PART III  Etiologic Agents of Infectious Diseases
SECTION B  Viruses
237 Hepatitis A Virus Melissa G. Collier and Noele P. Nelson
PATHOGEN
Hepatitis A virus (HAV) is a nonenveloped RNA virus and a member of
the Picornaviridae family.1 The single-stranded RNA genome is approxi-
mately 7500 nucleotides long and contains a single, long, open reading
frame. The encoded polyprotein includes structural proteins for the 27-
to 28-nm diameter capsid, nonstructural proteins with protease or
polymerase activities, and other proteins with functions that have not
been fully determined.2,3
Among infected people, HAV replicates in the liver, is excreted in bile,
and is found in high concentrations in stool. The incubation period aver-
ages 28 days (range, 15–50 days). Peak viral concentrations in stool and
greatest infectivity are during the 2 weeks before the onset of symptoms.
Virus concentrations in stool diminish markedly within 1 week after the
onset of symptoms. However, polymerase chain reaction assays have been
used to demonstrate low levels of viral RNA in stools of infected neonates
for up to 6 months after infection.4 In older children, HAV RNA can be
detected in stools for as long as 10 weeks after symptoms begin, but the
clinical significance of these findings is uncertain.5 Viremia occurs soon
after infection and persists at least through the period of elevation of
hepatic enzymes in serum.6,7
The pathogenesis of HAV infection is not completely understood.
However, the absence of cytopathic changes in cell culture and the
demonstration of HAV-directed natural killer and lymphokine-activated
killer cells in vitro suggest that cell-mediated immunity is responsible for
hepatocellular damage.8
HAV is a single serotype.9 Seven HAV genotypes have been identi-
fied with unique geographic distribution; 4 genotypes are found in
humans (I, II, II, IV).3 Genotype IA is the most commonly identified
genotype in US HAV cases (88%), followed by IB (11%) and IIIA
(0.7%).10
Immunity resulting from HAV infection is lifelong. In contrast to
infection with hepatitis B and hepatitis C viruses, HAV infection does
not result in chronic infection or chronic liver disease.
EPIDEMIOLOGY
The principal mode of HAV transmission is from person to person, by
the fecal-oral route. Transmission occurs most commonly among close
contacts, including household and sexual contacts of people infected
with HAV. HAV also is transmitted by contaminated food, most often
from an infected food handler, but also in association with food con-
taminated before retail distribution (e.g., produce contaminated during
growing or processing).11–13 Common-source food exposures are of
increasing concern. Several outbreaks of hepatitis A virus genotype IB
illness associated with food from the Middle East have been reported,
including frozen strawberries from Egypt and Morocco in Europe, frozen
pomegranate seeds from Egypt in Canada, semidried tomatoes from
Turkey in Europe and Australia, and pomegranate arils from Turkey
in the United States.14–19 Transmission by contaminated water is rare.
Because transient viremia occurs in HAV infection, bloodborne HAV
transmission can occur, such as among injection drug users.20 On rare
occasions, HAV infection has been transmitted by transfusion of blood
or blood products collected from donors during the viremic phase of
infection.21 In addition, outbreaks have been reported in Europe and
the US among patients who received factor VIII and factor IX concen-
trates prepared with the use of solvent detergent treatment.22 However,
changes in viral inactivation procedures, introduction of hepatitis A
vaccine, and improved donor screening have nearly eliminated the risk
for HAV transmission from clotting factors.23 Vertical transmission to
1214
children from pregnant women who develop hepatitis A during the
third trimester of pregnancy has been reported, but the risk appears
to be low. In approximately 50% of people with sporadic, community-
acquired hepatitis A, no source of infection is identified.24 When
a risk factor is identified, international travel is the most commonly
reported.10,25
Because most young children have asymptomatic or unrecognized
infections, they play an important role in the epidemiology of hepatitis
A and often serve as sources of infection for others. In several studies
using serologic testing of household contacts, 25% to 40% of contacts <6
years of age had serologic evidence of acute HAV infection.26,27 In 1 US
study, 52% of households of adults without an identified source of infec-
tion included a child <6 years of age, and the presence of a young child
was associated with HAV transmission in the household. In this study,
transmission chains were identified that involved as many as 6 genera-
tions and >20 cases.26
The relationship between risk of infection and likelihood of asymp-
tomatic infection during childhood is important to understanding HAV
transmission patterns worldwide and to developing prevention strategies.
Level of economic development, as indicated by hygienic and sanitary
conditions, is correlated with global HAV transmission patterns (Fig.
237.1). In areas where seroprevalence of antibody to HAV (anti-HAV)
is high even among young children (e.g., parts of Asia, Africa, Central
and South America), the lifetime risk of infection is greater than 90%,
and infection occurs primarily in early childhood.27,28 Asymptomatic
infection predominates, and nearly the entire population is infected
before reaching adolescence. The high rates of HAV transmission during
childhood may not be recognized because typical clinical manifestations
of hepatitis A are uncommon in children. The incidence of clinical hepa-
titis A generally is low, and outbreaks are rare because most adults are
immune. However, adults who remain susceptible to infection in these
areas are at high risk for HAV infection. Travelers to highly endemic areas
from the developed world also are at high risk. In areas of moderate
endemicity (e.g., Eastern Europe), HAV is not transmitted as readily
because of better sanitation and living conditions, and the average age
of infection is older than in areas of high endemicity. However, transmis-
sion among young children remains relatively common. Paradoxically,
the potential for large outbreaks can be increased (compared with
highly endemic areas) because of the relatively larger pool of susceptible
older children and adults who are at high risk for infection and who,
when infected with HAV, are likely to develop symptomatic illness.29
Unimmunized travelers from the developed world to these areas also
are at risk.30 In some instances, countries undergoing rapid develop-
ment accompanied by improvement in sanitation standards and clean
water supplies have experienced changes in the epidemiologic pattern
of HAV. In these countries, HAV is likely to become a more serious
problem.31 Declines in childhood and adolescent HAV seroprevalence
lead to susceptibility at a later age, with greater associated morbidity and
mortality. In most developed countries without universal vaccination
policies, the incidence of both HAV infection and hepatitis A clinical
disease is low. Most cases occur in the context of cyclic, community-
wide outbreaks that feature transmission among preschool and school-
aged children and their adult contacts.31 As endemicity continues to
decline in some parts of the developed world, most cases are identi-
fied in defined risk groups, such as travelers returning from endemic
areas, international adoptees from endemic countries, and injection
drug users.29,32
In the US, before hepatitis A vaccine was widely available, hepatitis A
occurred in large, nationwide epidemics approximately every decade.25
Until 2001, the highest rates of HAV infection in the US were observed
 Hepatitis A Virus 237

Pacific
Ocean Atlantic
Ocean

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

FIGURE 237.1  Prevalence of antibody to hepatitis A virus, 2006. Geographic distribution of hepatitis A virus (HAV) infection endemicity. For multiple countries, estimates
of prevalence of antibody to hepatitis A virus (anti-HAV), a marker of previous HAV infection, are based on limited data and may not reflect actual prevalence. In addition,
anti-HAV prevalence rates could vary within countries by subpopulation and locality. (Adapted from Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age
and world region, 1990 and 2005. Vaccine 2010;28:6653–6657.)

among children 5 to 14 years of age, with approximately one third of
reported cases involving children <15 years of age.33–35 The highest rates
and the majority of cases occurred in the western and southwestern
states.34–36
Since licensure of the first hepatitis A vaccines in 1995, incidence rates
have declined sharply (Figs. 237.2 and 237.3).25 Declines have been
especially prominent since implementation of targeted recommenda-
tions made in 1996 to 1999 for childhood vaccination in states with high
hepatitis A rates.33,34 In 2006, universal vaccination was recommended in
all states.28 The number of reported cases in the US reached an all-time
low of 1398 cases in 2011, thus representing a 96% decline in reported
cases since vaccine recommendation. The first increases in cases since
1995 occurred in 2012 (1562 total cases) and again in 2013 (1781 total
cases), coincident with the 2013 multistate outbreak of hepatitis A.19,25,37
The number of cases increased slightly in 2014 (1239 cases). Hepatitis A
rates declined since vaccine introduction from 11.7 cases per 100,000

0-9 yr
7
10-19 yr
Reported cases/100,000

6 20-29 yr 12
30-39 yr
Reported cases/100,000

5 40-49 yr 10 American Indian/Alaska Native

population

50-59 yr Asian/Pacific Islander

4  60+ yr 8
population

Black, Non-Hispanic
3 6 White, Non-Hispanic
 

2

 Hispanic
4

1   
      2
0
0
0 2 4 6 8 0 2 4 02 06 08 10 12 14
20
0
20
0
20
0
20
0
20
0
20
1
20
1
20
1 00 04 20 20 20
20 20 20 20 20
Year Year
FIGURE 237.2  Incidence of acute hepatitis A, by age group and year, United FIGURE 237.3  Cases of acute hepatitis A, by race or ethnicity in the United
States, 2000 to 2014. Incidence rates are per 100,000 population and were States, 2000 to 2014. Incidence rates are per 100,000 population and were
reported by the National Notifiable Diseases Surveillance System in 2014. (From reported by the National Notifiable Diseases Surveillance System in 2014. (From
Centers for Disease Control and Prevention. Incidence of acute hepatitis A, by Centers for Disease Control and Prevention. Incidence of acute hepatitis A,
age group—United States, 2000–2014. https://www.cdc.gov/hepatitis/statistics/ by race/ethnicity—United States 2000–2014. https://www.cdc.gov/hepatitis/
2014surveillance/index.htm#tabs-1170596-5.) statistics/2014surveillance/index.htm#tabs-1170596-5.)

1215
 PART III  Etiologic Agents of Infectious Diseases
SECTION B  Viruses
population in 1996 to 0.4 cases per 100,000 population in 2011, with a
slight increase to 0.5 and 0.6 cases per 100,000 population in 2012 and
2013, respectively, and declined in 2014 back to 0.4 cases per 100,000
population.25,37 Since the mid-2000s, age, regional, ethnic, and racial
differences in incidence rates of hepatitis A have been eliminated, thereby
indicating fundamental shifts in hepatitis A epidemiology (see Fig.
237.3).24,38,39 Moreover, with the lack of circulating HAV after massive
declines in HAV infections among children, the seroprevalence rates have
dropped for adults as the average ages of hepatitis A hospitalizations and
deaths have increased.40 The likely reason for this finding is that the adults
who were infected in childhood with subsequent immunity are aging out
of the population, to be replaced by adults who were too old to be vac-
cinated as children but who did not have the opportunity to be exposed
to the virus and develop disease at an earlier age. The 2013 multistate
outbreak of hepatitis A occurred largely in adults, with few cases in
unvaccinated children.38 This finding illustrates that future problems
with imported food contaminated with HAV may pose a risk to this large,
susceptible, adult population.
Methods to isolate and sequence HAV from sera of infected people
and to define the genetic variation of HAV are advancing understanding
of the epidemiology.41 The resulting database of HAV genome sequences
has been useful in investigations of foodborne outbreaks by demonstrat-
ing links among apparently sporadic cases and suggesting possible
sources of contamination.11,38,42
CLINICAL MANIFESTATIONS
HAV infection can be inapparent (the patient is asymptomatic with no
elevation in serum hepatic enzymes), subclinical (asymptomatic with
elevation of hepatic enzymes), anicteric (symptomatic without jaundice),
or icteric (symptomatic with jaundice). The likelihood of having symp-
toms with HAV infection is related directly to age. Most children <6 years
of age have asymptomatic infection or mild, nonspecific symptoms with
hepatitis A; <10% of children in this age group have jaundice.43 Among
older children and adults, 76% to 97% have symptoms when they are
infected with HAV, and 40% to 70% of patients with symptoms are
icteric.44
When symptoms occur, most patients have an onset of low-grade
fever, myalgia, anorexia, malaise, nausea, and vomiting. These symp-
toms are followed several days later by specific symptoms and signs
of hepatic dysfunction, including dark urine, light-colored stools,
jaundice, and scleral icterus.44 Many children (60%) and some adults
(20%) have diarrhea. Some children (<20%) have upper respiratory
tract symptoms (e.g., cough, coryza, sore throat). Urticaria can occur
at the onset of illness.45 Physical findings are variable and can include
jaundice, scleral icterus, hepatomegaly, right upper quadrant tenderness,
and splenomegaly. Abdominal ultrasonography showed edema of the
gallbladder wall in approximately 50% of children with uncomplicated
hepatitis A who were studied prospectively; transient ascites occurred
in a few patients.46 The symptoms of hepatitis A last for several weeks
on average and usually not longer than 2 months, although some
people can have prolonged or relapsing signs and symptoms for up to
6 months.
LABORATORY FINDINGS AND DIAGNOSIS
During HAV infection, inflammation of the liver is accompanied by
abnormalities in serum hepatic enzymes, with increases in serum levels
of alanine aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase, and γ-glutamyltranspeptidase. Usually in acute
hepatitis A, ALT and AST values are between 200 and 5000 IU/L; the ALT
value is higher than the AST value; and alkaline phosphatase levels are
only mildly elevated. Elevations in ALT and AST can precede symptoms
by a week or more and generally peak 3 to 10 days after the onset of
symptoms (Fig. 237.4).
The specific diagnosis of hepatitis A relies on serologic testing in
addition to the presence of symptoms. Virtually all people with acute
hepatitis A have detectable immunoglobulin (Ig) M anti-HAV during
the acute or early convalescent phase of infection (see Fig. 237.4).47 IgM
anti-HAV generally disappears within 6 months after the onset of symp-
toms, although people who test positive for IgM anti-HAV >1 year after
infection or with no known history of infection have been reported.48,49
1216
Clinical illness
Infection ALT
lgM lgG
Response
Viremia
HAV in stool
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Week
FIGURE 237.4  Typical serologic profile of hepatitis A virus (HAV) infection. ALT,
serum alanine aminotransferase level; Ig, immunoglobulin.
IgG anti-HAV, which appears in the convalescent phase of infection,
remains detectable in serum for the person’s lifetime and confers protec-
tion against disease. Commercial enzyme immunoassays are available for
detection of IgM and total anti-HAVs in serum. Because the test for total
anti-HAVs frequently is performed first in laboratories, and results are
positive for anyone who has been vaccinated or infected in the past, IgM
anti-HAV detection is necessary to make the diagnosis of HAV hepatitis.
Polymerase chain reaction assays can be used to detect HAV RNA in
stool specimens and sera of people with HAV infection, although these
tests are available only in a few research laboratories.3,6 To date, poly-
merase chain reaction assays cannot determine whether a person is
infectious because incomplete virus particles can be detected. On the
basis of epidemiologic studies, peak infectivity occurs during the 2 weeks
before the onset of symptoms. For practical purposes, people with hepa-
titis A can be assumed to be noninfectious 1 week after the onset of
jaundice.
Light microscopic examination of liver specimens in acute hepatitis A
reveals pathologic features common to all forms of viral hepatitis, includ-
ing hepatocellular necrosis, inflammatory infiltration of lymphocytes
and other mononuclear cells, and regeneration of hepatocytes. The extent
of involvement varies with the stage and severity of hepatitis and age of
the patient. Liver biopsy typically is not indicated for the diagnosis or
management of hepatitis A.
TREATMENT
Treatment generally is supportive. Hospitalization may be necessary
for patients who are dehydrated from nausea and vomiting or who
have fulminant hepatitis A. No specific diet or restriction of activity
is necessary. Medications that can cause hepatic damage or that are
metabolized by the liver should be used with caution. For the infrequent
presentations of cholestatic or relapsing hepatitis A, a short course of
corticosteroid therapy has been reported as effective in limiting symp-
toms and hastening recovery, but no controlled trials have evaluated this
approach.50,51
Liver transplantation is successful in some people with acute liver
failure. Criteria for choosing patients for liver transplantation are difficult
to establish because survival without transplantation is high (50%–70%),
even for patients in a coma, and no single factor is predictive of a poor
outcome.52
SPECIAL CONSIDERATIONS
HAV infection occasionally results in fulminant hepatitis and death. In
addition, hepatitis A has several atypical manifestations, including relaps-
ing hepatitis A, cholestatic hepatitis, autoimmune hepatitis, and extrahe-
patic symptoms.
Fulminant hepatitis A, characterized by the onset of severe liver injury
and hepatic encephalopathy in patients with no known preexisting liver
disease, is an infrequent occurrence.53 The case-fatality rate among

reported cases of hepatitis A in all age groups is approximately 0.6%.25
Host factors associated with a higher risk for fulminant hepatitis A
include older age (>50 years old) and underlying chronic liver disease.54
Molecular studies have not shown an association between fulminant
hepatitis A and any type of viral variant. Of 348 children with acute liver
failure from the US, Canada, and the United Kingdom who were entered
into a registry, only 3 (0.9%) had acute hepatitis A.55 Spontaneous
recovery occurs in 30% to 60% of people with fulminant HAV infection,
and survivors generally regain full liver function. Prognosis is influenced
by age, clotting factor level, stage of coma, and presence of renal disease.24
In approximately 10% to 15% of patients with hepatitis A, relapsing
hepatitis occurs, and approximately 20% of these patients have multiple
relapses.24,51 These patients typically have another episode of hepatitis 1
to 4 months after the initial acute hepatitis. The relapse is accompanied
by elevation of serum hepatic enzymes and persistence of IgM anti-HAV.
Molecular studies have demonstrated the presence of HAV in stool
specimens during relapse. Most patients recover completely within
several weeks.
Cholestatic hepatitis occurs rarely following infection with HAV.50
Patients with this disorder have substantially elevated concentrations
(>10 mg/dL) of bilirubin in serum and jaundice persisting for an
extended period (in some cases >3 months). This syndrome can be dis-
tinguished from obstructive jaundice by normal abdominal ultrasono-
graphic findings. A short course of corticosteroids can reduce symptoms
and hasten disease resolution.24
Several case series have been described in which HAV infection is
followed by autoimmune chronic active hepatitis, in some instances
requiring longterm corticosteroid therapy.56 Extrahepatic manifesta-
tions of hepatitis A include pruritus, arthralgia, cutaneous vasculitis,
cryoglobulinemia, and hemophagocytic syndrome (anemia and
thrombocytopenia, with hemophagocytosis apparent on biopsy of bone
marrow). These manifestations are rare and resolve with resolution of
hepatitis.
PREVENTION
The methods of prevention of hepatitis A include the following: (1)
general measures of good personal hygiene (with an emphasis on hand
hygiene), provision of safe drinking water, and adequate disposal of sani-
tary waste; and (2) pre-exposure or postexposure prophylaxis with
immune globulin (IG) or hepatitis A vaccine.
Immune Globulin
IG is a solution of antibodies prepared from human plasma by serial
ethanol precipitation for intramuscular administration. In the US,
GamaSTAN (Grifols Therapeutics, Inc., Research Triangle Park, NC) is
the only available hepatitis A immune globulin (IgG anti-HAV) product.
The manufacturing process removes model enveloped and nonenveloped
viruses, including human immunodeficiency virus, hepatitis B virus,
and hepatitis C virus, as well as low levels of Creutzfeldt-Jakob disease
(CJD)/variant CJD agent infectivity.57 The efficacy of IG (0.02 mL/kg
intramuscularly) in preventing hepatitis A is 80% to 90% when IG is
administered before exposure to HAV or within 2 weeks after expo-
sure.58,59 Seroprotective anti-HAVs (i.e., 10–20 mIU/mL) appear rapidly
after pre-exposure intramuscular injection and reach peak levels in
approximately 2 days after injection.59 No information exists regarding
the efficacy of IG or vaccine if it is administered >2 weeks after expo-
sure.36 The prevalence of anti-HAV in the population has been declining;
however, no clinical or epidemiologic evidence of decreased protection
from IG has been observed, though decreased potency of IG has been
found.60,60a IG is indicated in patients for whom the vaccine is contraindi-
cated, and in certain situations for international travel and postexposure
prophylaxis.61
IG should be administered intramuscularly only, preferably in the
deltoid muscle of the upper arm or the anterolateral aspects of the
upper thigh in children <24 months of age.61 Serious adverse events
from IG are rare. IG is contraindicated for patients with IgA deficiency
because of reports of anaphylaxis in these people, as well as for patients
who have severe thrombocytopenia or any coagulation disorder.62 IG
can be administered at the same time as most inactivated vaccines;
however, IG can interfere with the response to live, attenuated virus
Hepatitis A Virus 237
vaccines (e.g., measles, mumps, and rubella vaccine and varicella
virus vaccine) when administered either as individual or combination
vaccines.36,62,63
Vaccine
Hepatitis A vaccine is preferred over IG for pre-exposure and postexpo-
sure prophylaxis because of induction of active immunity and longer
protection, greater ease of administration, and often greater acceptability.
In the US, HAVRIX (GlaxoSmithKline Biologicals, Philadelphia) was
approved by the Food and Drug Administration in 1995 and VAQTA
(Merck & Co. Inc., Whitehouse Station, NJ) was approved in 1996; both
vaccines are licensed for people ≥12 months of age. In 2001, a combina-
tion hepatitis A and hepatitis B vaccine (TWINRIX, GlaxoSmithKline)
was approved for patients 18 years old or older. Inactivated hepatitis A
vaccines are prepared by methods including growth in cell culture,
purification by ultrafiltration or other methods, inactivation with forma-
lin, and adsorption to an aluminum hydroxide adjuvant.64,65 HAVRIX and
VAQTA are available in pediatric and adult formulations and are licensed
in a 2-dose series, with the second dose scheduled 6 to 18 months after
the first. However, if the second dose is given >18 months after the first
dose, no additional doses are required.63 The route of administration is
intramuscular, in the anterolateral thigh for children aged <2 years and
the deltoid muscle for children and adults. TWINRIX is licensed in a
3-dose series or a 4-dose alternate series.66–68 Monovalent hepatitis A
vaccine may be used to complete hepatitis A vaccination begun with
TWINRIX and vice versa.69
Inactivated hepatitis A vaccines have been studied extensively
in children and adults. In general, within 4 weeks after one dose of
vaccine, ≥90% of children aged ≥1 year and adults respond with levels
of antibody considered to be protective; a second dose is necessary 6 to
18 months later to boost antibody levels for longterm protection.70,71
Nearly 100% of patients will develop protective antibodies after receiving
2 doses. Response to vaccine may be lower in patients >40 years of
age, immunosuppressed patients, patients with advanced liver disease
or recipients of liver transplants, and infants with passively acquired
maternal antibody. Delayed administration of the second dose beyond
18 months does not appear to reduce immunogenicity.72 Available data
indicate that the vaccines are safe and immunogenic in children <12
months of age who do not have passively acquired maternal antibody.73
However, final antibody concentrations in infants with passively acquired
maternal antibody are one third to one tenth of those of anti-HAV–
negative infants who are vaccinated according to the same schedule, and
fewer infants with passively acquired maternal antibody have detectable
anti-HAV 6 years after vaccination compared with children vaccinated
as infants who did not have passively acquired maternal antibody.73,74
The immunogenicity of TWINRIX is considered equivalent to that of
the single antigen hepatitis vaccine when it is administered in a 3-dose
series.36
Inactivated hepatitis A vaccine is highly efficacious in preventing clini-
cal hepatitis A. In a large study conducted in Thailand among children 1
to 16 years of age, efficacy of the vaccine was 94% after 2 doses of vaccine
administered 1 month apart.75 In another study conducted in New York
among children 2 to 16 years of age and with a different inactivated
vaccine, efficacy was 100% starting 17 days after administration of 1
dose.76
The duration of protection after vaccination is unknown; however,
anti-HAVs have been shown to persist in vaccine recipients for at least
20 years.77–80 Detectable antibodies are estimated to persist for 20 to 25
years or longer, based on mathematical modeling and anti-HAV kinetic
studies.81,82
In prelicensure clinical trials among children, the most frequently
reported local reaction following hepatitis A vaccination was soreness at
the injection site (15%–19%).71,72 Systemic reactions that include fatigue,
fever, diarrhea, and vomiting occurred in <5% of vaccine recipients.36 No
serious adverse events among children or adults that could be attributed
definitively to the vaccine and no increases in serious adverse events
among vaccinated people compared with baseline rates have been
identified.33,83,84
In 1996, targeted hepatitis A vaccine was initially recommended by
the Advisory Committee on Immunization Practices (ACIP) for children
at 2 years of age and adolescents in communities with high rates of
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 PART III  Etiologic Agents of Infectious Diseases
SECTION B  Viruses

In 2009, the ACIP updated guidance by recommending hepatitis A

TABLE 237.1  Advisory Committee on Immunization Practices vaccination for all previously unvaccinated people who anticipate close
Recommendations for Routine Pre-Exposure Use of Hepatitis A personal contact with an international adoptee from a country of high
Vaccine or intermediate endemicity during the first 60 days following arrival of
Group Comments
the adoptee in the US.86
The use of vaccine largely is responsible for the >95% decrease in
All children at 12–23 mo of agea Integrate into routine childhood hepatitis A cases since vaccine introduction from 1996 to 2011.37 Geo-
immunization schedule; graphic variability and most disparities in nationally reported acute
children who are not hepatitis A disease by race or ethnicity have been eliminated.35 However,
vaccinated by 2 yr of age can 2-dose vaccine coverage remains low. Hepatitis A vaccine coverage for
be vaccinated at subsequent
children 19 to 35 months of age in 2015 was 86% and 60% for ≥1 and
visits
≥2 doses, respectively.87 Coverage for children 13 to 17 years of age in
Children 12–18 yr of age Maintain existing programsb; can 2012 was 60% and 48% for 1- and ≥2-dose coverage, respectively.88
be considered in areas Among adults 19 to 49 years of age in 2014, a group for which vaccine is
without existing programs recommended only for those at high risk of HAV infection, the total
International travelers Except people traveling to ≥2-dose coverage was 12%; coverage was 19% for travelers outside the
Canada, Western Europe, US and 18% for adults with chronic liver conditions.89 Reduced exposure
Japan, Australia, or New to HAV early in life, significant decreases in anti-HAV seroprevalence in
Zealand, who are at no older adults, and low 2-dose vaccination rates are causing an increasing
greater risk than in the United proportion of susceptible adults.19,89
States Sustained reduction in disease incidence in the US should be achieved
Men who have sex with men Includes adolescents through vaccination of successive cohorts of children and should provide
the opportunity to eliminate HAV transmission. To achieve this goal,
Illicit drug users Includes adolescents however, higher population vaccination coverage throughout the US
People with chronic liver disease Increased risk of fulminant must be achieved; rapid identification and control of outbreaks, includ-
hepatitis A ing common-source food exposures, must continue; and expanded rec-
People receiving clotting factor ommendations for single- or double-dose vaccination could be
concentrates considered.
People who work with HAV in
research settings International Travel (Pre-exposure)
Anyone wishing to obtain All susceptible people traveling to or working in countries that have high
immunity or intermediate hepatitis A endemicity should receive pre-exposure
People who anticipate close, prophylaxis. Hepatitis A vaccine at the age-appropriate dose is preferred
personal contact (e.g., to IG for children and adults 1 to 40 years of age. One dose of a mon-
household or regular ovalent hepatitis A vaccine administered any time before departure
babysitting) with an protects most healthy people 1 to 40 years of age. No data on single dose
international adoptee during hepatitis A vaccine efficacy are available for TWINRIX. For optimal
the first 60 days after arrival in protection, adults >40 years of age, immunocompromised people, and
the United States from a patients with chronic liver disease or other chronic medical conditions
country with high or who are planning to depart to an area in <2 weeks should receive the
intermediate endemicityc initial dose of vaccine along with IG (0.02 mL/kg) administered at a
a
Hepatitis A vaccine is not licensed for children <12 months of age. separate injection site. Travelers who are <12 months of age, who are
b
Areas covered by 1999 Advisory Committee on Immunization Practices recommendations allergic to a vaccine component, or who otherwise elect not to receive
(Alaska, Arizona, Arkansas, California, Colorado, Idaho, Missouri, Montana, Nevada, New vaccine should receive a single dose of IG (0.02 mL/kg), which provides
Mexico, Oklahoma, Oregon, South Dakota, Texas, Utah, Washington, Wyoming, and selected effective protection against HAV infection for up to 3 months. Those who
areas in other states).34 do not receive vaccination and who plan to travel for >2 months should
c
The first dose should be administered as soon as the adoption is planned, ideally 2 or more receive an IG dose of 0.06 mL/kg, which must be repeated if the duration
weeks before the arrival of the adoptee.88 of travel is >5 months.61
HAV, hepatitis A virus.
From Centers for Disease Control and Prevention. Prevention of hepatitis A through active or
passive immunization: recommendations of the Advisory Committee on Immunization Postexposure Prophylaxis
Practices. MMWR Recomm Rep 2006;55(RR-07):1–23. Hepatitis A vaccination has shown efficacy compared with placebo
when it is given up to 14 days after exposure to a person with HAV
infection.61,90,91 A controlled study that compared the efficacy of hepa-
titis A vaccine with that of IG when given after exposure showed the
performance of vaccine to be similar to that of IG in healthy children and
HAV disease or for outbreak control.33 In 1999, the ACIP recommended adults 12 months through 40 years of age.61,91 People who recently have
vaccination in counties, communities, and 11 states with hepatitis A been exposed to HAV and who previously have not received hepatitis
rates ≥20 cases per 100,000 population and consideration of vaccination A vaccine should be administered 1 dose of monovalent hepatitis A
in 6 additional states with rates of ≥10 cases but <20 cases per 100,000 vaccine or IG (0.02 mL/kg) as soon as possible, ideally within 2 weeks
population.34 By 2004, first-dose coverage rates among children 24 to of exposure. The relative efficacy of vaccine is comparable to that of IG
35 months of age who were living in these states had reached 25% for postexposure prophylaxis among people 1 to 40 years of age. For
to 50%.85 The impact of even limited routine vaccination of children healthy people 1 to 40 years of age, a dose of monovalent hepatitis A
on hepatitis A incidence was evidenced by historic reductions in vaccine is recommended. For people >40 years of age, IG is preferred,
incidence rates.35,40 In 2006, the ACIP extended recommendations to but vaccine can be used if IG is unavailable. IG is recommended for
routine vaccination of children 12 to 23 months of age and for anyone infants <12 months of age, people who are immunocompromised,
wishing to obtain immunity (Table 237.1).36 Vaccination of people at patients with chronic liver disease, and people for whom vaccine is
increased risk for hepatitis A also is recommended (see Table 237.1 contraindicated.61 TWINRIX is not approved for use as postexposure
and Fig. 237.1).36 In 2007, the ACIP updated recommendations for prophylaxis.
prevention of hepatitis A for international travel and postexposure
prophylaxis.61 All references are available online at www.expertconsult.com.

1218
 Key Points: Diagnosis and Management of Hepatitis A Virus Infection
MICROBIOLOGY
• Nonenveloped RNA virus and member of the Picornaviridae
family
• Replicates in the liver, is excreted in bile, and is found in high
concentrations in stool
• Average incubation period of 28 days (range, 15–50 days)
• Greatest infectivity 2 weeks before onset of symptoms
EPIDEMIOLOGY
• Primarily fecal-oral transmission by person-to-person contact or
consumption of contaminated food or water
• Endemic in many developing countries; infection occurs mainly in
childhood.
• Low prevalence in developed countries; infection occurs typically
among adolescents and adults.
• In the United States, international travel is the most frequently
reported risk factor.
• International adoption is a risk factor.
CLINICAL FEATURES
• Symptoms range from none to acute debilitating disease
• Symptomatic infection generally is characterized by acute onset
and
■ Early symptoms: low-grade fever, myalgia, anorexia, malaise,
and vomiting.
HAV, hepatitis A virus; Ig, immunoglobulin.
KEY REFERENCES
10. Klevens RM, Miller JT, Iqbal K, et al. The evolving epidemiology of hepatitis a in
the United States: incidence and molecular epidemiology from population-based
surveillance, 2005–2007. Arch Intern Med 2010;170:1811–1818.
19. Collier MG, Khudyakov YE, Selvage D, et al. Outbreak of hepatitis A in the USA
associated with frozen pomegranate arils imported from Turkey: an epidemiological
case study. Lancet Infect Dis 2014;14:976–981.
24. American Academy of Pediatrics. Hepatitis A vaccine recommendations. Pediatrics
2007;120:189–199.
30. Centers for Disease Control and Prevention. CDC Health Information for Inter-
national Travel 2016. New York, Oxford University Press, 2016.
36. Centers for Disease Control and Prevention. Prevention of hepatitis A through
active or passive immunization: recommendations of the Advisory Committee on
Immunization Practices. MMWR Recomm Rep 2006;55(RR-07):1–23.
Later symptoms or signs: hepatic dysfunction, dark urine,
■
light-colored stools, jaundice, and scleral icterus.
• Likelihood of developing symptoms increases with
patient’s age
• Average duration is 2 months; overall case-fatality rate is 0.3% to
0.6%
DIAGNOSIS
• Presence of serum antibodies to HAV: IgM detectable 5 to 10
days before onset of symptoms; IgG appears in convalescent
phase and is lifelong
• Polymerase chain reaction assay can be used to detect viral
RNA in blood or stool but is not widely available and typically is
used only in outbreak investigations.
TREATMENT
• Supportive care
PREVENTION
• General measures of good personal hygiene, provision of safe
drinking water, and adequate waste disposal
• Pre-exposure or postexposure prophylaxis with hepatitis vaccine
or immune globulin
40. Ly KN, Klevens RM. Trends in Disease and Complications of Hepatitis A Virus
Infection in the United States, 1999–2011: a new concern for adults. J Infect Dis
2015;212:176–182.
49. Centers for Disease Control and Prevention. Positive test results for acute
hepatitis A virus infection among persons with no recent history of acute
hepatitis—United States, 2002–2004. MMWR Morb Mortal Wkly Rep 2005;54:
453–456.
61. Centers for Disease Control and Prevention. Prevention of hepatitis A after exposure
to hepatitis A virus and in international travelers: updated recommendations of the
ACIP. MMWR Morb Mortal Wkly Rep 2007;56:1080–1084.
69. Hepatitis A. In: Atkinson W, McIntyre L, Wolfe S (eds) Epidemiology and Prevention
of Vaccine-Preventable Diseases, 10th ed. Washington, DC, Public Health Founda-
tion, 2008, pp 197–209.

REFERENCES
1. Minor PD. Picornaviridae: classification and nomenclature of viruses. Arch Virol
Suppl 1991;2:320.
2. Rachow A, Gauss-Müller V, Probst C. Homogenous hepatitis A particles: proteo-
lytic release of the assembly signal 2A from procapsids by factor Xa. J Biol Chem
2003;278:29744–29751.
3. Nainan OV, Xia G, Vaughan G, et al. Diagnosis of hepatitis A virus infection: a
molecular approach. Clin Microbiol Rev 2006;19:63–79.
4. Rosenblum LS, Villarino ME, Nainan OV, et al. Hepatitis A outbreak in a neonatal
intensive care unit: risk factors for transmission and evidence of prolonged viral
excretion among preterm infants. J Infect Dis 1991;164:476–482.
5. Robertson BH, Averhoff F, Cromeans TL, et al. Genetic relatedness of hepatitis A
virus isolates during a community-wide outbreak. J Med Virol 2000;62:144–150.
6. Bower WA, Nainan OV, Han X, et al. Duration of viremia in hepatitis A virus
infection. J Infect Dis 2000;182:12–17.
7. Normann A, Jung C, Vallbracht A, et al. Time course of hepatitis A viremia and viral
load in the blood of human hepatitis A patients. J Med Virol 2004;72:10–16.
8. Baba M, Fukai K, Hasegawa H, et al. The role of natural killer cells and lymphokine
activated killer cells in the pathogenesis of hepatic injury in hepatitis A. J Clin Lab
Immunol 1992;38:1–14.
9. Lemon SM, Binn LN. Antigenic relatedness of two strains of hepatitis A virus
determined by cross-neutralization. Infect Immun 1983;42:418–420.
10. Klevens RM, Miller JT, Iqbal K, et al. The evolving epidemiology of hepatitis A in
the United States: incidence and molecular epidemiology from population-based
surveillance, 2005–2007. Arch Intern Med 2010;170:1811–1818.
11. Hutin YJF, Pool V, Cramer EH, et al. A multistate foodborne outbreak of hepatitis
A. N Engl J Med 1999;340:595–602.
12. Rosenblum LS, Mirkin IR, Allen DT, et al. A multifocal outbreak of hepatitis A traced
to commercially distributed lettuce. Am J Public Health 1990;80:1075–1079.
13. Wheeler C, Vogt T, Armstrong GL, et al. A foodborne outbreak of hepatitis A in
Pennsylvania associated with green onions. N Engl J Med 2005;353:890–897.
14. Nordic Outbreak Investigation Team. Joint analysis by the Nordic countries of a
hepatitis A outbreak, October 2012 to June 2013: frozen strawberries suspected. Euro
Surveill 2013;18:20520.
15. Swinkels HM, Kuo M, Embree G, et al. Hepatitis A outbreak in British Columbia,
Canada: the roles of established surveillance, consumer loyalty cards and collabora-
tion, February to May 2012. Euro Surveill 2014;19:20792.
16. Donnan EJ, Fielding JE, Gregory JE, et al. A multistate outbreak of hepatitis A associ-
ated with semidried tomatoes in Australia, 2009. Clin Infect Dis 2012;54:775–781.
17. Gallot C, Grout L, Roque-Afonso AM, et al. Hepatitis A associated with semidried
tomatoes, France, 2010. Emerging Infect Dis 2011;17:566–567.
18. Petrignani M, Harms M, Verhoef L, et al. Update: a food-borne outbreak of hepatitis
A in the Netherlands related to semi-dried tomatoes in oil, January-February 2010.
Euro Surveill 2010;15:19572.
19. Collier MG, Khudyakov YE, Selvage D, et al. Outbreak of hepatitis A in the USA
associated with frozen pomegranate arils imported from Turkey: an epidemiological
case study. Lancet Infect Dis 2014;14:976–981.
20. Hutin YJF, Sabin KM, Hutwagner LC, et al. Multiple modes of hepatitis A virus
transmission among methamphetamine users. Am J Epidemiol 2000;152:186–192.
21. Lemon SM. The natural history of hepatitis A: the potential for transmission by
transfusion of blood or blood products. Vox Sang 1994;67(suppl 4):19–23.
22. Soucie JM, Robertson BH, Bell BP, et al. Hepatitis A virus infections associated with
clotting factor concentrate in the United States. Transfusion 1998;38:573–579.
23. Centers for Disease Control and Prevention. Blood safety monitoring among persons
with bleeding disorders—United States, May 1998–June 2002. MMWR Morb Mortal
Wkly Rep 2003;51:1152–1154.
24. American Academy of Pediatrics. Hepatitis A vaccine recommendations. Pediatrics
2007;120:189–199.
25. Centers for Disease Control and Prevention. Surveillance for Viral Hepatitis—United
States, 2014. https://www.cdc.gov/hepatitis/statistics/2014surveillance/index.htm
#tabs-1170596-4.
26. Staes CJ, Schlenker TL, Risk I, et al. Sources of infection among persons with acute
hepatitis A and no identified risk factors during a sustained community-wide
outbreak. Pediatrics 2000;106:e54.
27. Victor JC, Surdina TY, Suleimenova SZ, et al. Person-to-person transmission of
hepatitis A virus in an urban area of intermediate endemicity: implications for
vaccination strategies. Am J Epidemiol 2005;163:204–210.
28. Nothdurft HD. Hepatitis A vaccines. Expert Rev Vaccines 2008;7:535–545.
29. Bell BP, et al. Global epidemiology of hepatitis A: implications for control strategies.
In: Margolis HS, Alter MJ, Liang JT (eds) Viral Hepatitis and Liver Disease. London,
International Medical Press, 2002, pp 359–365.
30. Centers for Disease Control and Prevention. CDC Health Information for Inter-
national Travel 2016. New York, Oxford University Press, 2016.
31. Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region,
1990 and 2005. Vaccine 2010;28:6653–6657.
32. Pelletier AR, Mehta PJ, Burgess DR, et al. An outbreak of hepatitis A among
primary and secondary contacts of an international adoptee. Public Health Rep
2010;125:642–646.
33. Centers for Disease Control and Prevention. Prevention of hepatitis A through
active or passive immunization: Recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep 1996;45(RR-15):1–30.
34. Centers for Disease Control and Prevention. Prevention of hepatitis A through
active or passive immunization: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep 1999;48(RR-12):1–37.
Hepatitis A Virus 237
35. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the
era of vaccination. JAMA 2005;294:194–201.
36. Centers for Disease Control and Prevention. Prevention of hepatitis A through
active or passive immunization: recommendations of the Advisory Committee on
Immunization Practices. MMWR Recomm Rep 2006;55(RR-07):1–23.
37. Centers for Disease Control and Prevention. Notice to readers: final 2013 reports
of nationally notifiable infectious diseases. MMWR Morb Mortal Wkly Rep
2014;63:702.
38. Bialek SR, Thoroughman DA, Hu D, et al. Hepatitis A incidence and hepatitis A
vaccination among American Indians and Alaska Natives, 1990–2001. Am J Public
Health 2004;94:996–1001.
39. Dagan R, Leventhal A, Anis E, et al. Incidence of hepatitis A in Israel following
universal immunization of toddlers. JAMA 2005;294:202–210.
40. Ly KN, Klevens RM. Trends in disease and complications of hepatitis A virus
infection in the United States, 1999–2011: a new concern for adults. J Infect Dis
2015;212:176–182.
41. Nainan OV, Armstrong GL, Han XH, et al. Hepatitis A molecular epidemiology in
the United States, 1996–1997: sources of infection and implications of vaccination
policy. J Infect Dis 2005;191:957–963.
42. Amon JJ, Devasia R, Xia G, et al. Molecular epidemiology of foodborne hepatitis A
outbreaks in the United States, 2003. J Infect Dis 2005;192:1323–1330.
43. Gingrich GA, Hadler SC, Elder HA, et al. Serologic investigation of an outbreak of
hepatitis A in a rural day-care center. Am J Public Health 1983;73:1190–1193.
44. Lednar WM, Lemon SM, Kirkpatrick JW, et al. Frequency of illness associated with
epidemic hepatitis A virus infection in adults. Am J Epidemiol 1985;122:226–233.
45. Dolberg S, Berkun Y, Gross-Kieselstein E. Urticaria in patients with hepatitis A
infection. Pediatr Infect Dis J 1991;10:702–703.
46. Cohen HA, Amir J, Frydman M, et al. Infection with the hepatitis A virus associated
with ascites in children. Am J Dis Child 1992;146:1014–1016.
47. Liaw YF, Yang CY, Chu CM, et al. Appearance and persistence of hepatitis A
IgM antibody in acute clinical hepatitis A observed in an outbreak. Infection
1986;14:156–158.
48. Kao HW, Ashcavai M, Redeker AG. The persistence of hepatitis A IgM antibody after
acute clinical hepatitis A. Hepatology 1984;4:933–936.
49. Centers for Disease Control and Prevention. Positive test results for acute hepatitis
A virus infection among persons with no recent history of acute hepatitis—United
States, 2002–2004. MMWR Morb Mortal Wkly Rep 2005;54:453–456.
50. Schiff ER. Atypical clinical manifestations of hepatitis A. Vaccine 1992;10(suppl
1):S18–S20.
51. Glikson M, Galun E, Oren R, et al. Relapsing hepatitis A: review of 14 cases and
literature survey. Medicine (Baltimore) 1992;71:14–23.
52. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of
acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med
2002;137:947–954.
53. Schiodt FV, Davern TJ, Shakil AO, et al. Viral hepatitis–related acute liver failure. Am
J Gastroenterol 2003;98:448–453.
54. Datta D, Williams I, Culver D, et al. Association between deaths due to hepati-
tis A and chronic liver disease, United States, 1981–1997. Antivir Ther 2000;
5(suppl 1):79.
55. Squires RH, Schneider BL, Bucurvalas J, et al. Acute liver failure in children:
the first 348 patients in the pediatric acute liver failure study group. J Pediatr
2006;148:652–658.
56. Vento S, Garofano T, Di Perri G, et al. Identification of hepatitis A virus as a
trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet
1991;337:1183–1187.
57. Food and Drug Administration. Immune Globulin (Human). 2013 http://
www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/
ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/
UCM371376.pdf.
58. Kluge T. Gamma-globulin in the prevention of viral hepatitis: a study of the effect
of medium-size doses. Acta Med Scand 1963;174:469–477.
59. Winokur PL, Stapleton JT. Immunoglobulin prophylaxis for hepatitis A. Clin Infect
Dis 1992;14:580–586.
60. Farcet MR, Planitzer CB, Stein O, et al. Hepatitis A virus antibodies in immuno-
globulin preparations. J Allergy Clin Immunol 2010;125:198–202.
60a.  Tejada-Strop A, Costafreda MI, Dimitrova Z, et al. Evaluation of potencies of
immune globulin products against hepatitis A. JAMA Intern Med 2017;[Epub ahead
of print].
61. Centers for Disease Control and Prevention. Prevention of hepatitis A after exposure
to hepatitis A virus and in international travelers: updated recommendations of the
ACIP. MMWR Morb Mortal Wkly Rep 2007;56:1080–1084.
62. Ellis EF, Henney CS. Adverse reactions following administration of human gamma
globulin. J Allergy 1969;43:45–54.
63. Centers for Disease Control and Prevention. General recommendations on immu-
nization: recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep 2011;60:1–64.
64. Peetermans J. Production, quality control and characterization of an inactivated
hepatitis A vaccine. Vaccine 1992;10(suppl 1):S99–S101.
65. Armstrong ME, Giesa PA, Davide JP, et al. Development of the formalin-inactivated
hepatitis A vaccine VAQTA from the live attenuated virus strain CR326F. J Hepatol
1993;18(suppl 2):S20–S26.
66. Joines RW, Blatter M, Abraham B, et al. A prospective, randomized, comparative
US trial of a combination hepatitis A and B vaccine (Twinrix®) with correspond-
ing monovalent vaccines (Havrix® and Engerix-B®) in adults. Vaccine 2001;19:
4710–4719.
1219.e1
 PART III  Etiologic Agents of Infectious Diseases
SECTION B  Viruses
67. Centers for Disease Control and Prevention. FDA approval for a com-
bined hepatitis A and B vaccine. MMWR Morb Mortal Wkly Rep 2001;50:
806–807.
68. Centers for Disease Control and Prevention. FDA approval of an alternate dosing
schedule for Twinrix®. MMWR Morb Mortal Wkly Rep 2007;56:1057.
69. Hepatitis A. In: Atkinson W, McIntyre L, Wolfe S (eds) Epidemiology and Prevention
of Vaccine-Preventable Diseases, 10th ed. Washington, DC, Public Health Founda-
tion, 2008, pp 197–209.
70. Clemens R, Safary A, Hepburn A, et al. Clinical experience with an inactivated
hepatitis A vaccine. J Infect Dis 1995;17(suppl 1):S44–S49.
71. Newcomer W, Rivin B, Reid R, et al. Immunogenicity, safety and tolerability of
varying doses and regimens of inactivated hepatitis A virus vaccine in Navajo
children. Pediatr Infect Dis J 1994;13:640–642.
72. Williams JL, Bruden DA, Cagle HH, et al. Hepatitis A vaccine: immunogenicity
following administration of a delayed immunization schedule in infants, children
and adults. Vaccine 2003;21:3208–3211.
73. Letson GW, Shapiro CN, Kuehn D, et al. Effect of maternal antibody on immuno-
genicity of hepatitis A vaccine in infants. J Pediatr 2004;144:327–332.
74. Fiore AE, Shapiro CN, Sabin K, et al. Hepatitis A vaccination of infants: effect of
maternal antibody status on antibody persistence and response to a booster dose.
Pediatr Infect Dis J 2003;22:354–359.
75. Innis BL, Snitbhan R, Kunasol P, et al. Protection against hepatitis A by an inactivated
vaccine. JAMA 1994;271:1363.
76. Werzberger A, Mensch B, Kuter B, et al. A controlled trial of a formalin-inactivated
hepatitis A vaccine in healthy children. N Engl J Med 1992;327:453–457.
77. Hammitt LL, Bulkow L, Hennessy TW, et al. Persistence of antibody to hepa-
titis A virus 10 years after vaccination among children and adults. J Infect Dis
2008;198:1776–1782.
78. Van Herck K, Van Damme P, Lievens M, et al. Hepatitis A vaccine: indirect evi-
dence of immune memory 12 years after the primary course. J Med Virol 2004;72:
194–196.
79. Raczniak GA, Bulkow LR, Bruce MG, et al. Long-term immunogenicity of
hepatitis A virus vaccine in Alaska 17 years after initial childhood series. J Infect Dis
2013;207:493–496.
1219.e2
80. Plumb ID, Bulkow LR, Bruce MG, et al. Persistence of antibody to hepatitis A Virus
20 years after receipt of hepatitis A vaccine in Alaska. J Viral Hepat 2017;[Epub ahead
of print].
81. Hens N, Habteab Ghebretinsae A, Hardt K, et al. Model based estimates of long-term
persistence of inactivated hepatitis A vaccine-induced antibodies in adults. Vaccine
2014;32:1507–1513.
82. Van Damme P, Banatvala J, Fay O, et al. Hepatitis A booster vaccination: is there a
need? Lancet 2003;362:1065–1071.
83. Niu MT, Salive M, Krueger C, et al. Two-year review of hepatitis A vaccine safety:
data from the Vaccine Adverse Event Reporting System (VAERS). Clin Infect Dis
1998;26:1475–1476.
84. Black S, Shinefield H, Hansen J, et al. A post-licensure evaluation of the safety of
inactivated hepatitis A vaccine (VAQTA, Merck) in children and adults. Vaccine
2004;22:766–772.
85. Amon JJ, Darling N, Fiore AE, et al. Factors associated with hepatitis A vaccination
among children 24–35 months of age: United States, 2003. Pediatrics 2006;117:30–33.
86. Centers for Disease Control and Prevention. Updated recommendations from the
Advisory Committee on Immunization Practices for use of hepatitis A vaccine in
close contacts of newly arriving international adoptees. MMWR Morb Mortal Wkly
Rep 2009;58:1006–1007.
87. Hill HA, Elam-Evans LD, Yankey D, et al. Vaccination coverage among children
aged 19-35 months—United States, 2015. MMWR Morb Mortal Wkly Rep
2016;65(39):1065–1071.
88. Department of Health and Human Services Centers for Disease Control and Preven-
tion, Advisory Committee on Immunization Practices (ACIP). Summary report,
October 29-30, 2014. http://www.cdc.gov/vaccines/acip/meetings/downloads/min-
archive/min-2014-10.pdf.
89. Williams WW, Lu PJ, O’Halloran A, et al; Centers for Disease Control and Preven-
tion. Surveillance of vaccination coverage among adult populations—United States,
2014. MMWR Surveill Summ 2016;65(1):1–36.
90. Sagliocca L, Amoroso P, Stroffolini T, et al. Efficacy of hepatitis A vaccine in prevention
of secondary hepatitis A infection: a randomised trial. Lancet 1999;353:1136–1139.
91. Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin
for postexposure prophylaxis. N Engl J Med 2007;357:1685–1694.