Primary immunization consists of three doses, given on a 0-, 1-, and 6-month
schedule, the same that is used for single-antigen hepatitis B vaccine.
18 years of age and older having an indication for both hepatitis A and hepatitis B
vaccine can receive Twinrix, including persons with chronic liver disease, injection
drug users, men who have sex with men (MSM), persons who have occupational risk
for infection (e.g., who work with HAV-infected primates), and persons with clotting
factor disorders who receive therapeutic blood products.
34,35 For international travel,
hepatitis A vaccine is recommended; hepatitis B vaccine is recommended for
travelers to areas of high or intermediate hepatitis B endemicity who plan to stay for
longer than 6 months and have frequent close contact with the local population.
Efficacy, Safety, and Duration of Response
The efficacy of the hepatitis A vaccine is well established, with protective efficacy
34 The vaccine is well tolerated, with soreness at the injection site,
headache, myalgias, and malaise as the most commonly reported adverse effects.
The duration of protection from the vaccines has not been studied extensively.
However, protective levels of antibody to HAV could be present for at least 14 to 20
years in children and at least 25 years in adults.
recommendations regarding the need for booster doses at this time. The safety of
HAV vaccine during pregnancy has not been established. However, because the
vaccine is produced from inactivated HAV, the
theoretic risk to the developing fetus is low. The benefits versus risks associated
with vaccination for HAV in women who might be at high risk for exposure to the
infection should be discussed with her primary care physician and obstetrician.
The ACIP recommends hepatitis A vaccination for several high-risk groups,
including travelers to countries with high endemicity of infection (South and Central
America, Africa, South and Southeast Asia, Caribbean, and the Middle East),
travelers to countries with intermediate endemicity of infection (Eastern and Southern
Europe and the former Soviet Union), children living in communities with high rates
of hepatitis A infection and periodic hepatitis A outbreaks (Alaskan Native villages,
American Indian reservations), MSM, injection drug users, researchers or persons
who have occupational risk for hepatitis A (healthcare workers), persons with
clotting factor disorders, and persons with chronic liver disease who are at increased
risk for fulminant hepatitis A.
20,27,31,32 Thus, M.D. should receive either Havrix 1,440
ELISA units or Vaqta 50 units. This initial injection will provide adequate protection
from HAV infection during his travel, and he can receive the booster injection on his
return, at least 6 months after the first injection. If M.D. decides to travel within the
next 2 weeks, he should receive both vaccination and immunoglobulin before
Which of L.W.’s contacts require postexposure prophylaxis for HAV?
Although immune globulin has been recommended in the past for unvaccinated
people recently exposed to HAV, hepatitis A vaccines (Havrix and Vaqta) are
effective in preventing secondary HAV infection in healthy people. Twinrix is not
recommended for postexposure prophylaxis.
19 A vaccine can be administered in
healthy people age 12 months to 40 years within 2 weeks after exposure to HAV.
However, at this time, individuals outside of this age range or with significant
comorbid conditions should receive immune globulin instead of the vaccine.
Therefore, L.W.’s wife should receive prophylactic administration of HAV vaccine
and his 10-month-old infected daughter should receive immune globulin at a dose of
0.02 mL/kg, administered IM as soon as possible but no later than 2 weeks after
exposure. Contacts who have received a dose of hepatitis A vaccine at least 1 month
before exposure do not need immune globulin, because protective antibody titers are
achieved in greater than 95% of patients 1 month after vaccination.
not recommended for casual contacts at work or school.
Administration of immune globulin within 2 weeks after exposure to HAV is 80%
to 90% effective in preventing acute HAV infection.
early, immune globulin prevents both clinical and subclinical HAV illness.
Protection after immune globulin administration is immediate and complete, but
short-lived. Other situations in which immune globulin administration may be
indicated include hepatitis A infection in day-care centers and in settings with
infected persons who prepare and serve food. Immune globulin is recommended for
all staff and children in day-care settings when a case of HAV infection is diagnosed
15,19,20 When a food handler is diagnosed with hepatitis
A, immune globulin is recommended for other food handlers at the same location.
Given the improbability of disease transmission to persons consuming food prepared
or served by workers infected with hepatitis A, the routine administration of immune
globulin in this setting is not recommended.
When immune globulin is required for infants or pregnant women, preparations
free of thimerosal should be used.
15 Although immune globulin does not impede the
immune response to inactivated vaccines, oral poliovirus vaccine, or yellow fever
vaccine, it may interfere with the response to live attenuated vaccines such as
measles, mumps, rubella (MMR) vaccine and varicella vaccine. Therefore, MMR
and varicella vaccines should be delayed for at least 3 months after administration of
immune globulin for HAV prophylaxis. Immune globulin should not be given within 2
weeks after the administration of MMR or varicella vaccine. Finally, if immune
globulin is administered within 2 weeks of MMR, the person requires revaccination,
but not sooner than 3 months after the immune globulin administration for MMR.
Serologic tests for varicella vaccination should be performed 3 months after immune
globulin administration to determine whether revaccination is required.
Hepatitis B virus is an icosahedral, enveloped, and encapsulated virus measuring 42
nm diameter and belongs to the Hepadnaviridae family of viruses.
genome is a partially double-stranded, circular DNA linked to a DNA polymerase.
Unlike HAV, HBV is antigenically complex and results in an acute illness with or
without a chronic disease state. HBV infection can produce either asymptomatic or
symptomatic infection. The average incubation period is 90 days (range: 60–150
days) from exposure to the onset of jaundice and 60 days (range: 40–90 days) from
exposure to onset of abnormal serum ALT levels.
The life cycle of HBV is described in Figure 80-2. Elucidation of the HBV life
cycle has resulted in opportunities for drug development. Of special importance, the
viral DNA polymerase functions as both a reverse transcriptase (RT) for synthesis of
the negative DNA strand from genomic RNA and as an endogenous DNA
polymerase. Because the HBV polymerase is remotely related to the RT enzymes of
retroviruses (e.g., HIV), some inhibitors of HIV polymerase or RT also have activity
against the HBV polymerase. Thus, several RT inhibitors have been evaluated for
treating and preventing HBV; however, rapid emergence of resistance occurs with
Globally, approximately 2 billion persons are infected with HBV, and between 350
and 400 million persons are living with chronic HBV infection.
causes approximately 1 million deaths from cirrhosis, liver failure, and
hepatocellular carcinoma (HCC).
In 2002, more than 600,000 persons died of
HBV-associated acute and chronic liver disease.
infection affects an estimated 2.2 million persons and accounts for an estimated 5,500
Acute HBV infection is usually asymptomatic in infants and children aged less than
5 years compared to 30% to 50% of children older than 5 years and adults who could
develop clinical signs and symptoms.
49 Clinical signs and symptoms can include
anorexia, nausea, vomiting, abdominal pain, malaise and jaundice. Extrahepatic
manifestations of HBV disease may include skin rashes, arthralgias, and arthritis.
reinfection. Progression from acute to chronic HBV infection is influenced by the
person’s age at acquisition of the virus. Chronic HBV infection occurs in
approximately 30% of infected children younger than 5 years old, and less than 5%
of infected persons older than 5 years.
49 Persons who are HBV infected and are at
risk for developing chronic HBV disease include immunosuppressed persons (e.g.,
persons with diabetes, HIV, or on hemodialysis).
Figure 80-2 Life cycle of hepatitis B virus. ER, endoplasmic reticulum. (Reprinted from Ganem D.
PA: Lippincott-Raven; 1996:1199, with permission.)
With respect to HBV infection in certain parts of the world, HBV infection is
acquired perinatally in Asia. The cellular immune responses to hepatocyte-membrane
HBV proteins that are associated with acute hepatitis do not occur, and chronic,
lifelong infection is established in more than 90% of persons infected in Asia.
the other hand, most acute HBV infections that occur in the West are reported during
adolescence and early adulthood because of behaviors and environments that favor
the transmission of bloodborne infections, such as sexual activity, injection drug use,
and occupational exposure. There are no specific treatment for acute HBV, and
supportive care is the mainstay of therapy.
Similar to HAV infection, chronic HBV infection is defined as persons positive
for HBsAg for >6 months (Fig. 80-3). The incidence of acute HBV infection has
declined in the United States by approximately 82% since 1991.
of infection occurs in all age, racial, ethnic, and high-risk groups, particularly among
children and healthcare workers—the groups with the highest rate of vaccination.
groups (e.g., Alaskan Eskimos, Asian Pacific Islanders), first-generation immigrants
from regions of high endemicity (e.g., India, Central and Southeast Asia), injection
drug users, MSM, African-Americans, and males (more than females).
prominent risk factors associated with acute HBV infection include heterosexual
contact (42%), MSM (15%), and injection drug use (21%).
opportunities include clinics for sexually transmitted disease (STD), correctional
facilities, and holding centers for incarceration.
Figure 80-3 Acute hepatitis B virus infection. (Source: AASLD/IDSA Guidelines.)
The transmission of HBV is from exposure to blood, semen, and other body fluids
infected with HBV. Furthermore, HBV transmission could occur among unvaccinated
adults with risky behaviors, including sexual contact, and percutaneous or perinatal
exposure to infectious blood or body fluids. HBV is highly concentrated in serum
with lower concentrations in semen and saliva.
49 The modes of HBV transmission
include sexual, blood transfusion, perinatal transmission, and injection drug use are
summarized in the following sections.
Sexual activity, especially unprotected sex and having multiple sex partners, is the
most significant mode of HBV transmission worldwide, including North America,
where the prevalence of infection is low.
52–54 Heterosexual intercourse accounts for
the majority of US infections (26%). In heterosexual persons, factors associated with
an enhanced risk of HBV infection include duration of sexual activity, number of
sexual partners, and history of STD. Sexual partners of injection drug users, sex
workers, and clients of sex workers are at a very high risk for infection. Sexual
partners of infected individuals are at high risk for infection, even in the absence of
high-risk behavior. Because most patients with chronic HBV infection are unaware
of their infection and are “silent carriers,” sexual transmission is a significant mode
of transmission. Many of the HBV infections could have been prevented through
universal vaccination. The use of condoms appears to reduce the risk of sexual
From 1980 to 1985, a very high rate of HBV infection was observed in MSM,
accounting for 20% of all reported cases of infection.
52–54 Multiple sexual partners,
anal-receptive intercourse, and duration of sexual activity were the most common
factors associated with HBV acquisition in the MSM population. Current rates of
HBV infection in this population have fallen and are estimated to be about 8%,
possibly as a result of modifications of sexual behavior in response to HIV. Similar
to heterosexuals, the use of condoms in this population has reduced the risk of sexual
Although the risk of transfusion-associated HBV infection has been greatly reduced
with the screening of blood (tests for HBsAg and anti-HBc) and the exclusion of
donors who engage in high-risk activities, it is estimated that 1 of 50,000 transfused
units could transmit HBV infection.
Early-childhood exposure and perinatal exposure are additional modes of
transmission of HBV infection. High serum concentrations of virus have been linked
with increased risk of transmission by vertical routes (and needlestick exposure).
Infants born to HBeAg-positive mothers with high viral replication (>80 pg/mL) have
a 70% to 90% risk of perinatal HBV acquisition compared with a 10% to 40% risk
in infants born to mothers infected with HBV who are HBeAg-negative.
generally occurs via inoculation of the infant at the time of birth or soon thereafter,
and even with active and passive immunization, 10% to 15% of babies acquire HBV
In developing countries with high prevalence rates and in regions of the United
States with high endemicity, children born to HBsAg-positive mothers with HBV are
at risk for acquiring HBV infection in the perinatal period, with infection rates
reported to be between 7% and 13%.
In addition, children of HBsAg-positive
mothers who are not infected at birth remain at very high risk of early-childhood
infection, with 60% of those born to HBsAg-positive mothers becoming infected by
the age of 5 years. The mechanism of the later infection, which is neither perinatal
nor sexual, is not known however. Although HBsAg is detectable in breast milk,
breast-feeding is not believed to be a primary mode of HBV transmission.
Recreational and illicit drug use in the United States and globally is a significant
mode of HBV transmission, accounting for approximately 23% of all patients.
The risk increases with the duration of injection drug use; thus, serologic markers of
ongoing or prior HBV infection are usually positive after 5 years of drug use.
Other risk factors for transmission of HBV include working in a healthcare setting,
receiving blood transfusion (not properly screened) and dialysis, receiving
acupuncture and tattoos from contaminated needles, traveling to regions of the world
endemic for HBV infection, and living in correctional facilities or prisons.
Sporadic cases of HBV transmission have been attributed to nonpercutaneous
transmission by way of small breaks in the skin, biting, or mucous membranes.
Although HBsAg is found in bodily fluids (e.g., saliva, tears, sweat, semen, vaginal
secretions, breast milk, cerebrospinal fluid, ascites, pleural fluid, synovial fluid,
gastric juice, and urine), only semen, saliva, and serum actually contain infectious
Similar to HAV infection, clinical observations suggest that host immune responses
are more important than virologic factors in the pathogenesis of liver injury. Host
cellular and humoral immune responses are linked to T lymphocytes, which enhance
viral clearance from hepatocytes and cause liver injury.
The presence of HBsAg in serum is diagnostic for HBV infection. In 5% to 10% of
acute cases in which the HBsAg levels fall below sensitivity thresholds of current
assays, the presence of IgM anti-HBc in serum confirms a recent acute HBV
infection. Another highly reliable marker of active HBV replication and diagnosis is
the presence of HBV DNA in serum through qualitative or quantitative assays,
detectable early during the course of acute HBV infection.
HBV DNA indicate ongoing infection and a high degree of active viral replication
Antigens and antibodies associated with HBV infection include HBsAg and antibody
serologic markers that differentiate between acute, resolving, and chronic infection
are HBsAg, anti-HBc, and anti-HBs. HBeAg and anti-HBe screening are used for the
management of patients with chronic infection.
49 Serologic patterns, general
definitions, and diagnostic criteria of HBV infection are depicted in Table 80-3.
Within the first several weeks after exposure (range: 2–10 weeks), HBsAg appears
in the blood and is present for several weeks before serum concentrations of
aminotransferases increase and symptoms (Fig. 80-4).
57–58 Clinical illness usually
follows HBV exposure by 1 to 3 months. HBsAg can be detected in serum until the
clinical illness resolves and usually becomes undetectable after 4 to 6 months.
Persistence of HBsAg beyond 6 months implies progression to chronic HBV
infection. The antibody to HBsAg (anti-HBs) often appears after a short “window”
period during which neither HBsAg nor anti-HBs are detectable. In most patients,
anti-HBs persists for years after HBV infection, conferring immunity to reinfection
Hepatitis B Virus: Laboratory Markers and Interpretations
Laboratory Marker Interpretation
Hepatitis B surface antigen (HBsAg) Marker of infection; presence indicates person is
Hepatitis B surface antibody (anti-HBs) Past infection, or person has been vaccinated
Hepatitis B core antibody (anti-HBc) Marker of previous or ongoing infection
IgM antibody to Hepatitis B core antigen (IgM antiHBc)
Indicates acute infection; first reaction of the body’s
Hepatitis B e antigen (HBeAg) Marker of active replication of virus and infectiveness
Hepatitis B e antibody (HBeAb or anti-HBe) Virus is no longer replicating; predictor of long-term
clearance of HBV in patients undergoing antiviral
Hepatitis B virus DNA (HBV-DNA) Indicates active replication of virus; more accurate
than HBeAg; used mainly for monitoring response to
Interpretation of serologic markers is described in Table 80-4. A soluble viral
protein, HBeAg, is detectable early during the acute phase of the disease and persists
in chronic hepatitis B infection. HBeAg is a marker of active HBV replication, and
its presence correlates with circulating HBV particles. The presence of both HBeAg
and HBsAg indicates high levels of viral replication and infectivity and a need for
antiviral therapy. Generally, seroconversion from HBeAg to hepatitis B envelope
antibody (anti-HBe) results in a reduction in HBV DNA and suggests resolution of
HBV infection. Some patients may, however, continue to have active liver disease
and detectable serum HBV DNA levels as a result of the presence of wild-type virus
or the presence of precore or promoter mutations that impair HBeAg secretion
Figure 80-4 Sequence of events after acute hepatitis B virus infection with resolution. ALT, alanine
Philadelphia, PA:J.B. Lippincott; 1996, with permission.
Hepatitis B Virus: Interpretation of Laboratory Results
Laboratory Markers Laboratory Results Clinical Interpretation
Immune due to natural infection
Immune due to hepatitis B vaccination
Interpretation unclear; 4 possibilities:
Resolved infection (most common)
False-positive anti-HBc, thus susceptible
Hepatitis B core antigen does not circulate freely in the bloodstream and is not
measured. Anti-HBc, the antibody directed against hepatitis B core antigen, is usually
detected 1 to 2 weeks after the appearance of HBsAg and just before the onset of
clinical symptoms, and it persists for life. The detection of IgM anti-HBc is the most
sensitive diagnostic test for acute HBV infection. During the recovery phase of
infection, the predominant form of anti-HBc is in the IgG class. The presence of this
antibody suggests prior or ongoing infection with HBV. Furthermore, in areas where
HBV is not endemic, isolated detection of anti-HBc in a patient’s serum may
correlate with low levels of HBV DNA. The presence of HBV DNA may enhance the
risk of transmission of HBV and progression to cirrhosis and HCC. Patients
immunized against HBV do not develop anti-HBc; therefore, the presence of this
antibody differentiates successful vaccination from actual HBV infection.
Of those patients with acute HBV infection, only 1% develop FHF with associated
coagulopathy, encephalopathy, and cerebral edema.
infection is a heightened immune response to the virus, in the absence of HDV or
HCV coinfections. Patients with ALF often have early clearance of HBsAg, which
may complicate the diagnosis, but a positive IgM antibody to hepatitis B core antigen
generally confirms the diagnosis.
Four phases of HBV infection are present: immune tolerance, immune clearance,
low-level replication or nonreplication phase
(inactive carrier), and reactivation phase. Up to 12% (average 5%) of
immunocompetent patients acutely infected with HBV remain chronically infected
(historically defined as detectable HBsAg in serum for 6 months or longer).
these patients, HBsAg generally remains detectable indefinitely and anti-HBs fails to
appear. The risk of chronicity after neonatally acquired infection is high (>90%),
possibly because neonates have immature immune systems. Of infected neonates,
50% have evidence of active viral replication. Furthermore, patients who have a
reduced ability to clear viral infections—including those receiving chronic
hemodialysis, immunosuppression after transplantation, or chemotherapy, or patients
with HIV infection—may have a greater risk for developing chronic HBV
40,62 Ultimate outcomes are linked with the presence or absence of viral
replication and by the severity of liver damage. Approximately 50% of all chronic
carriers have ongoing viral replication, especially with elevated aminotransferases,
and 15% to 20% of these develop cirrhosis within 5 years.
HBeAg (7%–20%/year) has been reported, possibly as a result of the use of antiviral
therapy, whereas loss of HBsAg occurs less frequently (1%–2%/year). In general,
chronic carriers remain infected throughout their life.
40–43,62 Five-year survival rates
decline depending on the severity of disease (55% survival with cirrhosis).
Asymptomatic HBV carriers tend to have mild disease manifestations with few
complications, even with a long period of follow-up. Finally, the risk of HCC is
increased up to 300 times in chronic carriers with active viral replication (HBeAg
QUESTION 1: W.H. is a 35-year-old man who developed nausea, vomiting, anorexia, scleral icterus, and
jaundice within the past month. Within the past week he became increasingly lethargic, confused, and
mm Hg), bradycardic (heart rate, 58 beats/minute) man in respiratory distress (respiratory rate, 26
reveals him to be stuporous and nonarousable.
The laboratory evaluation shows the following results:
International normalized ratio (INR): 3.8
Alkaline phosphatase: 101 units/mL
Hepatitis serologic tests are positive for HBsAg, HBeAg, IgM anti-HBc, and HBV DNA. IgM anti-HAV,
IgM anti-HDV, and anti-HCV are negative. STAT blood gases reveal a metabolic acidosis with a
What clinical findings does W.H. have that support the diagnosis of acute hepatitis and ALF?
The clinical features of acute HBV infection are similar to those described for
HAV infection. W.H.’s initial symptoms included a recent history of nausea,
vomiting, anorexia, scleral icterus, and jaundice. These are consistent with diagnosis
of acute hepatitis B. His serologies, notably a positive IgM anti-HBc and HBV DNA,
The most significant complication of acute HBV infection is ALF, widely defined as
a coagulation abnormality (INR >1.5) and any degree of mental alteration
(encephalopathy) in a patient of less than 26 weeks’ duration.
encephalopathy, lethargy, confusion, coma, coagulopathy, hemodynamic instability,
declining liver function, and acidosis. Patients with ALF often have cerebral edema
(80% mortality rate), a complication of a disrupted blood–brain barrier that allows
protein-rich fluid to cross into the extracellular spaces of the brain tissue leading to
edema and increased intracranial pressure (ICP) or intracranial hypertension
(vasogenic model). Clinical symptoms (sluggish pupillary response and increasing
muscle tone) develop when the ICP is greater than 30 mm Hg.
in the confinement of the cranial vault raises the ICP, which may reduce intracerebral
perfusion. The edema can result in cerebral ischemia if the cerebral perfusion
pressure (systemic blood pressure minus ICP) is not maintained at greater than 40
mm Hg. Of note, intracranial hypertension in ALF is related to the severity of
encephalopathy. Cerebral edema is rarely reported in patients with grade I or II
encephalopathy but occurs in up to 75% of patients with grade IV coma.
head imaging tests (computerized tomography), elevation of the head of the bed, and
intubation (and subsequent hyperventilation) may be necessary medical interventions
W.H. has symptoms of cerebral edema and may benefit from 100 to 200 mL of a
20% solution of mannitol (0.5–1.0 g/kg) administered by rapid IV infusion to induce
an osmotic diuresis with a subsequent decrease in ICP. The dose may be repeated at
least once after several hours provided serum osmolality has not exceeded 320
67,68 Because W.H. also has a blood pressure of 158/99 mm Hg and a heart
rate of 58 beats/minute, and is at risk for intracranial hemorrhage, an ICP monitoring
67,68 Although placement of this device is invasive and
bleeding is a potential complication, ICP monitoring devices provide important
prognostic information. Patients with a cerebral perfusion pressure of greater than 40
mm Hg that is refractory to mannitol therapy are not candidates for liver
transplantation. W.H. also has a coagulopathy typical of ALF. Decreased levels of
clotting factors II, V, VII, IX, and X normally synthesized by the liver account for his
prolonged PT and elevated INR.
64–66 Recombinant activated factor VII has been used
selectively in patients with ALF, but is usually reserved for administration before
any invasive procedures. In addition, consumption of clotting factors by low-grade
disseminated intravascular coagulation is common in ALF. W.H. is also
thrombocytopenic and at risk for GI ulceration.
68,69 A platelet transfusion should be
considered if his counts drop to less than 10,000/μL. Because he is not actively
bleeding, fresh-frozen plasma is not indicated at this time.
W.H. also should be monitored for cardiovascular and renal abnormalities as a
64,67 Although W.H. is hypertensive, most patients with ALF are
hypotensive and hypovolemic and present with interstitial edema owing to low levels
of oncotic proteins. Functional renal failure, also known as hepatorenal syndrome or
acute tubular necrosis, occurs in 43% to 55% of patients with ALF.
hepatorenal syndrome, renal blood flow is reduced, renin and aldosterone levels are
increased, and levels of atrial natriuretic factor are unchanged.
As seen in W.H., patients may develop acid–base disturbances, including
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