Review of Medical Microbiology and Immunology, 13th Edition

41. Hepatitis Viruses

CHAPTER CONTENTS

Introduction

Hepatitis A Virus (HAV)

Hepatitis B Virus (HBV)

Non-A, Non-B Hepatitis Viruses

Hepatitis C Virus (HCV)

Hepatitis D Virus (HDV, Delta Virus)

Hepatitis E Virus (HEV)

Hepatitis G Virus (HGV)

Self-Assessment Questions

Summaries of Organisms

Practice Questions: USMLE & Course Examinations

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

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TABLE 41–2 Important Properties of Hepatitis Viruses

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HEPATITIS A VIRUS (HAV)

Disease

HAV causes hepatitis A.

Important Properties

HAV is a typical enterovirus classified in the picornavirus family. It has a single-stranded 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. Common-source 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 IgG antibody.

Pathogenesis & Immunity

The pathogenesis of HAV infection is not completely understood. The virus probably replicates in the gastrointestinal tract and spreads to the liver via the blood. Hepatocytes are infected, but the mechanism by which cell damage occurs is unclear. HAV infection of cultured cells produces no cytopathic effect. It is likely that attack by cytotoxic T cells causes the damage to the hepatocytes. The infection is cleared, the damage is repaired, and no chronic infection ensues. Hepatitis caused by the 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 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 to 4 weeks. 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 are asymptomatic and are detected solely by the presence of IgG antibody. No chronic hepatitis or chronic carrier state occurs, and there is no predisposition to hepatocellular carcinoma.

TABLE 41–3 Clinical Features of Hepatitis Viruses

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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

No antiviral therapy is available. Active immunization with a vaccine containing inactivated HAV is available. The virus 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 long-term protection. This is an example of passive–active immunization.

Because many adults have antibodies to HAV, it may be cost-effective 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.

Important Properties

HBV is a member of the hepadnavirus family. It is a 42-nm enveloped virion,1 with an icosahedral nucleocapsid core containing a partially double-stranded circular DNA genome (Figure 41–1 and Table 41–2).

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FIGURE 41–1 Hepatitis B virus (HBV). Left: Cross-section of the HBV virion. Right: The 22-nm 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. (Modified and reproduced with permission from Ryan K et al. Sherris Medical Microbiology. 3rd ed. Originally published by Appleton & Lange. Copyright 1994 McGraw-Hill.)

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-dependent 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 RNA-dependent (reverse transcriptase) and DNA-dependent activity.

Electron microscopy of a patient’s serum reveals three different types of particles: a few 42-nm virions and many 22-nm spheres and long filaments 22 nm 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.

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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. (Figure courtesy of 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, whereas 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 group-specific 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: virus-specific 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.

Summary of Replicative Cycle

After entry of the virion into the cell and its uncoating, the virion DNA polymerase synthesizes the missing portion of DNA, and a double-stranded closed-circular DNA is formed in the nucleus. This DNA serves as a template for mRNA synthesis by cellular RNA polymerase. After the individual mRNAs are made, a full-length positive-strand transcript 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. This RNA-dependent DNA synthesis catalyzed by reverse transcriptase encoded by HBV takes place within the newly assembled virion core in the cytoplasm. The RNA-dependent DNA synthesis that produces the genome and the DNA-dependent DNA synthesis that fills in the missing portion of DNA soon after infection of the next cell are carried out by the same enzyme (i.e., the HBV genome encodes only one polymerase).

Hepadnaviruses are the only viruses that produce genome DNA by reverse transcription with mRNA 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.) Some of the progeny DNA integrates into the host cell genome, and this seems likely to be the DNA that maintains the carrier state. Progeny HBV with its HBsAg-containing envelope is released from the cell by budding through the cell membrane.

Transmission & Epidemiology

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 addicts who use intravenous drugs. Screening of blood for the presence of HBsAg has greatly decreased the number of transfusion-associated 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 breast feeding.

Note that enveloped viruses, such as HBV, are more sensitive to the environment 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 hepatocellular carcinoma (hepatoma) in many Asian countries—a finding that indicates that HBV is a human tumor virus (see Chapter 43). Immunization against HBV has significantly reduced the incidence of hepatoma in children. It appears that the HBV vaccine is the first vaccine to prevent a human cancer.

Pathogenesis & Immunity

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 cell-mediated 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 below). A chronic carrier is someone who has HBsAg persisting in their blood for at least 6 months. 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 T-cell response. HBV DNA exists primarily as an episome in the cytoplasm of persistently infected cells; a small number of copies of HBV DNA are integrated into cell DNA.

A high rate of hepatocellular carcinoma 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, hepatocellular carcinoma 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 genome integrates into the hepatocyte DNA. Integration of the HBV DNA could activate a cellular oncogene, leading to a loss of growth control.

Chronic carriage is more likely to occur when infection occurs in a newborn than in an adult, probably because a newborn’s immune system is less competent than that of an adult’s. Approximately 90% of infected neonates become chronic carriers. Chronic carriage resulting from neonatal infection is associated with a high risk of hepatocellular carcinoma.

Lifelong immunity occurs after the natural infection and is mediated by humoral antibody against HBsAg. Antibody against HBsAg (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 life-threatening hepatitis can occur. Most chronic carriers are asymptomatic, but some have chronic active hepatitis, which can lead to cirrhosis and death.

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 suggested that HBV be treated prior to treating HIV.

Laboratory Diagnosis

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. HBsAg appears during the incubation period and is detectable in most patients during the prodrome and acute disease (Figure 41–3). 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. 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.

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FIGURE 41–3 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. anti-HBc, hepatitis B core antibody; anti-HBe, hepatitis B e antibody; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. (Modified and reproduced with permission from Hollinger FB, Dienstag JL. Hepatitis viruses. In: Lennette EH et al., eds. Manual of Clinical Microbiology. 4th ed. Washington, DC: ASM Press; 1985.)

TABLE 41–4 Serologic Test Results in Four Stages of HBV Infection

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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 indicates a high likelihood of transmissibility, and, conversely, 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. For chronic hepatitis B, entecavir (Baraclude) or tenofovir (Viread) are the drugs of choice. They are nucleoside analogues that inhibit the reverse transcriptase of HBV. Interferon in the form of peginterferon alfa-2a (Pegasys) is also used. Other nucleoside analogues such as lamivudine (Epivir-HBV), adefovir (Hepsera), and telbivudine (Tyzeka) are used less frequently. A combination of tenofovir and emtricitabine (Emtriva) is also used.

These drugs reduce hepatic inflammation and lower the viral load of HBV in patients with chronic active hepatitis. Neither interferon nor the nucleoside analogues cure the HBV infection. In most patients when the drug is stopped, HBV replication resumes.

Prevention

Prevention involves the use of either the vaccine or hyperimmune globulin or both.

(1) The vaccine (e.g., Recombivax) 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. It is indicated for people who are frequently exposed to blood or blood products, such as certain health care personnel (e.g., medical students, surgeons, and dentists), patients receiving multiple transfusions or dialysis, patients with frequent sexually transmitted disease, and abusers of illicit intravenous 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 three-dose 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 hepatocellular carcinoma 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 HBsAg-positive blood (e.g., after an accidental needle-stick injury).

Precise recommendations for use of the vaccine and HBIG are beyond the scope of this book. However, the recommendation regarding one common concern of medical students, the needle-stick injury from a patient with HBsAg-positive 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 needle-stick injuries and in neonates is a good example of passive–active immunization, in which both immediate protection and long-term protection are provided.

The effectiveness of Cesarean section to reduce HBV infection of neonates is uncertain. It is currently not recommended. Breast feeding 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 non-A, non-B viruses may be present. Screening of high-risk populations to detect chronic carriers using serologic testing should be done because identification and treatment of carriers will reduce transmission.

NON-A, NON-B HEPATITIS VIRUSES

The term “non-A, non-B 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 non-A, non-B hepatitis, namely, HCV, has been identified. In addition, HDV and HEV have been described. Cross-protection experiments indicate additional hepatitis viruses exist.

HEPATITIS C VIRUS (HCV)

Disease

HCV causes hepatitis C.

Important Properties

HCV is a member of the flavivirus family. It is an enveloped virion containing a genome of single-stranded, positive-polarity RNA. It has no virion polymerase.

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 virion-encoded RNA polymerase. As a result, multiple subspecies (quasispecies) often occur in the blood of an infected individual at the same time. Genotypes 1a and 1b are the most common in the United States.

Summary of Replicative Cycle

The replication of HCV is uncertain because it has not been grown in cell culture. Other flaviviruses replicate in the cytoplasm and translate their genome RNA into large polyproteins, from which functional viral proteins are cleaved by a virion-encoded protease. This protease is the target of potent anti-HCV therapy (see treatment section). It is likely that HCV replication follows this model.

The replication of HCV in the liver is enhanced by a liver-specific micro-RNA called miR-122. This micro-RNA acts by increasing the synthesis of HCV mRNA. (Micro-RNAs are known to enhance cellular mRNA synthesis in many tissues.) In 2013, a clinical trial of an antisense nucleotide that bound to and blocked the activity of miR-122 showed prolonged reduction in HCV RNA levels in infected patients.

Transmission & Epidemiology

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 very common mode of transmission. Transmission via blood transfusion rarely occurs because donated blood containing antibody to HCV is discarded. Transmission via needle-stick 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 breast feeding.

HCV is the most prevalent blood-borne pathogen in the United States. (In the nationally reported incidence data, HCV ranks below HIV and HBV as a blood-borne 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 high-risk individuals for HCV antibody should be done. In addition, screening of those who were born between 1945 and 1965 should be done because they have a high rate of infection.

In the United States, about 1% of blood donors have antibody to HCV. People who share needles when taking intravenous drugs are very commonly infected. Commercially prepared immune globulin preparations are generally very safe, but several instances of the transmission of HCV have occurred. This is the only example of an infectious disease transmitted by commercial preparations of immune globulins.

Pathogenesis & Immunity

HCV infects hepatocytes primarily, but there is no evidence for a virus-induced 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 hepatocellular carcinoma, 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.

Alcoholism greatly enhances the rate of hepatocellular carcinoma in HCV-infected 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 hepatocellular carcinoma. (A report in 1998 that the core protein of HCV causes hepatocellular carcinoma in mice may lead to a greater understanding of oncogenesis by HCV.)

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 active hepatitis and cirrhosis occur in approximately 10% of these patients. For patients who clear the infection, it is not known whether reinfection can occur or whether there is lifelong immunity.

Clinical Findings

Clinically, the acute infection with HCV is milder than infection with HBV. 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 hepatocellular carcinoma are concerned. Note that a chronic carrier state occurs 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 autoimmune reactions, including vasculitis, arthralgias, purpura, and membranoproliferative glomerulonephritis. HCV is the main cause of essential mixed cryoglobulinemia. The cryoprecipitates often are composed of HCV antigens and antibodies.

Laboratory Diagnosis

HCV infection is diagnosed by detecting antibodies to HCV in an enzyme-linked immunosorbent assay (ELISA). 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, or resolved infection.

Because false-positive results can occur in the ELISA, a recombinant immunoblot assay (RIBA) should be performed as a confirmatory test. If the results of RIBA are positive, a polymerase chain reaction–based 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 RIBA, 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. The treatment of choice for chronic hepatitis C is a combination of peginterferon alfa-2a (Pegasys), ribavirin and a protease inhibitor (see next paragraph). Peginterferon is alpha interferon conjugated to polyethylene glycol. Polyethylene glycol significantly enhances the half-life of alpha interferon. In some patients, treatment significantly reduces viral replication, and viral RNA (viral load) becomes undetectable. HCV genotype 1 is less responsive to interferon and ribavirin than are genotypes 2 and 3. As a result, patients infected with genotype 1 are treated for 12 months, whereas those infected with genotypes 2 and 3 are usually treated for 6 months.

The addition of a protease inhibitor, either boceprevir (Victrelis), simeprevir (Olysio), or telaprevir (Incivek), to the combination of peginterferon and ribavirin significantly improved the duration of the suppression of viral replication of HCV genotype 1.

In 2013, the FDA approved the use of sofosbuvir (Sovaldi) for the treatment of chronic HCV infection caused by genotypes 1, 2, 3, and 4. It is a uridine analogue that inhibits the RNA polymerase of HCV. Sofosbuvir is effective either alone or in combination with ribavirin but does not require the use of interferon.

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 needle-stick injury; only monitoring is recommended.

Blood found to contain antibody is discarded—a procedure that has prevented virtually all cases of transfusion-acquired 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 antibody-positive 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 hepatocellular carcinoma and cirrhosis. Patients with chronic HCV infection and cirrhosis should be monitored with alpha-fetoprotein 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 highly active antiretroviral therapy (HAART) with caution because recovery of cell-mediated immunity (immune reconstitution) can result in an exacerbation of hepatitis. Consideration should be given to treat the HCV infection prior to starting HAART.

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 41–4).

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FIGURE 41–4 Hepatitis D virus. Note that hepatitis B surface antigen (HBsAg) forms the outer envelope and the genome consists of circular RNA. (Modified and reproduced with permission from Ryan K et al. Sherris Medical Microbiology. 3rd ed. Originally published by Appleton & Lange. Copyright 1994 McGraw-Hill.)

HDV is an enveloped virus with an RNA genome that is a single-stranded, negative-polarity, 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 self-cleave and self-ligate—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.

Transmission & Epidemiology

HDV is transmitted by the same means as is HBV (i.e., sexually, by blood, and perinatally). In the United States, most HDV infections occur in intravenous drug users who share needles. HDV infections occur worldwide, with a similar distribution to that of HBV infections.

Pathogenesis & Immunity

It seems likely that the pathogenesis of hepatitis caused by HDV and HBV is the same (i.e., the virus-infected 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 long-term 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, life-threatening hepatitis, chronic hepatitis, and liver failure is significantly higher.

Laboratory Diagnosis

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.

Treatment & Prevention

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, single-stranded 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. Chronic liver disease does not occur, and there is no prolonged carrier state.

The test for HEV antibody is not readily available; the diagnosis is therefore typically made by excluding HAV and other causes. There is no antiviral treatment and no vaccine. In 2007, a recombinant vaccine against HEV was shown to be safe and effective, but the vaccine is not available as of this writing.

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 hepatocellular carcinoma, 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 coinfected 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. (HGV is also known as GB virus C.)

SELF-ASSESSMENT 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, negative-polarity, single-stranded 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 globulins (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 double-stranded DNA as its genome and has a DNA polymerase in the virion.

(C) Health care personnel who sustain a needle-stick 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) 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 RNA-dependent 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 day care centers because the virus is transmitted primarily by the fecal–oral route.

7. Your patient is a 35-year-old 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 long-term 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 20-year-old woman with chronic hepatitis B that 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 27-year-old man with a history of intravenous 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) Peginterferon and ribavirin

(D) Zidovudine and lamivudine

(E) Zidovudine and ritonavir

ANSWERS

1. (A)

2. (C)

3. (D)

4. (B)

5. (A)

6. (B)

7. (D)

8. (C)

9. (C)

SUMMARIES OF ORGANISMS

Brief summaries of the organisms described in this chapter begin on page 648. 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 page 703. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.

1 Also 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.

3In the United States, donated blood is screened for HBsAg and antibodies to HBcAg, HCV, HIV-1, HIV-2, and HTLV-1. 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.