Chapter 41 - Hepatitis Viruses

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Levinson's Review of Medical Microbiology & Immunology, A Guide to Clinical Infectious Diseases, 18th Edition
Chapter 41: Hepatitis Viruses
INTRODUCTION
Many viruses cause hepatitis. Of these, five medically important viruses are commonly described as “hepatitis viruses” because their main site of
infection is the liver. These five are hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV, delta virus), and
hepatitis E virus (HEV) (Tables 41–1 and 41–2). Other viruses, such as Epstein–Barr virus (the cause of infectious mononucleosis), cytomegalovirus, and
yellow fever virus, infect the liver but also infect other sites in the body and therefore are not exclusively hepatitis viruses. They are discussed
elsewhere.
TABLE 41–1
Glossary of Hepatitis Viruses and Their Serologic Markers
Abbreviation Name and Description
HAV Hepatitis A virus, a picornavirus (nonenveloped RNA virus)
IgM HAV Ab IgM antibody to HAV; best test to detect acute hepatitis A
HBV Hepatitis B virus, a hepadnavirus (enveloped, partially doublestranded DNA virus); also known as Dane particle
HBsAg Antigen found on surface of HBV, also found on noninfectious particles in patient’s blood; positive during acute disease; continued
presence indicates carrier state
HBsAb Antibody to HBsAg; provides immunity to hepatitis B
HBcAg Antigen associated with core of HBV
HBcAb Antibody to HBcAg; positive during window phase; IgM HBcAb is an indicator of recent disease
HBeAg A second, different antigenic determinant in the HBV core; important indicator of transmissibility
HBeAb Antibody to e antigen; indicates low transmissibility
NonA, nonB Hepatitis viruses that are neither HAV nor HBV
HCV Hepatitis C virus, a flavivirus (enveloped RNA virus); one of the nonA, nonB viruses
HDV Hepatitis D virus, small RNA virus with HBsAg envelope; defective virus that replicates only in HBVinfected cells
HEV Hepatitis E virus, a hepevirus (nonenveloped RNA virus); one of the nonA, nonB viruses
TABLE 41–2
Important Properties of Hepatitis Viruses
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HAV ssRNA No No No Picornavirus
HDV Hepatitis D virus, small RNA virus with HBsAg envelope; defective virus that replicates only in HBVinfected cells
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HEV Hepatitis E virus, a hepevirus (nonenveloped RNA virus); one of the nonA, nonB viruses
TABLE 41–2
Important Properties of Hepatitis Viruses
Virus Genome Replication Defective DNA Polymerase in Virion HBsAg in Envelope Virus Family
HAV ssRNA No No No Picornavirus
HBV dsDNA1 No Yes Yes Hepadnavirus
HCV ssRNA No No No Flavivirus
HDV ssRNA2 Yes No Yes Deltavirus
HEV ssRNA No No No Hepevirus
ds = double stranded; ss = single stranded.
1Interrupted, circular dsDNA.
2Circular, negativestranded ssRNA.
Additional information regarding the clinical aspects of infections caused by the viruses in this chapter is provided in Part IX, titled Infectious Diseases
beginning on Bone & Joint Infections.
Note that these viruses belong to different viral families; some are DNA viruses, whereas others are RNA viruses, and some are enveloped, whereas
others are nonenveloped. They are united by their ability to infect hepatocytes because they have proteins on their surface that attach to receptors on
the surface of hepatocytes.
Note also that these viruses are all noncytotoxic (i.e., they do not kill hepatocytes directly). The death of hepatocytes is mediated by cytotoxic T cells
directed against viral antigen displayed on the surface of the hepatocyte in association with class I major histocompatibility complex (MHC) proteins.
HEPATITIS A VIRUS (HAV)

Disease
HAV causes hepatitis A.
Important Properties
HAV is a typical enterovirus classified in the picornavirus family. It has a singlestranded RNA genome and a nonenveloped icosahedral nucleocapsid
and replicates in the cytoplasm of the cell. It is also known as enterovirus 72. It has one serotype, and there is no antigenic relationship to HBV or other
hepatitis viruses.
Summary of Replicative Cycle
HAV has a replicative cycle similar to that of other enteroviruses (the replicative cycle of poliovirus is discussed in Chapter 40).
Transmission & Epidemiology
HAV is transmitted by the fecal–oral route. Humans are the reservoir for HAV. Virus appears in the feces roughly 2 weeks before the appearance of
symptoms, so quarantine of patients is ineffective. Children are the most frequently infected group, and outbreaks occur in special living
situations such as summer camps and boarding schools and among the homeless. Commonsource outbreaks arise from fecally contaminated water
or food such as oysters grown in polluted water and eaten raw. Unlike HBV, HAV is rarely transmitted via the blood, because the level of viremia is
Chapter 41: Hepatitis Viruses, Page 2 / 22
low
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HAV is transmitted by the fecal–oral route. Humans are the reservoir for HAV. Virus appears in the feces roughly 2 weeks before the appearance of
symptoms, so quarantine of patients is ineffective. Children are the most frequently infected group, and outbreaks occur in special living
situations such as summer camps and boarding schools and among the homeless. Commonsource outbreaks arise from fecally contaminated water
or food such as oysters grown in polluted water and eaten raw. Unlike HBV, HAV is rarely transmitted via the blood, because the level of viremia is
low and chronic infection does not occur. About 50% to 75% of adults in the United States have been infected, as evidenced immunoglobulin (Ig) G
antibody.
Pathogenesis & Immunity
The virus replicates in the gastrointestinal tract, spreads to the liver via the portal vein, and infects hepatocytes. Attack by cytotoxic T cells causes the
damage to the hepatocytes. The infection is subsequently cleared, the damage is repaired, and no chronic infection ensues. Hepatitis caused by
different viruses cannot be distinguished pathologically.
The immune response consists initially of IgM antibody, which is detectable at the time jaundice appears. It is therefore important in the laboratory
diagnosis of hepatitis A. The appearance of IgM is followed 1 to 3 weeks later by the production of IgG antibody, which provides lifelong protection.
Clinical Findings
The clinical manifestations of acute hepatitis are virtually the same, regardless of which hepatitis virus is the cause (Table 41–3). Fever, anorexia,
nausea, vomiting, and jaundice are typical. Dark urine, pale feces, and elevated transaminase levels are seen. Most cases resolve spontaneously in 2–4
weeks.
TABLE 41–3
Clinical Features of Hepatitis Viruses
Mode of Chronic Laboratory Test Usually Used for Vaccine Immune Globulins
Virus
Transmission Carriers Diagnosis Available Useful
HAV Fecal–oral No IgM HAV Yes Yes
HBV Blood, sexual, at birth Yes HBsAg, HBsAb, IgM HBcAb Yes Yes
HCV Blood, sexual1 Yes HCV Ab No No
HDV Blood, sexual1 Yes Ab to delta Ag No2 No
HEV Fecal–oral No None No No
Ab = antibody; Ag = antigen.
1Sexual transmission seems likely but is poorly documented.
2HBV vaccination provides protection against HDV.
Hepatitis A has a short incubation period (3–4 weeks) in contrast to that of hepatitis B, which is 10 to 12 weeks. Most HAV infections in children are
asymptomatic whereas HAV infections in adults are often symptomatic. Asymptomatic HAV infections are detected by the presence of IgG antibody. No
chronic hepatitis or chronic carrier state occurs, and there is no predisposition to hepatocellular carcinoma (HCC).
Laboratory Diagnosis
The detection of IgM antibody is the most important test. A fourfold rise in IgG antibody titer can also be used. Isolation of the virus in cell culture is
possible but not available in the clinical laboratory.
Treatment & Prevention

Chapter 41:therapy
No antiviral Hepatitis
is indicated
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Viruses, for acute hepatitis A. Prevention of hepatitis A is achieved by active immunization with a vaccine containing
inactivated HAV. The virus in the vaccine is grown in human cell culture and inactivated with formalin. Two doses, an initial dose followed by a booster
6 to 12 months later, should be given. No subsequent booster dose is recommended.
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The detection of IgM antibody is the most important test. A fourfold rise in IgG antibody titer can also be used. Isolation of the virus in cell culture is
possible but not available in the clinical laboratory.
No antiviral therapy is indicated for acute hepatitis A. Prevention of hepatitis A is achieved by active immunization with a vaccine containing
inactivated HAV. The virus in the vaccine is grown in human cell culture and inactivated with formalin. Two doses, an initial dose followed by a booster
6 to 12 months later, should be given. No subsequent booster dose is recommended.
The vaccine is recommended for travelers to developing countries, for children ages 2 to 18 years, and for men who have sex with men. If an
unimmunized person must travel to an endemic area within 4 weeks, then passive immunization (see later) should be given to provide immediate
protection and the vaccine given to provide longterm protection. This is an example of passive–active immunization.
Because many adults have antibodies to HAV, it may be costeffective to determine whether antibodies are present before giving the vaccine. The
vaccine is also effective in postexposure prophylaxis if given within 2 weeks of exposure. A combination vaccine that immunizes against both HAV and
HBV called Twinrix is available. Twinrix contains the same immunogens as the individual HAV and HBV vaccines.
Passive immunization with immune serum globulin prior to infection or within 14 days after exposure can prevent or mitigate the disease.
Observation of proper hygiene (e.g., sewage disposal and handwashing after bowel movements) is of prime importance.
HEPATITIS B VIRUS (HBV)

Disease
HBV causes hepatitis B.
HBV is a member of the hepadnavirus family. It is a 42nm enveloped virion,1 with an icosahedral nucleocapsid core containing a partially double
stranded circular DNA genome (Figure 41–1 and Table 41–2).
FIGURE 41–1
Hepatitis B virus (HBV). Left: Crosssection of the HBV virion. Right: The 22nm spheres and filaments composed only of hepatitis B surface antigen.
Because there is no viral DNA in the spheres and filaments, they are not infectious. (Reproduced with permission from Ryan K: Sherris Medical
Microbiology, 3rd ed. New York, NY: McGraw Hill; 1994.)
The envelope contains a protein called the surface antigen (HBsAg), which is important for laboratory diagnosis and immunization.2
Within the core is a DNA polymerase. The genome contains four genes (four open reading frames) that encode five proteins; namely, the S gene
encodes the surface antigen, the C gene encodes the core antigen and the e antigen, the P gene encodes the polymerase, and the X gene encodes the X
protein (HBx). HBx is an activator of viral RNA transcription and may be involved in oncogenesis because it can inactivate the p53 tumor suppressor
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42nm virions and many 22nm spheres and long filaments
22nm wide, which are composed of surface antigen (Figure 41–2). HBV is the only human virus that produces these spheres and filaments in such large
numbers in the patient’s blood. The ratio of filaments and small spheres to virions is 1000:1.
The envelope contains a protein called the surface antigen (HBsAg), which is important for laboratory diagnosis and immunization.2
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Within the core is a DNA polymerase. The genome contains four genes (four open reading frames) that encode five proteins; namely, the S gene
encodes the surface antigen, the C gene encodes the core antigen and the e antigen, the P gene encodes the polymerase, and the X gene encodes the X
protein (HBx). HBx is an activator of viral RNA transcription and may be involved in oncogenesis because it can inactivate the p53 tumor suppressor
protein (see Chapter 43). The DNA polymerase has both RNAdependent (reverse transcriptase) and DNAdependent activity.
Electron microscopy of a patient’s serum reveals three different types of particles: a few 42nm virions and many 22nm spheres and long filaments
22nm wide, which are composed of surface antigen (Figure 41–2). HBV is the only human virus that produces these spheres and filaments in such large
numbers in the patient’s blood. The ratio of filaments and small spheres to virions is 1000:1.
FIGURE 41–2
Hepatitis B virus. Electron micrograph. Long arrow points to a typical virion of hepatitis B virus. Short arrow points to a small sphere (just left of
arrowhead) and a long rod (just right of arrowhead), both composed only of hepatitis B surface antigen. (Reproduced with permission from Public
Health Image Library, Centers for Disease Control and Prevention.)
In addition to HBsAg, there are two other important antigens both located in the core of the virus: the core antigen (HBcAg) and the e antigen
(HBeAg). The core antigen, as the name implies, is located on the nucleocapsid protein that forms the core of the virion. The e antigen is produced by
proteolytic cleavage of the core protein during passage through the endoplasmic reticulum. The e antigen is soluble and is released from infected cells
into the blood. The e antigen is an important indicator of transmissibility.
For vaccine purposes, HBV has one serotype based on HBsAg. However, for epidemiologic purposes, there are four serologic subtypes of HBsAg based
on a groupspecific antigen, “a,” and two sets of mutually exclusive epitopes, d or y and w or r. This leads to four serotypes—adw, adr, ayw, and ayr—
which are useful in epidemiologic studies because they are concentrated in certain geographic areas.
The specificity of HBV for liver cells is based on two properties: virusspecific receptors located on the hepatocyte cell membrane (facilitate entry) and
transcription factors found only in the hepatocyte that enhance viral mRNA synthesis (act postentry).
Humans are the only natural hosts of HBV. There is no animal reservoir.
1Also known as a Dane particle (named for the scientist who first published electron micrographs of the virion).
2HBsAg was known as Australia antigen because it was first found in the serum of an Australian aborigine.
The replicative cycle of HBV is depicted in Figure 41–3. The infecting virion attaches to the surface of the hepatocyte via its receptor, the sodium
taurocholate cotransporting polypeptide. After entry of the virion into the cell and its uncoating, the nucleocapsid moves to the nucleus via
microtubules. The nucleocapsid binds to a nuclear pore and the DNA genome is released into the nucleus. In the nucleus, the host cell DNA polymerase
synthesizes the missing portion of DNA, and a doublestranded circular DNA is formed (CCC DNA). The minus strand of CCC DNA serves as a template
for mRNA synthesis by cellular RNA polymerase. After the individual mRNAs are made and translated into viral proteins, a fulllength positivestrand
RNA is made, which
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Chapter 41: Hepatitis Viruses,
genome DNA. Page 5 / 22
FIGURE 41–3
The replicative cycle of HBV is depicted in Figure 41–3. The infecting virion attaches to the surface of the hepatocyte via its receptor, the sodium
taurocholate cotransporting polypeptide. After entry of the virion into the cell and its uncoating, the nucleocapsid moves to the nucleus via
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microtubules. The nucleocapsid binds to a nuclear pore and the DNA genome is released into the nucleus. In the nucleus, the host cell DNA polymerase
synthesizes the missing portion of DNA, and a doublestranded circular DNA is formed (CCC DNA). The minus strand of CCC DNA serves as a template
for mRNA synthesis by cellular RNA polymerase. After the individual mRNAs are made and translated into viral proteins, a fulllength positivestrand
RNA is made, which is the template for the minus strand of the progeny DNA. The minus strand then serves as the template for the plus strand of the
genome DNA.
FIGURE 41–3
Replication cycle of hepatitis B virus. Note virusencoded reverse transcriptase synthesizes the progeny DNA genomes using viral RNA as the template.
CCC DNA is covalently closed circular DNA in the nucleus (blue circle).
Note that the synthesis of the progeny DNA genome is catalyzed by the virusencoded RNAdependent DNA polymerase (reverse transcriptase).
Synthesis of the genome takes place within the newly assembled virion nucleocapsid core in the cytoplasm. The completed nucleocapsid acquires its
envelope containing HBsAg in the endoplasmic reticulum. Progeny virions are released from the cell by budding through the cell membrane.
Hepadnaviruses are the only viruses that produce genome DNA by reverse transcription with viral RNA as the template. (Note that this type of RNA
dependent DNA synthesis is similar to but different from the process in retroviruses, in which the genome RNA is transcribed into a DNA intermediate.)
In chronic HBV infection, a carrier state occurs and progeny HBV continues to be made. In this carrier state, most of the circular HBV DNA is found free in
the nucleus as an episome. A small amount of HBV DNA is integrated into host cell DNA. How episomal HBV DNA is maintained in the carrier state for
many years is unclear.
The three main modes of transmission are via blood, during sexual intercourse, and perinatally from mother to newborn. The observation that needle
stick injuries can transmit the virus indicates that only very small amounts of blood are necessary. HBV infection is especially prevalent in those who
use intravenous drugs. Screening of blood for the presence of HBsAg has greatly decreased the number of transfusionassociated cases of hepatitis B.3
However, because blood transfusion is a modern procedure, there must be another natural route of transmission. HBV is found in semen and vaginal
fluids, so it is likely that sexual transmission is important. Transmission from mother to child during birth is another important natural route.
Transplacental transmission, if it occurs, is rare. There is no evidence that transmission of HBV occurs during breastfeeding.
Note that enveloped viruses, such as HBV, are more sensitive to environmental damage, for example, heat and dryness, than nonenveloped viruses and
hence are more efficiently transmitted by intimate contact (e.g., sexual contact). Nonenveloped viruses, such as HAV, are quite stable and are
transmitted well via the environment (e.g., fecal–oral transmission).
Hepatitis B is found worldwide but is particularly prevalent in Asia. Globally, more than 300 million people are chronically infected with HBV, and about
75% of them are Asian. There is a high incidence of HCC in many Asian countries—a finding that indicates that HBV is likely to be a human tumor virus
(see Chapter 43). Immunization against HBV has significantly reduced the incidence of HCC in children. It appears that the HBV vaccine is the first
vaccine to prevent human cancer.
3In the United States, donated blood is screened for HBsAg and antibodies to HBcAg, HCV, HIV1, HIV2, and HTLV1. Two other tests are also performed:
a VDRL test for syphilis and a transaminase assay, which, if elevated, indicates liver damage and is a surrogate marker of viral infection.
transmitted well via the environment (e.g., fecal–oral transmission).
Hepatitis B is found worldwide but is particularly prevalent in Asia. Globally, more than 300 million people are chronically infected with HBV,
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Provided
75% of them are Asian. There is a high incidence of HCC in many Asian countries—a finding that indicates that HBV is likely to be a human tumor virus
(see Chapter 43). Immunization against HBV has significantly reduced the incidence of HCC in children. It appears that the HBV vaccine is the first
vaccine to prevent human cancer.
3In the United States, donated blood is screened for HBsAg and antibodies to HBcAg, HCV, HIV1, HIV2, and HTLV1. Two other tests are also performed:
a VDRL test for syphilis and a transaminase assay, which, if elevated, indicates liver damage and is a surrogate marker of viral infection.
After entering the blood, the virus infects hepatocytes, and viral antigens are displayed on the surface of the cells. Cytotoxic T cells mediate an immune
attack against the viral antigens and inflammation and necrosis occur. Immune attack against viral antigens on infected hepatocytes is mediated by
cytotoxic T cells. The pathogenesis of hepatitis B is probably the result of this cellmediated immune injury, because HBV itself does not cause a
cytopathic effect. Antigen–antibody complexes cause some of the early symptoms (e.g., arthralgias, arthritis, and urticaria) and some of the
complications in chronic hepatitis (e.g., glomerulonephritis, cryoglobulinemia, and vasculitis).
About 5% of adult patients with HBV infection become chronic carriers. In contrast, 90% of infected newborns become chronic carriers (see two
paragraphs later). A chronic carrier is someone who has HBsAg persisting in their blood for 6 months or longer. The chronic carrier state is
attributed to a persistent infection of the hepatocytes, which results in the prolonged presence of HBV and HBsAg in the blood. The main determinant
of whether a person clears the infection or becomes a chronic carrier is the adequacy of the cytotoxic Tcell response. HBV DNA exists primarily as an
episome in the nucleus of persistently infected cells; a small number of copies of HBV DNA are integrated into cell DNA.
A high rate of HCC occurs in chronic carriers. The HBx gene may be an oncogene because the HBx protein inactivates the p53 tumor suppressor
protein (see Chapter 43). In addition, HCC may be the result of persistent cellular regeneration that attempts to replace the dead hepatocytes.
Alternatively, malignant transformation could be the result of insertional mutagenesis, which could occur when the HBV DNA integrates into the
hepatocyte DNA. Integration of the HBV DNA could activate a cellular oncogene, leading to a loss of growth control. Almost all HCC cells have HBV DNA
integrated into the cell DNA. Note that although viral DNA is integrated into cell DNA in most HCC cells, integration of viral DNA is not a required step in
HBV replication. (See section on viral replication above.)
Chronic carriage is more likely to occur when infection occurs in a newborn than in an adult through multiple immunologic mechanisms. One leading
hypothesis is that persistent exposure to HBVantigens in utero leads to immunologic tolerance to HBVantigens and decreased newborn HBV specific
cytotoxic Tcell response. Approximately 90% of infected neonates become chronic carriers. Chronic carriage resulting from neonatal
infection is associated with a high risk of HCC.
Some chronic carriers make e antigen (they are said to be e antigen positive) and therefore have a high probability of making infectious virions and
being able to transmit the disease. The e antigen is the indicator of transmissibility because it is encoded by the same gene that encodes the
core protein indicating that the HBV DNA genome is present. Some chronic carriers do not make e antigen (they are said to be e antigen negative),
and therefore have a low probability of making infectious virions and are less likely to transmit the disease.
Lifelong immunity occurs after the natural infection and is mediated by antibody against HBsAg (HBsAb). HBsAb is protective because it binds to
surface antigen on the virion and prevents it from interacting with receptors on the hepatocyte. Another way of saying this is that HBsAb neutralizes the
infectivity of HBV. Note that antibody against the core antigen (HBcAb) is not protective because the core antigen is inside the virion and the antibody
cannot interact with it.
Clinical Findings
Many HBV infections are asymptomatic and are detected only by the presence of antibody to HBsAg. The mean incubation period for hepatitis B is 10 to
12 weeks, which is much longer than that of hepatitis A (3–4 weeks). The clinical appearance of acute hepatitis B is similar to that of hepatitis A.
However, with hepatitis B, symptoms tend to be more severe, and lifethreatening hepatitis can occur. Most chronic carriers are asymptomatic, but
some have chronic active hepatitis, which can lead to cirrhosis and death.
Chronic hepatitis B can be managed but it cannot be cured. HBV infection persists for the lifetime of the individual, not only in those who have chronic
hepatitis but also in those who are asymptomatic and have antibody to HB surface antigen. The clinical importance of this is that patients who are
immunosuppressed later in life can manifest a reactivation of disease, including active hepatitis and liver failure. Patients at high risk for this
reactivation include those who are HBsAg positive and who are treated with antiCD20 drugs, such as rituximab, or have a hematopoietic stem cell
transplant. Patients in this highrisk category should be treated prophylactically with either tenofovir or entecavir to prevent this severe complication
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section later).
In addition to liverrelated findings, extrahepatic manifestations of HBV infection occur. In acute infection, serum sicknesslike symptoms, such as
fever, rash, and arthralgias, can occur. In chronic HBV infection, neuropathies, glomerulonephritis, and polyarteritis nodosa (a vasculitis of small and
Chronic hepatitis B can be managed but it cannot be cured. HBV infection persists for the lifetime of the individual, not only in those Ilia
whoState
haveUniversity
chronic
hepatitis but also in those who are asymptomatic and have antibody to HB surface antigen. The clinical importance of this is that patients who are
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immunosuppressed later in life can manifest a reactivation of disease, including active hepatitis and liver failure. Patients at high risk for this
reactivation include those who are HBsAg positive and who are treated with antiCD20 drugs, such as rituximab, or have a hematopoietic stem cell
transplant. Patients in this highrisk category should be treated prophylactically with either tenofovir or entecavir to prevent this severe complication
(see Treatment section later).
In addition to liverrelated findings, extrahepatic manifestations of HBV infection occur. In acute infection, serum sicknesslike symptoms, such as
fever, rash, and arthralgias, can occur. In chronic HBV infection, neuropathies, glomerulonephritis, and polyarteritis nodosa (a vasculitis of small and
mediumsized arteries) may occur. Autoantibodies, such as cryoglobulins and rheumatoid factor, may be detected.
Patients coinfected with both HBV and human immunodeficiency virus (HIV) may have increased hepatic damage if HIV is treated prior to treating HBV.
This occurs because the immune reconstitution that results when HIV is treated successfully leads to increased damage to the hepatocytes by the
restored, competent cytotoxic T cells. For this reason, it is recommended that an antiretroviral (ARV) regimen for patients with both HIV and HBV should
include tenofovir plus lamivudine or emtricitabine as the nucleoside reverse transcriptase inhibitor (NRTI) backbone.
The two most important serologic tests for the diagnosis of early hepatitis B are the tests for HBsAg and for IgM antibody to the core antigen. Both
appear in the serum early in the disease. The hallmark test for acute hepatitis B is IgM antibody to core antigen. The test for HBsAg is also positive but
that occurs in chronic hepatitis B also so is not a specific marker for acute infection.
HBsAg appears during the incubation period and is detectable in most patients during the prodrome and acute disease (Figure 41–4). It falls to
undetectable levels during convalescence in most cases; its prolonged presence (at least 6 months) indicates the carrier state and the risk of chronic
hepatitis and hepatic carcinoma.
FIGURE 41–4
A : Important diagnostic tests during various stages of hepatitis B. B : Serologic findings in a patient with acute hepatitis B. C : Duration of increased liver
enzyme activity and of symptoms in a patient with acute hepatitis B. D : Serologic findings in a patient with chronic hepatitis B. antiHBc = hepatitis B
core antibody; antiHBe = hepatitis B e antibody; antiHBs = hepatitis B surface antibody; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface
antigen; HBV = hepatitis B virus. (Adapted with permission from Lennette EH: Manual of Clinical Microbiology. 4th ed. Washington, DC: ASM Press;
1985.)

enzyme activity and of symptoms in a patient with acute hepatitis B. D : Serologic findings in a patient with chronic hepatitis B. antiHBc = hepatitis B
core antibody; antiHBe = hepatitis B e antibody; antiHBs = hepatitis B surface antibody; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface
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antigen; HBV = hepatitis B virus. (Adapted with permission from Lennette EH: Manual of Clinical Microbiology. 4th ed. Washington, DC: ASM Press;
1985.)
As described in Table 41–4, HBsAb is not detectable in the chronic carrier state. Note that HBsAb is, in fact, being made but is not detectable in the
laboratory tests because it is bound to the large amount of HBsAg present in the blood. HBsAb is also being made during the acute disease but is
similarly undetectable because it is bound in antigen–antibody complexes.
TABLE 41–4
Serologic Test Results in Four Stages of HBV Infection
Test Acute Disease Window Phase Complete Recovery Chronic Carrier State1
HBsAg Positive Negative Negative Positive

Chapter 41: Hepatitis
HBsAb Viruses,
Negative Negative Positive Negative2 Page 9 / 22
HBcAb Positive3 Positive Positive Positive

As described in Table 41–4, HBsAb is not detectable in the chronic carrier state. Note that HBsAb is, in fact, being made but is not detectable in the
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laboratory tests because it is bound to the large amount of HBsAg present in the blood. HBsAb is also being made during the acute disease but is
similarly undetectable because it is bound in antigen–antibody complexes.
TABLE 41–4
Serologic Test Results in Four Stages of HBV Infection
Test Acute Disease Window Phase Complete Recovery Chronic Carrier State1
HBsAg Positive Negative Negative Positive
HBsAb Negative Negative Positive Negative2
HBcAb Positive3 Positive Positive Positive
Note: People immunized with HBV vaccine have HBsAb but not HBcAb because the immunogen in the vaccine is purified HBsAg.
1Chronic carriers who are HBeAg positive are highly likely to transmit HBV, whereas those who are HBeAb positive are less likely to transmit HBV.
2Chronic carriers have negative antibody tests, but HBsAb is being made by these individuals. It is undetected in the tests because it is bound to the large amount of
HBsAg present in the plasma. They are not tolerant to HBsAg.
3IgM is found in the acute stage; IgG is found in subsequent stages.
Note that there is a period of several weeks when HBsAg has disappeared but HBsAb is not yet detectable. This is the window phase. At this time, the
HBcAb is always positive and can be used to make the diagnosis. HBcAb is present in those with acute infection and chronic infection, as well as in
those who have recovered from acute infection. Therefore, it cannot be used to distinguish between acute and chronic infection. The IgM form of
HBcAb is present during acute infection and disappears approximately 6 months after infection. The test for HBcAg is not readily available. Table 41–4
describes the serologic test results that characterize the four important stages of HBV infection.
HBeAg arises during the incubation period and is present during the prodrome and early acute disease and in certain chronic carriers. Its presence in
chronic carriers indicates a high likelihood of transmissibility, and, conversely, the absence of HBeAg indicates a low likelihood of transmission. In
addition, the finding of HBeAb indicates a lower likelihood, but transmission can still occur. DNA polymerase activity is detectable during the
incubation period and early in the disease, but the assay is not available in most clinical laboratories.
The detection of viral DNA (viral load) in the serum is strong evidence that infectious virions are present. Reduction of the viral load in patients with
chronic hepatitis B is used to monitor the success of drug therapy.
Treatment
No antiviral therapy is typically used in acute hepatitis B. Chronic hepatitis B can be treated with various antiviral drugs but the infection cannot be
cured.
For chronic hepatitis B, entecavir (Baraclude) or tenofovir (Viread, Vemlidy) are the drugs of choice. They are nucleoside analogues that inhibit the
reverse transcriptase of HBV. Interferon in the form of peginterferon alfa2a (Pegasys) may also be used. Other nucleoside analogues such as
lamivudine (EpivirHBV), adefovir (Hepsera), and telbivudine (Tyzeka) are used less frequently. A combination of tenofovir and emtricitabine (Emtriva)
is also used. Resistance to several of these antiretroviral drugs has emerged during longterm treatment of chronic HBV.
These drugs reduce hepatic inflammation, reduce the risk of cirrhosis and hepatocellular carcinoma, and lower the viral load of HBV in patients with
chronic active hepatitis. Note, however, that neither interferon nor the nucleoside analogues cure the HBV infection. In most patients, when the drug is
stopped, HBV replication resumes.
Patients coinfected with HBV and HIV should be prescribed highly active antiretroviral therapy (HAART) with caution because recovery of cellmediated
immunity can result in an exacerbation of hepatitis (immune reconstitution syndrome, IRIS). Consideration should be given to treat the HBV infection
prior to starting HAART.
Prevention
The two main modes of prevention involve the use of either the vaccine or hyperimmune globulin or both.
stopped, HBV replication resumes.
Patients coinfected with HBV and HIV should be prescribed highly active antiretroviral therapy (HAART) with caution because recovery of cellmediated
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immunity can result in an exacerbation of hepatitis (immune reconstitution syndrome, IRIS). Consideration should be given to treat the HBV infection
prior to starting HAART.
Prevention
The two main modes of prevention involve the use of either the vaccine or hyperimmune globulin or both.
1. The subunit vaccine (e.g., Recombivax, EngerixB, or HeplisavB) contains HBsAg produced in yeasts by recombinant DNA techniques.
The vaccine is highly effective in preventing hepatitis B and has few side effects. The seroconversion rate is approximately 95% in healthy adults.
Recombivax and EngerixB are given in a threedose regimen whereas HeplisavB is given as a twodose regimen.
It is indicated for people who are frequently exposed to blood or blood products, such as certain healthcare personnel (e.g., medical students,
surgeons, and dentists), patients receiving multiple transfusions or dialysis, patients with frequent sexually transmitted infections, and people who
inject drugs. Travelers who plan a long stay in areas of endemic infection, such as many countries in Asia and Africa, should receive the vaccine. The
U.S. Public Health Service recommends that all newborns and adolescents receive the vaccine.
At present, booster doses after the initial two or threedose regimen are not recommended. However, if antibody titers have declined in immunized
patients who are at high risk, such as dialysis patients, then a booster dose should be considered.
Widespread immunization with the HBV vaccine has significantly reduced the incidence of HCC in children. A vaccine called Twinrix that contains
both HBsAg and inactivated HAV provides protection against both hepatitis B and hepatitis A.
2. Hepatitis B immune globulin (HBIG) contains a high titer of HBsAb. It is used to provide immediate, passive protection to individuals
known to be exposed to HBsAgpositive blood (e.g., after an accidental needlestick injury).
Precise recommendations for the use of the vaccine and HBIG are beyond the scope of this book. However, the recommendation regarding one
common concern of medical students, the needlestick injury from a patient with HBsAgpositive blood, is that both the vaccine and HBIG be given (at
separate sites). This is true even if the patient’s blood is HBeAb positive.
Both the vaccine and HBIG should also be given to a newborn whose mother is HBsAg positive. This regimen is very effective in reducing the infection
rate of newborns whose mothers are chronic carriers. The regimen of vaccine plus HBIG in those with needlestick injuries and in neonates is a good
example of passive–active immunization, in which both immediate protection and longterm protection are provided.
The effectiveness of cesarean section to reduce HBV infection in neonates is uncertain. It is currently not recommended. Breastfeeding of immunized
neonates by mothers who are chronic carriers entails little risk of infection of the neonate.
All blood for transfusion should be screened for HBsAg. No one with a history of hepatitis (of any type) should donate blood, because other viruses,
such as HCV, may be present. Screening of highrisk populations to detect chronic carriers using serologic testing should be done because
identification and treatment of carriers will reduce transmission.
Note that preexposure prophylaxis using Truvada (tenofovir plus emtricitabine) to prevent HIV infection also prevents HBV infection. These two drugs
inhibit the reverse transcriptase of both HBV and HIV.
NONA, NONB HEPATITIS VIRUSES

The term “nonA, nonB hepatitis” was coined to describe the cases of hepatitis for which existing serologic tests had ruled out all known viral causes.
The term is not often used because the main cause of nonA, nonB hepatitis, namely, HCV, has been identified. In addition, HDV and HEV have been
described. Crossprotection experiments indicate additional hepatitis viruses exist.
HEPATITIS C VIRUS (HCV)

Disease
HCV causes hepatitis C.
HCV is a member
Chapter of theViruses,
41: Hepatitis flavivirus family. It is an enveloped virion containing a genome of singlestranded, nonsegmented, positivepolarityPage
RNA.11
It /has
22
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virion.
HCV has at least six genotypes and multiple subgenotypes based on differences in the genes that encode one of its two envelope glycoproteins. This
HEPATITIS C VIRUS (HCV)
Disease Access Provided by:
HCV causes hepatitis C.
HCV is a member of the flavivirus family. It is an enveloped virion containing a genome of singlestranded, nonsegmented, positivepolarity RNA. It has
no polymerase in the virion.
HCV has at least six genotypes and multiple subgenotypes based on differences in the genes that encode one of its two envelope glycoproteins. This
genetic variation results in a “hypervariable” region in the envelope glycoprotein. The genetic variability is due to the high mutation rate in the
envelope gene coupled with the absence of a proofreading function in the virionencoded RNA polymerase. As a result, multiple subspecies
(quasispecies) often occur in the blood of an infected individual at the same time. Genotype 1 causes approximately 75% of infections in the United
States.
More than 50% of HCV infections result in chronic infection, a rate much higher than that of HBV. Chronic HCV infection predisposes to HCC. The
high rate of chronic infection is attributed to the ability of the HCV protease to inactivate a signal protein involved in inducing interferon in hepatocytes.
HCV replicates in the cytoplasm and translates its genome RNA into large polyproteins, from which functional viral proteins are cleaved by a virion
encoded protease. This protease is the target of potent antiHCV therapy (see Treatment section). In addition, HCV genome RNA encodes a protein
called NS5A that cooperates with the RNA polymerase of the virus to synthesize progeny genome RNAs. The NS5A protein also functions in the
assembly of progeny virions. The NS5A protein is the target of potent antiHCV therapy (see Treatment section).
The replication of HCV in the liver is enhanced by a liverspecific microRNA called miR122. This microRNA acts by increasing the synthesis of HCV
mRNA. (MicroRNAs are known to enhance cellular mRNA synthesis in many tissues.) A clinical trial of an antisense nucleotide called miravirsen that
bound to and blocked the activity of miR122 showed prolonged reduction in HCV RNA levels in infected patients.
Humans are the reservoir for HCV. It is transmitted primarily via blood. At present, injection drug use accounts for almost all new HCV infections.
Transmission from mother to child during birth is another important mode of transmission. Transmission via blood transfusion rarely occurs because
donated blood containing antibody to HCV is discarded. Transmission via needlestick injury occurs, but the risk is lower than for HBV. Sexual
transmission is uncommon, and there is no evidence for transmission across the placenta or during breastfeeding.
HCV is the most prevalent bloodborne pathogen in the United States. (In the nationally reported incidence data, HCV ranks below HIV and HBV as
a bloodborne pathogen, but it is estimated that HCV is more prevalent.) Approximately 4 million people in the United States (1%–2% of the
population) are chronically infected with HCV. Unlike yellow fever virus, another flavivirus that infects the liver and is transmitted by mosquitoes, there
is no evidence for an insect vector for HCV. Worldwide, it is estimated that 180 million people are infected with HCV.
Many infections are asymptomatic, so screening of highrisk individuals for HCV antibody should be done. In addition, the United States Prevention
Services Task Force (USPSTF) in 2020 expanded screening recommendations to all adults ages 18 to 79 years.
In the United States, about 1% of blood donors have antibody to HCV. People who share needles when taking injected drugs are very commonly
infected. Commercially prepared Ig preparations are generally very safe, but several instances of the transmission of HCV have occurred.
HCV infects hepatocytes primarily, but there is no evidence for a virusinduced cytopathic effect on the liver cells. Rather, death of the hepatocytes is
probably caused by immune attack by cytotoxic T cells. HCV infection strongly predisposes to HCC, but there is no evidence for an oncogene in
the viral genome or for insertion of a copy of the viral genome into the DNA of the cancer cells.
Alcohol use disorder greatly enhances the rate of HCC in HCVinfected individuals. This supports the idea that the cancer is caused by prolonged liver
damage and the consequent rapid growth rate of hepatocytes as the cells attempt to regenerate rather than by a direct oncogenic effect of HCV. Added
support for this idea is the observation that patients with cirrhosis of any origin, not just alcoholic cirrhosis, have an increased risk of HCC.
Antibodies against HCV are made, but approximately 75% of patients are chronically infected and continue to produce virus for at least 1 year.
Downloaded
(Note that the2024417 4:9 A Your
rate of chronic IP is 217.147.233.195
carriage of HCV is much higher than the rate of chronic carriage of HBV.) Chronic infection is likely to be
encouraged by the suppression of interferon synthesis by the protease of HCV that cleaves a signal transduction protein required to activate interferon
synthesis. Chronic active hepatitis and cirrhosis occur in approximately 10% of patients with chronic HCV infection.
the viral genome or for insertion of a copy of the viral genome into the DNA of the cancer cells.
Alcohol use disorder greatly enhances the rate of HCC in HCVinfected individuals. This supports the idea that the cancer is caused by prolonged liver
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damage and the consequent rapid growth rate of hepatocytes as the cells attempt to regenerate rather than by a direct oncogenic effect of HCV. Added
support for this idea is the observation that patients with cirrhosis of any origin, not just alcoholic cirrhosis, have an increased risk of HCC.
Antibodies against HCV are made, but approximately 75% of patients are chronically infected and continue to produce virus for at least 1 year.
(Note that the rate of chronic carriage of HCV is much higher than the rate of chronic carriage of HBV.) Chronic infection is likely to be
encouraged by the suppression of interferon synthesis by the protease of HCV that cleaves a signal transduction protein required to activate interferon
synthesis. Chronic active hepatitis and cirrhosis occur in approximately 10% of patients with chronic HCV infection.
Clinical Findings
The acute infection is often asymptomatic. If symptoms such as malaise, nausea, and right upper quadrant pain do occur, they are milder than with
infection by the other hepatitis viruses. Fever, anorexia, nausea, vomiting, and jaundice are common. Dark urine, pale feces, and elevated
transaminase levels are seen.
Hepatitis C resembles hepatitis B as far as the ensuing chronic liver disease, cirrhosis, and the predisposition to HCC are concerned. Note that a chronic
carrier state occurs much more often with HCV infection than with HBV.
Liver biopsy is often done in patients with chronic infection to evaluate the extent of liver damage and to guide treatment decisions. Many infections
with HCV, including both acute and chronic infections, are asymptomatic and are detected only by the presence of antibody. The mean incubation
period is 8 weeks. Cirrhosis resulting from chronic HCV infection is the most common indication for liver transplantation.
HCV infection also leads to significant extrahepatic autoimmune reactions, including vasculitis, arthralgias, purpura, and membranoproliferative
glomerulonephritis. Hepatitis C infection also markedly increases the risk of Bcell nonHodgkin’s lymphoma.
HCV is the main cause of essential mixed cryoglobulinemia. Cryoglobulins are defined by their ability to precipitate at cold temperature (cryo = cold).
The cryoprecipitates are immune complexes composed of HCV antigens and antibodies. Peripheral neuropathy is one of the most common
complications of chronic HCV infections. Damage to the nerves is thought to be caused by cryoprecipitates.
Reinfection can occur after a patient has a documented undetectable viral load following drug therapy. This occurs primarily in people who inject
drugs who are frequently exposed to HCV. Reinfection in the face of existing antibody is thought to be caused by the high rate of antigenic variants
combined with a diminishing T cell response. High risk patients with prior HCV infection should be screened every 6 to 12 months with a PCR assay to
detect viral RNA to determine whether reinfection has occurred.
HCV infection is diagnosed by detecting antibodies to HCV in an enzymelinked immunosorbent assay (ELISA) (Table 41–5). The antigen in the assay is a
recombinant protein formed from three immunologically stable HCV proteins and does not include the highly variable envelope proteins. The test
does not distinguish between IgM and IgG and does not distinguish between an acute, chronic, and resolved infection.
TABLE 41–5
Laboratory Test Results at Different Stages of HCV Infection
Diagnostic Test Acute HCV Infection Chronic HCV Infection Recovered from HCV Infection
Antibody to HCV Positive in 6–24 weeks. Negative Positive Positive

early in infection
Viral load (HCV RNA in serum) Detectable within 1–2 weeks Detectable Undetectable
Transaminase (alanine Elevated Typically elevated but fluctuates to May be normal but may be positive
aminotransferase, ALT) near normal and fluctuate
If the result of ELISA antibody test is positive, a PCRbased test that detects the presence of viral RNA (viral load) in the serum should be performed to
determine whether active disease exists. Reduction of the viral load in patients with hepatitis C is used to monitor the success of drug therapy. Isolation
of the virus from patient specimens is not done. A chronic infection is characterized by elevated transaminase levels, a positive ELISA antibody test, and
detectable
Chapter 41: viral RNAViruses,
Hepatitis for at least 6 months. Page 13 / 22
Treatment
aminotransferase, ALT) near normal and fluctuate
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If the result of ELISA antibody test is positive, a PCRbased test that detects the presence of viral RNA (viral load) in the serum should be performed to
determine whether active disease exists. Reduction of the viral load in patients with hepatitis C is used to monitor the success of drug therapy. Isolation
of the virus from patient specimens is not done. A chronic infection is characterized by elevated transaminase levels, a positive ELISA antibody test, and
detectable viral RNA for at least 6 months.
Treatment
Treatment of acute hepatitis C with peginterferon alfa significantly decreases the number of patients who become chronic carriers. An oral regimen of
ledipasvir and sofosbuvir is now used for acute hepatitis C infection by genotype1 HCV.
The treatment of choice for chronic hepatitis C is a combination of drugs from three classes: RNA polymerase inhibitors, NS5A inhibitors, and
protease inhibitors (Figure 41–5 and Table 41–6). These drugs are administered orally, which is an improvement over the drugs in previous regimens
that often included pegylated interferon alfa, which is administered parenterally and has significant adverse effects.
FIGURE 41–5
Site of action of drugs used in treatment of chronic hepatitis C virus infection.
TABLE 41–6
Oral Drugs for Chronic HCV Infection
Name of
Class of Drug Mechanism of Action
Drug
RNA polymerase Sofosbuvir Inhibits synthesis of genome RNA; nucleoside (uridine) analogue; chainterminating drug
inhibitor
RNA polymerase Dasabuvir Inhibits synthesis of genome RNA; nonnucleoside inhibitor

inhibitor
NS5A inhibitor Ledipasvir Inhibits synthesis of genome RNA; blocks action of NS5A protein, which is a cofactor required for RNA
Ombitasvir polymerase activity
Daclatasvir
Elbasvir
Velpatasvir
Chapter 41: Hepatitis Viruses,Pibrentasvir Page 14 / 22
Protease inhibitor Boceprevir Inhibits cleavage of precursor polypeptide; blocks production of functional HCV structural and nonstructural
Simeprevir proteins
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TABLE 41–6
Oral Drugs for Chronic HCV Infection
Name of
Class of Drug Mechanism of Action
Drug
RNA polymerase Sofosbuvir Inhibits synthesis of genome RNA; nucleoside (uridine) analogue; chainterminating drug
inhibitor
RNA polymerase Dasabuvir Inhibits synthesis of genome RNA; nonnucleoside inhibitor

inhibitor
NS5A inhibitor Ledipasvir Inhibits synthesis of genome RNA; blocks action of NS5A protein, which is a cofactor required for RNA
Ombitasvir polymerase activity
Daclatasvir
Elbasvir
Velpatasvir
Pibrentasvir
Protease inhibitor Boceprevir Inhibits cleavage of precursor polypeptide; blocks production of functional HCV structural and nonstructural
Simeprevir proteins
Telaprevir
Paritaprevir
Grazoprevir
Glecaprevir
Voxilaprevir
Currently available combinations are described in Table 41–7. Note that these drug combinations are more effective against certain genotypes of HCV,
although some drug combinations are effective against all six of the major genotypes. These various drug combinations offer the prospect of a “cure”
for chronic hepatitis C.
TABLE 41–7
Drug Combinations Effective for Treatment of Chronic HCV Infection
HCV Genotype Against Which Treatment Is Effective Name of Drug Name of HCV Inhibitor Site of Action of HCV Inhibitor
1 Sovaldi plus Sofosbuvir RNA polymerase

Olysio Simeprevir Protease
1 Viekira Pak Dasabuvir RNA polymerase

Ombitasvir NS5A
Paritaprevir Protease
Ritonavir Booster of protease inhibitor
1 or 3 Sovaldi plus Sofosbuvir RNA polymerase

Daklinza Daclatasvir NS5A
1 or 4 Zepatier Elbasvir NS5A

Grazoprevir Protease
Chapter
1, 4,41: Hepatitis
5, or 6 Viruses, Harvoni Sofosbuvir RNA polymerase Page 15 / 22
Ledipasvir NS5A
4 Technivie Ombitasvir NS5A

Currently available combinations are described in Table 41–7. Note that these drug combinations are more effective against certain genotypes of HCV,
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although some drug combinations are effective against all six of the major genotypes. These various drug combinations offer the prospect of a “cure”
for chronic hepatitis C.
TABLE 41–7
Drug Combinations Effective for Treatment of Chronic HCV Infection
HCV Genotype Against Which Treatment Is Effective Name of Drug Name of HCV Inhibitor Site of Action of HCV Inhibitor
1 Sovaldi plus Sofosbuvir RNA polymerase

Olysio Simeprevir Protease
1 Viekira Pak Dasabuvir RNA polymerase

Ombitasvir NS5A
1 or 3 Sovaldi plus Sofosbuvir RNA polymerase

Daklinza Daclatasvir NS5A
1 or 4 Zepatier Elbasvir NS5A

Grazoprevir Protease
1, 4, 5, or 6 Harvoni Sofosbuvir RNA polymerase

Ledipasvir NS5A
4 Technivie Ombitasvir NS5A

All 6 Epclusa Sofosbuvir RNA polymerase

Velpatasvir NS5A
All 6 Mavyret Pibrentasvir NS5A

Glecaprevir Protease
All 6 Vosevi Sofosbuvir RNA polymerase

Velpatasvir NS5A
Voxilaprevir Protease
One important adverse effect of these drugs used in the treatment of chronic HCV infection is the reactivation of HBV infection. The mechanism of
reactivation of HBV is unknown.
Prevention
There is no vaccine, and hyperimmune globulins are not available. Pooled immune serum globulins are not useful for postexposure prophylaxis.
There is no effective regimen for prophylaxis following needlestick injury; only monitoring is recommended.
Blood found to contain antibody is discarded—a procedure that has prevented virtually all cases of transfusionacquired HCV infection since 1994,
when screening began. Screening of individuals born in the United States between 1945 and 1965 for HCV antibody is recommended because they have
a high rate of infection. Treatment of those who are antibodypositive should reduce transmission.
Patients with chronic HCV infection should be advised to reduce or eliminate their consumption of alcoholic beverages to reduce the risk of HCC and
cirrhosis. Patients with chronic HCV infection and cirrhosis should be monitored with alphafetoprotein tests and liver sonograms to detect carcinoma
at an early stage. Patients with liver failure due to HCV infection can receive a liver transplant, but infection of the graft with HCV typically occurs.
Patients coinfected
©2024 McGraw Hill.with HCV and
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Reserved. be prescribed
of Use •antiretroviral
Privacy Policytherapy
• Notice(ART) as it may slow progression of liver disease by preserving or
• Accessibility
restoring immune function. However, when HIV and HCV treatment are both indicated, special consideration should be given for potential drugdrug
interactions.
when screening began. Screening of individuals born in the United States between 1945 and 1965 for HCV antibody is recommended because they have
a high rate of infection. Treatment of those who are antibodypositive should reduce transmission.
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Patients with chronic HCV infection should be advised to reduce or eliminate their consumption of alcoholic beverages to reduce the risk of HCC and
cirrhosis. Patients with chronic HCV infection and cirrhosis should be monitored with alphafetoprotein tests and liver sonograms to detect carcinoma
at an early stage. Patients with liver failure due to HCV infection can receive a liver transplant, but infection of the graft with HCV typically occurs.
Patients coinfected with HCV and HIV should be prescribed antiretroviral therapy (ART) as it may slow progression of liver disease by preserving or
restoring immune function. However, when HIV and HCV treatment are both indicated, special consideration should be given for potential drugdrug
interactions.
HEPATITIS D VIRUS (HDV, DELTA VIRUS)

Disease
HDV causes hepatitis D (hepatitis delta).
Important Properties & Replicative Cycle
HDV is unusual in that it is a defective virus (i.e., it cannot replicate by itself because it does not have the genes for its envelope protein). HDV can
replicate only in cells also infected with HBV because HDV uses the surface antigen of HBV (HBsAg) as its envelope protein. HBV is therefore the helper
virus for HDV (Figure 41–6).
FIGURE 41–6
Hepatitis D virus. Note that hepatitis B surface antigen (HBsAg) forms the outer envelope and the genome consists of circular RNA. (Reproduced with
permission from Ryan KJ, Ray C: Sherris Medical Microbiology, 6th ed. New York, NY: McGraw Hill; 2014.)
HDV is an enveloped virus with an RNA genome that is a singlestranded, negativepolarity, covalently closed circle. The RNA genome of HDV is very
small and encodes only one protein, the internal core protein called delta antigen. HDV genome RNA has no sequence homology to HBV genome
DNA. HDV has no virion polymerase; the genome RNA is replicated and transcribed by the host cell RNA polymerase. HDV genome RNA is a “ribozyme”
(i.e., it has the ability to selfcleave and selfligate—properties that are employed during replication of the genome). HDV replicates in the nucleus, but
the specifics of the replicative cycle are complex and beyond the scope of this book.
HDV has one serotype because HBsAg has only one serotype. There is no evidence for the existence of an animal reservoir for HDV.
HDV is transmitted by the same means as is HBV (i.e., sexually, by blood, and perinatally). In the United States, the incidence of HDV infections is low;
most infections occur in people who share needles when injecting drugs. HDV infections occur worldwide, with a similar distribution to that of HBV
infections.
It seems likely that the pathogenesis of hepatitis caused by HDV and HBV is the same (i.e., the virusinfected hepatocytes are damaged by cytotoxic T
cells). There is some evidence that delta antigen is cytopathic for hepatocytes.
IgG antibody against delta antigen is not detected for long periods after infection; it is therefore uncertain whether longterm immunity to HDV exists.
Clinical
Chapter 41:Findings
Hepatitis Viruses, Page 17 / 22
Because HDV can replicate only in cells also infected with HBV, hepatitis delta can occur only in a person infected with HBV. A person can either be
infected with both HDV and HBV at the same time (i.e., be “coinfected”) or be previously infected with HBV and then “superinfected” with HDV.
It seems likely that the pathogenesis of hepatitis caused by HDV and HBV is the same (i.e., the virusinfected hepatocytes are damaged by cytotoxic T
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cells). There is some evidence that delta antigen is cytopathic for hepatocytes.
IgG antibody against delta antigen is not detected for long periods after infection; it is therefore uncertain whether longterm immunity to HDV exists.
Clinical Findings
Because HDV can replicate only in cells also infected with HBV, hepatitis delta can occur only in a person infected with HBV. A person can either be
infected with both HDV and HBV at the same time (i.e., be “coinfected”) or be previously infected with HBV and then “superinfected” with HDV.
Hepatitis in patients coinfected with HDV and HBV is more severe than in those infected with HBV alone, but the incidence of chronic hepatitis is about
the same in patients infected with HBV alone. However, hepatitis in chronic carriers of HBV who become superinfected with HDV is much more severe,
and the incidence of fulminant, lifethreatening hepatitis, chronic hepatitis, and liver failure is significantly higher.
The diagnosis of HDV infection in the laboratory is made by detecting either delta antigen or IgM antibody to delta antigen in the patient’s serum. Tests
for HDV RNA in the blood are also available.
Peginterferon alfa can mitigate some of the effects of the chronic hepatitis caused by HDV but does not eradicate the chronic carrier state. There is no
specific antiviral therapy against HDV. There is no vaccine against HDV, but a person immunized against HBV will not be infected by HDV because HDV
cannot replicate unless HBV infection also occurs.
HEPATITIS E VIRUS (HEV)

HEV is a major cause of hepatitis transmitted by the fecal–oral route. It is thought to be more common than HAV in many developing countries. It is a
common cause of waterborne epidemics of hepatitis in Asia, Africa, India, and Mexico but is uncommon in the United States. HEV is a nonenveloped,
singlestranded RNA virus classified as a member of the hepevirus family.
Clinically, the disease resembles hepatitis A, with the exception of a high mortality rate in pregnant women. Most cases resolve without sequelae.
Chronic infection resulting in chronic hepatitis and cirrhosis, but not HCC, occurs in immunocompromised individuals such as people living with HIV,
those who are receiving cancer chemotherapy, and patients who are receiving immunosuppressive drugs to prevent rejection of solid organ
transplants.
The diagnosis is typically made by detecting IgM antibody to HEV. A PCR assay that detects HEV RNA in patient specimens is available. There is no
antiviral drug available for acute infection in immunocompetent patients. In immunocompromised patients, ribavirin cleared HEV viremia in solid
organ transplant recipients. A recombinant HEV vaccine (Hecolin) has been developed and licensed in China for the control outbreaks, but not readily
available elsewhere.
HEPATITIS G VIRUS (HGV)

In 1996, hepatitis G virus (HGV) was isolated from patients with posttransfusion hepatitis. HGV is a member of the flavivirus family, as is HCV. However,
unlike HCV, which is clearly the cause of both acute hepatitis and chronic active hepatitis and predisposes to HCC, HGV has not been documented to
cause any of these clinical findings. The role of HGV in the causation of liver disease has yet to be established, but it can cause a chronic infection
lasting for decades. Approximately 60% to 70% of those infected clear the virus and develop antibodies.
HGV is transmitted via sexual intercourse and blood. It is carried in the blood of millions of people worldwide. In the United States, it is found in the
blood of approximately 2% of random blood donors, 15% of those infected with HCV, and 35% of those infected with HIV. Patients living with HIV and
HGV have a lower mortality rate and have less HIV in their blood than those infected with HIV alone. It is hypothesized that HGV may interfere with the
replication of HIV. Similarly, a retrospective study found patients with Ebola virus and HGV had significantly higher survival rates suggesting HGV may
attenuate pathogenicity of Ebola virus. (HGV is also known as GB virus C, human hepegivirus, and pegivirus H.)
SELFASSESSMENT QUESTIONS
1 . An outbreak of jaundice occurs in several young children who attend the same day care center. If the outbreak was caused by a virus, which one of
the following
Chapter is the most
41: Hepatitis likely cause?
Viruses, Page 18 / 22
( A ) Hepatitis A virus
replication of HIV. Similarly, a retrospective study found patients with Ebola virus and HGV had significantly higher survival rates suggesting HGV may
attenuate pathogenicity of Ebola virus. (HGV is also known as GB virus C, human hepegivirus, and pegivirus H.) Ilia State University
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SELFASSESSMENT QUESTIONS
1 . An outbreak of jaundice occurs in several young children who attend the same day care center. If the outbreak was caused by a virus, which one of
the following is the most likely cause?
( A ) Hepatitis A virus
(B) Hepatitis B virus
(C) Hepatitis C virus
( D ) Hepatitis D virus
2 . Regarding hepatitis A virus (HAV), which one of the following statements is most accurate?
( A ) The HAV vaccine contains live, attenuated virus as the immunogen.
(B) The screening of blood for transfusion has greatly reduced the spread of this virus.
(C) The diagnosis is typically made by serologic tests rather than by culturing the virus.
( D ) Multiple episodes of hepatitis A are common because it has three serotypes.
(E) It has a segmented, negativepolarity, singlestranded RNA genome and an RNA polymerase in the virion.
3 . A woman who is hepatitis B surface antigen (HBsAg) positive and hepatitis B surface antibody (HBsAb) negative has just given birth. Which one of the
following is the most appropriate thing to do for the newborn?
( A ) Nothing. The child is protected against hepatitis B.
(B) Immunize with the vaccine containing HBsAg (HBV vaccine).
(C) Give hepatitis B hyperimmune globulin (HBIG).
( D ) Give both the HBV vaccine and HBIG.
4 . Regarding hepatitis B virus (HBV) and the disease hepatitis B, which one of the following is most accurate?
( A ) The most reliable indicator that a person can transmit HBV is the presence of HBsAg in the blood.
(B) HBV has a circular, partially doublestranded DNA as its genome and has a DNA polymerase in the virion.
(C) Healthcare personnel who sustain a needlestick injury while taking blood from a person with hepatitis B should receive acyclovir.
( D ) HBV infection induces antibody to HBcAg (core antigen), which protects the person from a second attack by the same strain of HBV.
(E) A person in the “window period” can be diagnosed as having been infected by HBV if antibody to the surface antigen (HBsAg) is present.
5 . Regarding hepatitis C virus (HCV), which one of the following is most accurate?
( A ) Chronic infection with HCV predisposes to hepatocellular carcinoma.
(B) HCV is a defective virus that requires concurrent hepatitis B virus (HBV) infection in order to replicate.
(C) Chronic infection with HCV occurs less frequently than chronic infection with HBV.
( D ) The killed vaccine against HCV is poorly immunogenic, so booster doses must be given at least every 5 years.
(E) Proper sewage disposal has significantly decreased the incidence of hepatitis C.
6 . Regarding hepatitis D virus (HDV), which one of the following is most accurate?
( A ) Alpha41:
Chapter interferon can
Hepatitis eradicate the latent state established by HDV.
Viruses, Page 19 / 22
(B) Immunization against hepatitis B virus (HBV) will reduce the incidence of hepatitis caused by HDV.
(C) Chronic infection with HCV occurs less frequently than chronic infection with HBV.
( D ) The killed vaccine against HCV is poorly immunogenic, so booster doses must be given at least every 5 years. Access Provided by:
(E) Proper sewage disposal has significantly decreased the incidence of hepatitis C.
6 . Regarding hepatitis D virus (HDV), which one of the following is most accurate?
( A ) Alpha interferon can eradicate the latent state established by HDV.
(B) Immunization against hepatitis B virus (HBV) will reduce the incidence of hepatitis caused by HDV.
(C) HDV has DNA as its genome and an RNAdependent DNA polymerase in the virion.
( D ) The laboratory diagnosis of HDV infection is made by growing HDV in cells coinfected with HBV.
(E) Many HDV infections occur in young children in the diaper stage in daycare centers because the virus is transmitted primarily by the fecal–oral
route.
7 . Your patient is a 35yearold man who complains that the whites of his eyes have turned yellow. After taking a history and doing a physical, you order
serologic tests to determine whether he has viral hepatitis. On the basis of the results, you tell him that he has a mild form of hepatitis that does not
cause longterm damage to the liver. Your conclusion is based on a positive result on which one of the following tests?
( A ) Antibody to hepatitis C virus
(B) Hepatitis B surface antigen
(C) Hepatitis delta antigen
( D ) IgM antibody to hepatitis A virus
8 . Your patient is a 20yearold woman with chronic hepatitis B who was diagnosed by detecting hepatitis B antigen in her blood more than 6 months
after her acute infection. Which one of the following is the best choice of drug to treat her chronic hepatitis B?
( A ) Acyclovir
(B) Foscarnet
(C) Entecavir
( D ) Ritonavir
(E) Zidovudine
9 . Your patient is a 27yearold man with a history of injection drug use who now is diagnosed with chronic hepatitis C. He is HIV antibody negative.
Which one of the following is the best choice of drugs to treat his chronic hepatitis C?
( A ) Acyclovir and foscarnet
(B) Ganciclovir and enfuvirtide
(C) Sofosbuvir and velpatasvir
( D ) Zidovudine and lamivudine
(E) Tenofovir and simeprevir
10. Treatment with a drug whose mode of action is inhibition of reverse transcriptase is used in which one of the following diseases?
( A ) Acute hepatitis A
(B) Chronic hepatitis A
(C) Acute hepatitis B
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( D ) Chronic hepatitis B 4:9 A Your IP is 217.147.233.195
(E) Acute hepatitis C
( F ) Chronic hepatitis C
( A ) Acute hepatitis A Ilia State University
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( D ) Chronic hepatitis B
11. Treatment with a drug whose mode of action is inhibition of NS5A protein is used in which one of the following diseases?
12. Treatment with a drug whose mode of action is inhibition of a virusencoded protease is used in which one of the following diseases?
ANSWERS
1. ( A )
2. (C)
3. ( D )
4. (B)
5. ( A )
6. (B)
7. ( D )
8. (C)
9. (C)
10. ( D )
11. ( F )
12. (F)
SUMMARIES OF ORGANISMS
Brief summaries of the organisms described in this chapter begin on Hepatitis Viruses. Please consult these summaries for a rapid review of the
9. (C)
10. ( D ) Access Provided by:
11. ( F )
12. ( F )
SUMMARIES OF ORGANISMS
Brief summaries of the organisms described in this chapter begin on Hepatitis Viruses. Please consult these summaries for a rapid review of the
essential material.
PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Clinical Virology section of Part XIII: USMLE (National Board) Practice Questions
starting on Clinical Virology. Also see Part XIV: USMLE (National Board) Practice Examination.


Chapter 41 - Hepatitis Viruses

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Chapter 41 - Hepatitis Viruses

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Chapter 41: Hepatitis Viruses

Abbreviation Name and Description

HAV Hepatitis A virus, a picornavirus (nonenveloped RNA virus)

HBsAb Antibody to HBsAg; provides immunity to hepatitis B

HBcAg Antigen associated with core of HBV

HBeAb Antibody to e antigen; indicates low transmissibility

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HAV ssRNA No No No Picornavirus

HBV dsDNA1 No Yes Yes Hepadnavirus

HCV ssRNA No No No Flavivirus

HDV ssRNA2 Yes No Yes Deltavirus

HEV ssRNA No No No Hepevirus

ds = double stranded; ss = single stranded.

1Interrupted, circular dsDNA.

2Circular, negative­stranded ssRNA.

HEPATITIS A VIRUS (HAV)

HAV causes hepatitis A.

Summary of Replicative Cycle

Transmission & Epidemiology

Pathogenesis & Immunity

HAV Fecal–oral No IgM HAV Yes Yes

HCV Blood, sexual1 Yes HCV Ab No No

HDV Blood, sexual1 Yes Ab to delta Ag No2 No

HEV Fecal–oral No None No No

1Sexual transmission seems likely but is poorly documented.

2HBV vaccination provides protection against HDV.

Treatment & Prevention

Treatment & Prevention

HEPATITIS B VIRUS (HBV)

HBV causes hepatitis B.

Summary of Replicative Cycle

Transmission & Epidemiology

Pathogenesis & Immunity

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HBsAg Positive Negative Negative Positive

HBcAb Positive3 Positive Positive Positive

HBsAg Positive Negative Negative Positive

HBsAb Negative Negative Positive Negative2

HBcAb Positive3 Positive Positive Positive

HBsAg present in the plasma. They are not tolerant to HBsAg.

3IgM is found in the acute stage; IgG is found in subsequent stages.

NON­A, NON­B HEPATITIS VIRUSES

HEPATITIS C VIRUS (HCV)

HCV causes hepatitis C.

HCV causes hepatitis C.

Summary of Replicative Cycle

Transmission & Epidemiology

Pathogenesis & Immunity

Antibody to HCV Positive in 6–24 weeks. Negative Positive Positive

Site of action of drugs used in treatment of chronic hepatitis C virus infection.

RNA polymerase Dasabuvir Inhibits synthesis of genome RNA; nonnucleoside inhibitor

RNA polymerase Dasabuvir Inhibits synthesis of genome RNA; nonnucleoside inhibitor

1 Sovaldi plus Sofosbuvir RNA polymerase

1 Viekira Pak Dasabuvir RNA polymerase

1 or 3 Sovaldi plus Sofosbuvir RNA polymerase

1 or 4 Zepatier Elbasvir NS5A

4 Technivie Ombitasvir NS5A

1 Sovaldi plus Sofosbuvir RNA polymerase

1 Viekira Pak Dasabuvir RNA polymerase

1 or 3 Sovaldi plus Sofosbuvir RNA polymerase

1 or 4 Zepatier Elbasvir NS5A

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2Circular, negativestranded ssRNA.

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NONA, NONB HEPATITIS VIRUSES

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