign countries by families in the
vaccination, the 1999 recommendations called for routine vaccination United States each year. Of these, 99.8% came from countries where
of children living in areas where rates of hepatitis A consistently had hepatitis A is considered of high or intermediate endemicity and
been elevated. Various vaccination strategies that were suggested included approximately 85% were younger than 5 years.
vaccinating one or more single-age cohorts of children or adolescents, ACIP also considered reports of HAV infection among persons in
vaccinating children in selected settings (e.g., daycare), and vaccinating close contact with new adoptees from countries of high or intermediate
children and adolescents over a wide range of ages in a variety of settings, endemicity. In 2007, the CDC was notified of a case of fulminant hepatitis
such as when they seek health care for other purposes. The final step A in a non-traveling household contact of an asymptomatic Ethiopian
in this incremental strategy, routine vaccination of children older than adoptee confirmed to have acute hepatitis A (IgM HAV positive). This
12 months nationwide, was recommended by the ACIP in 2006.61 case prompted an investigation that led to an identification of 20
The impact of routine vaccination of children initially was shown additional cases of acute hepatitis A among persons who had close
in areas that historically have had the highest hepatitis A rates (e.g., contact with newly arriving international adopted children and no
Native American communities), where this strategy had been recom- history of traveling abroad.137,291,292 HAV infection in international
mended since 1996. Surveys conducted in 1999 to 2000 indicated adoptees and their contacts between 2007 and 2009 was also reported
vaccination coverage of 50% to 80% of preschool- and school-age Native in Minnesota.356
American and Alaska Native children, thus suggesting that the recom- HAV infection during pregnancy may be associated with a risk for
mendation for routine vaccination was being implemented.32 By 2000, gestational complications. HAV serology and vaccination for pregnant
the incidence of hepatitis A in Native Americans and Alaska Natives women should be considered in areas of high prevalence of acute
had declined by 97% in contrast to the beginning of the preceding hepatitis A.319
decade and was the same as the overall US rate.32 Hepatitis A vaccination is not routinely recommended for health
National surveillance data indicate that routine vaccination of children care personnel, persons attending or working in childcare centers, or
living in areas with consistently elevated rates, which was recommended persons who work in liquid or solid waste management (e.g., sewer
in 1999, has had an impact on the overall incidence of hepatitis A in workers or plumbers). ACIP does not recommend routine hepatitis A

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