HEPATITIS A, B, D, AND E

HEPATITIS A, B, D, AND E

  1. 1
    Current Diagnosis

    Hepatitis A

    • Typical prodromal symptoms are nonspecific (i.e., fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, and weight loss). In about half of patients, prodromal symptoms are followed by icterus (i.e., jaundice, pruritus, and dark urine) lasting 2 weeks.

    • Serum aminotransferase levels increase to 10 to 20 times the upper limit of normal during the prodromal phase. Total serum bilirubin rises but rarely exceeds 10 mg/dL during the icteric phase. Biochemical recovery usually occurs within 3 months.

    • Acute hepatitis A virus (HAV) infection is diagnosed by the presence of anti-HAV immunoglobulin M (IgM). Anti-HAV IgG appears in the convalescent phase and remains detectable for life. Anti-HAV IgG positivity with the absence of anti-HAV IgM antibodies reflects past exposure or vaccination. The antibody test for HAV usually includes total antibodies (IgM and IgG); thus, diagnosis of acute hepatitis A requires specific anti-HAV IgM testing.

    Hepatitis B

    • Acute hepatitis B virus (HBV) infection may be asymptomatic or present with nonspecific symptoms of anorexia, nausea, and fever with development of icterus, pruritus, right upper quadrant pain, or, rarely, acute liver failure. Globally, it is a major cause of chronic hepatitis.

    • Serum alanine aminotransferase (ALT) levels peak with the onset of symptoms.

    • Suspected acute HBV infection is diagnosed by the detection of hepatitis B surface antigen (HBsAg), hepatitis B e-antigen (HBeAg), IgM antibody to hepatitis B core antigen (anti-HBc), and HBV DNA in serum in the appropriate clinical setting. Anti-HBc IgM is detected during acute HBV infection and may be detected during reactivation of chronic HBV infection.

    • Chronic infection is defined as the persistence of serum HBsAg for greater than 6 months. If HBsAg is present, serum HBeAg, antibody to hepatitis B e-antigen (anti-HBe), HBV DNA, and serum ALT are used to determine the four phases of chronic infection (immune tolerant, HBeAg-positive and HBeAg-negative immune active, and inactive carrier).

  2. 2
    Current Therapy

    Hepatitis A

    • Treatment is predominately supportive. Avoid hepatotoxic medications and drugs metabolized by the liver. Acute liver failure with encephalopathy and impaired synthetic function occurs rarely and is more common in patients older than 50 years of age and/or those who have coexisting chronic HBV or hepatitis C virus (HCV) infections.

    • Prevention includes administration of the inactivated or attenuated vaccine for children at age 1 year or older and for at-risk populations (e.g., intravenous drug users, travelers to regions with high or intermediate HAV rates, men who have sex with men, patients with chronic liver disease or clotting factor disorders).

    • Preexposure passive immunization with pooled human anti-HAV immunoglobulin may be used for those at high or intermediate risk of hepatitis A virus exposure.

    • Postexposure passive immunization with pooled human anti-HAV immunoglobulin may be used for close personal contacts of an individual with laboratory-confirmed HAV infection, staff and attendees of child care centers if one or more children and/or staff are diagnosed with HAV infection, and food handlers during a common-source exposure. Concurrent immunization with inactivated or attenuated vaccines for these at-risk contacts is also warranted.

    Hepatitis B

    • Acute HBV infection in an adult generally only requires supportive care owing to high rates of spontaneous recovery. For people with evidence of acute liver failure, prompt institution of antiviral therapy with a potent nucleos(t)ide analog and referral to a transplant center is recommended. Peginterferon iscontraindicated in persons with acute liverfailure.

    • Chronic HBV treatment goals are sustained suppression of HBV DNA to prevent the development of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Cure of chronic HBV infection is currently not possible. Treatment recommendations for chronic HBV differ but are generally indicated for HBeAg-positive subjects with confirmed HBV DNA greater than 2000 to 20,000 IU/mL and serum ALT two or more times the upper limit of normal, and for HBeAg-negative patients with HBV DNA greater than or equal to 2000 IU/mL with serum ALT two or more times the upper limit of normal and severe liver disease with liver biopsy– proven moderate to severe inflammation and/or moderate fibrosis. Treatment decisions outside these parameters should be individualized based on the risk for complications and the risk of therapy. Four agents are considered first line—peginterferon, entecavir, tenofovir, and tenofovir alafenamide—based on their safety, effectiveness, and low rates of antiviral resistance.

    Peginterferon is generally recommended for those who prefer a finite course of treatment and who have clinical and laboratory features predictive of a response to peginterferon (high ALT, low HBV DNA, young age, female gender, and HBV genotype A or B). Peginterferon is contraindicated in persons with decompensated cirrhosis, autoimmune illnesses, or active psychiatric illness.

    Nucleos(t)ide analogs are more potent inhibitors of HBV DNA replication, generally better tolerated than peginterferon, and usually administered long term. The ideal endpoint of treatment is loss of HBsAg, though it is rarely observed with any therapy.

    • Prevention includes completion of a three-dose HBV vaccination series for all children by 18 months of age with the first dose administered within 24 hours of birth. Infants whose mothers are HBsAg positive or whose HBsAg status is unknown should receive the last dose by 6 months of age.

    • Hepatitis B immune globulin and HBV vaccination is recommended at birth for infants whose mothers are HBsAg positive. In mothers with viral loads greater than 200,000 IU/mL, antiviral therapy with tenofovir, telbivudine (Tyzeka), or lamivudine in the third trimester of pregnancy can be considered.

    Five viruses hepatitis A through E account for the majority of cases of acute and chronic viral hepatitis. Chronic hepatitis is arbitrarily defined as the persistence of serum aminotransferase levels for 6 months or more. Complications of chronic hepatitis (predominantly cirrhosis and hepatocellular carcinoma) account for the majority of morbidity and mortality due to viral hepatitis. Effective vaccines are available for the prevention of hepatitis A, B, and D infections. In addition, safe and effective therapy is available for treatment of chronic hepatitis B and C. Therefore, it is important to screen individuals who are at high risk for chronic viral hepatitis to provide them access to care, reduce complications, and offer counseling to prevent transmission of infection.

  3. 3
    Hepatitis A Virus

    Introduction

    HAV is a positive-sense, single-stranded RNA virus of the Hepatovirus genus belonging to the Picornaviridae family. Its genome encodes four structural and seven nonstructural proteins. Four genotypes have been identified, but there is only one serotype. Therefore, exposure to one HAV genotype confers immunity to all genotypes.

    Natural History

    HAV is a cause of acute hepatitis and acute liver failure but not chronic hepatitis (Table 1). In ~ 5% of cases, a prolonged cholestasis lasting more than 3 months may occur, and in ~ 10% of patients, a relapsing hepatitis has been observed up to 6 months after the acute illness with recrudescence of symptoms and flare of hepatitis. Cases of relapsing hepatitis continue to remain infectious with fecal shedding of the virus. These atypical presentations of acute hepatitis A should not be mistaken for evolution to chronic hepatitis, as resolution is the rule. Recovery of HAV is associated with development of lifelong immunity.

    Table 1

    Hepatitis A, B, D, and E Characteristics

    Abbreviation: HCC = hepatocellular  carcinoma.

    *  Not available in United States

    #  Higher in pregnancy at 5-20%

    HAV replication occurs in hepatocytes and the virus is shed into the intestine via the biliary system. Viral levels peak during the asymptomatic period and virus shedding continues until around 2 weeks into the icteric phase. HAV is detectable in the blood, but levels are 1000-fold higher in the feces than in the blood. Children may shed the virus longer than adults.

    The incubation period usually lasts 14 to 28 days. This is followed by the onset of symptoms. The presence and severity of symptoms are variable and age related. Typically, more than 70% of adult patients have a symptomatic illness compared with only 10% of children younger than the age of 10 years. Typical symptoms are nonspecific and include fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, and weight loss. This prodromal phase is followed by an icteric phase in 40% to 70% of patients with jaundice, pruritus, and dark urine. Physical examination findings are usually unremarkable, but hepatomegaly may be observed. Extrahepatic manifestations are uncommon and may include an evanescent rash and arthralgias.

    Laboratory studies during the prodromal phase reveal elevated serum aminotransferase levels greater than 10 to 20 times the upper limit of normal. During the icteric phase, total serum bilirubin rises but generally does not exceed 10 mg/dL. In most patients, jaundice lasts 2 weeks and a complete clinical and biochemical recovery can be expected in 2 to 3 months.

    Epidemiology

    Hepatitis A occurs throughout the world (Figure 1), either sporadically or in epidemics. The prevalence of HAV correlates with the level of sanitation and hygiene. In developing countries, more than 90% of children are infected before the age of 10. In developed countries including the United States, infection rates are low. Lack of exposure at a young age leads to higher susceptibility in certain high- risk adults including travelers to endemic areas, injection drug users, and men who have sex with men.

    FIGURE 1    Global prevalence of hepatitis A and infection  risk.

    Hepatitis A has a worldwide prevalence. Prevalence is related to the regional income, sanitation, and hygiene. High-income areas (e.g., North America, Western Europe, Australia, New Zealand, Japan, the Republic of Korea, and Singapore) have low levels of hepatitis A virus (HAV) endemicity and subsequently a high proportion of susceptible adults. Low-income regions (Sub-Saharan Africa and parts of South Asia) have high endemicity levels and very few susceptible adolescents and adults. Middle-income regions have a mix of intermediate and low endemicity levels.

    In the United States, HAV infection rates have declined by 95% since the introduction of mandatory childhood vaccination in 1995. The overall incidence rate in 2014 was 0.4% per 100,000 persons. HAV is spread primarily by the fecal–oral route through the ingestion of contaminated food or water. Humans are the only known reservoir of the virus.

    Diagnosis

    Serologic testing for antibody to HAV can confirm the diagnosis of acute infection, past exposure, and immunity to the virus. Acute HAV infection is diagnosed by the presence of anti-HAV IgM. Anti-HAV IgG appears in the convalescent phase of infection and remains detectable for life. Past exposure or vaccination confers immunity and is reflected by anti-HAV IgG positivity with the absence of anti-HAV IgM antibodies. The antibody test for HAV usually includes total antibodies (IgM and IgG). Thus, to diagnose acute hepatitis A, it is important to order anti-HAV IgM.

    Treatment

    Given the self-limiting nature of acute hepatitis A, treatment is predominately supportive. Caution should be taken when using hepatotoxic medications or medications metabolized predominately in the liver. Rarely, acute liver failure with encephalopathy and impaired synthetic function can occur. The patients at highest risk for this complication are generally older than 50 years of age and may have coexisting chronic HBV or HCV infections. Individuals presenting with acute liver failure are more appropriately managed at a liver transplant center.

    Prevention

    Both inactivated and attenuated vaccines have been licensed against HAV. Inactivated vaccines include HARVIX (GlaxoSmithKline), VAQTA (Merck), TWINRIX (a combined hepatitis A and B vaccine from GlaxoSmithKline), AVAXIM (Sanofi Pasteur),2 EPAXAL (Crucell),2 and HEALIVE (Sinovac).2 The only live attenuated vaccine is BIOVAC-A (Pukang).2 According to the World Health Organization (WHO), routine childhood vaccination for HAV is generally recommended in areas with intermediate infection rates. In the United States, the Advisory Committee on Immunization Practices recommends that all children at age 1 year be vaccinated. Other at-risk populations for whom vaccination is recommended include intravenous drug users, travelers to regions with high or intermediate HAV rates, men who have sex with men, and patients with chronic liver disease or clotting factor disorders.

    Passive immunization with immunoglobulin may also be used for preexposure protection among individuals who are at high or intermediate risk of HAV exposure. Pooled human anti-HAV immunoglobulins (GamaSTAN [IGIM]) decrease the HAV infection risk by 90% for up to 3 months. Passive immunization is also recommended for postexposure protection in cases of close personal contacts to an individual with laboratory-confirmed HAV infection, to staff and attendees of child care centers if one or more children and/or staff are diagnosed with HAV infection, and to food handlers during a common-source exposure. Concurrent immunization for HAV in these at-risk contacts is also warranted.

  4. 4
    Hepatitis E

    Introduction

    Hepatitis E virus (HEV) is a nonenveloped, single-stranded, positive- sense RNA virus of ~ 7300 bases in length and the sole member of the Hepeviridae family. Its genome contains three overlapping open reading frames. ORF1 encodes four nonstructural proteins, ORF2 encodes the capsid protein, and ORF3 a protein of unknown function. Four genotypes are known to infect humans, but similar to HAV, only one serotype exists and infection with one strain confers immunity to all others. HEV is likely a zoonosis with multiple nonhuman vectors.

    Natural History

    HEV is a cause of acute hepatitis and acute liver failure (see Table 1). It can cause chronic hepatitis in immunocompromised individuals.

    The majority of acute HEV infections are asymptomatic or minimally symptomatic. The incubation period is between 15 and 60 days, and if symptoms arise, they generally consist of anorexia, nausea, vomiting, diarrhea, and abdominal pain. Acute HEV infection rarely causes jaundice, and most symptoms resolve within 6 weeks from onset. A notable exception to the generally favorable outcome is an increased risk of acute liver failure among pregnant women during the second and third trimesters in endemic regions. This leads to a high maternal mortality rate of 15% to 25% and worse maternofetal outcomes in third-trimester infections. Acute HEV infection may also be associated with a lymphocytic destructive cholangitis.

    Chronic HEV infection is defined as the presence of HEV RNA in the serum or stool for more than 6 months. It is uncommon and has been observed in solid-organ transplant recipients, HIV-positive subjects, and other immunocompromised hosts. Chronic HEV infection has only been reported with HEV genotype 3 infections. It is unknown if other HEV genotypes can cause chronic HEV infection.

    Development of cirrhosis has been described as a consequence of chronic infection.

    Epidemiology

    HEV is found worldwide and can be divided into three distinct geographical patterns: highly endemic, endemic, and nonendemic (sporadic) (Figure 2). Large waterborne epidemics in highly endemic regions are due to infection with HEV genotypes 1 and 2 in Central America, Africa, and Asia. Sporadic cases of HEV in developed countries (Europe, North America, and Far East Asia) are due to HEV genotypes 3 and 4. The reservoir for autochthonous HEV is unknown but thought to be domestic swine. Sporadic cases may occur in travelers to endemic areas. Interestingly, males are more affected than females in sporadic infections, but this gender bias is not observed during epidemics. HEV is spread by the fecal–oral route, usually through ingestion of contaminated water.

    FIGURE 2    Global prevalence of hepatitis E virus. Hepatitis E is  found worldwide. High endemic areas, defined by greater than or equal to 25% prevalence of sporadic non-A, non-B hepatitis, include parts of Central America and Mexico, Africa, the Middle East, and most of  Asia.

    Endemic areas, defined as less than 25% prevalence of sporadic non- A, non-B hepatitis, include the United States, Europe, Russia, and parts of South America. Remaining regions are regarded as nonendemic.

    Diagnosis

    There are no commercially licensed tests for HEV detection in the United States. Testing is limited to research laboratories and can be obtained through the Centers for Disease Control and Prevention.

    The diagnosis of acute HEV is made by detection of anti-HEV IgM in serum or HEV RNA in stool or serum. Anti-HEV IgG has limited utility in diagnosis of HEV infections and may be a serologic marker for past infection. In immunocompromised patients, antibody testing can be falsely negative, making HEV RNA the more reliable marker of acute and chronic infection. Chronic HEV is diagnosed when HEV RNA is present in sera or stool for more than 6 months in suspected cases.

    Treatment

    Since most acute HEV infections are mild, the treatment is generally supportive. Patients who develop acute liver failure should be managed at a liver transplant center. The initial approach to management of chronic HEV infection in posttransplant recipients is to reduce the level of immunosuppression. If this is unsuccessful, then antiviral therapy with peginterferon (Pegasys)1 or ribavirin (Rebetol)may be considered. In immunocompromised individuals therapy with peginterferon1 or ribavirin1 may be considered.

    Prevention

    Prevention of transmission in travelers to endemic areas includes avoidance of tap water and consumption of street foods, raw vegetables, or raw or undercooked meats, such as pork and seafood. A commercially available vaccine for HEV, HECOLIN2 (Xiamen Innovax Biotech), has been available in China since 2012.

  5. 5
    Hepatitis B

    Introduction

    HBV is a partially double-stranded DNA virus of ~ 3200 bases belonging to the Hepadnaviridae family. HBV consists of an outer lipid shell that surrounds a nucleocapsid consisting of the viral DNA and the polymerase. HBV has four overlapping reading frames (core, surface, polymerase, and x), which encode for seven viral proteins.

    HBsAg is the marker of infection and HBeAg is a marker of high viral replication and infectivity. The virus is classified into 10 major genotypes (A through J) that have a distinct geographical distribution. Four major serotypes have been described. Humans and old world primates (e.g., chimpanzees) are the only known hosts.

    Natural History

    HBV is a cause of acute hepatitis and acute liver failure (see Table 1). Globally, it is a major cause of chronic hepatitis. Infection with HBV is notable for a long incubation period ranging from 1 to 6 months. The majority (two-thirds) of persons with acute HBV infection are asymptomatic, one-third have an icteric presentation, and less than 1% present with acute liver failure. Symptoms of acute HBV are nonspecific and include anorexia, nausea, pruritus, and right upper quadrant pain. Symptoms usually resolve in ~ 1 to 3 months. Serum ALT levels peak with the onset of symptoms. The outcome of acute hepatitis B is strongly influenced by age at exposure. Resolution of acute infection occurs in 95% of persons exposed as adults, but chronic infection ensues in more than 90% of persons exposed as infants.

    The natural history of chronic HBV infection depends on a complex interplay between the virus and the host immune response. Chronic HBV infection is often viewed in four phases (immune tolerant, HBeAg-positive and HBeAg-negative immune active, and inactive carrier) based on HBeAg status and serum HBV DNA and ALT levels (Figure 3). This classification is useful for providing advice on prognosis and need for treatment. Approximately 25% to 40% of persons with chronic infection will be at risk for development of cirrhosis. The 5-year cumulative incidence of cirrhosis in untreated chronic HBV infection is 8% to 20%. Once cirrhosis develops, the 5- year cumulative incidence of decompensated liver disease (ascites, variceal hemorrhage, hepatic encephalopathy) is approximately 20%, and the annual risk of hepatocellular carcinoma is 2% to 5%. Persons who have resolved chronic infection (cleared HBsAg) should be informed of the risk for viral reactivation with use of chemotherapy or other immunosuppressive therapies.

    FIGURE 3    Phases of chronic hepatitis B virus (HBV)  infection.

    Chronic hepatitis B can be viewed in phases defined by HBeAg status and serum HBV DNA and ALT levels. The initial phase is the immune- tolerant phase, characterized by HBeAg positivity, high HBV DNA level (> 107 IU/mL), and persistently normal ALT levels. This is seen only in persons who acquire the infection at birth or infancy and that persists for two to three decades of life. The next phase is the immune-active phase, defined by continued HBeAg positivity, high HBV viral  load (> 105 IU/mL), and elevated ALT levels. The next phase is characterized by loss of HBeAg and development of anti-HBe and heralds a transition from a phase of high viral replication to one of low replication. The viral load is typically less than 103 IU/mL and serum ALT is normal. This phase is termed the inactive carrier phase. A proportion of individuals develop raised HBV DNA and ALT levels after HBeAg seroconversion. These persons are said to have transitioned to the immune-escape or HBeAg-negative immune-active  phase.

    Epidemiology

    An estimated 2 billion people worldwide have evidence of past HBV infection, and of these an estimated 240 million have chronic HBV infection. The prevalence of HBV infection is declining worldwide owing to the availability of an effective vaccine and implementation of successful vaccination programs. The prevalence of HBsAg, the serologic marker of chronic infection, is highest in Sub-Saharan Africa and Central Asia (≥ 8%) (see Figure 2) and lowest (< 2%) in Western Europe, Australia, Canada, and the United States (except Alaska) (Figure 4). HBV is transmitted vertically, sexually, or through percutaneous routes and is more infectious than human immunodeficiency virus or hepatitis C virus. Individuals considered at high risk for acquiring HBV infection should be screened for chronic hepatitis B by testing for HBsAg (Table 2).

    FIGURE 4    Global prevalence of chronic hepatitis B virus  (HBV). Hepatitis B is found worldwide with varying geographical prevalence. High-prevalence areas defined as a prevalence of HBsAg greater than or equal to 8% include West Sub-Saharan Africa and  Mongolia.

    Regions of high intermediate prevalence, defined as HBsAg prevalence of 5% to 7%, include China, Southeast Asia, and the remainder of Sub- Saharan Africa. Regions of low to intermediate prevalence, defined as HBsAg prevalence of 2% to 4%, include the Mediterranean region, India, the Middle East, Australia, and Japan. Regions with low prevalence, defined as HBsAg prevalence of less than or equal to 2%, include North America and Western Europe. Overall, the prevalence of HBV is declining worldwide.

    Table 2

    Centers for Disease Control and Prevention Guidelines for Hepatitis B Virus (HBV) Screening

    Populations recommended or required for routine testing

    for chronic HBV infections

    Persons born in regions of high and intermediate HBV

    endemicity (HBsAg prevalence > 2%)

    U.S.-born persons not vaccinated as infants whose parents

    were born in regions with high HBV endemicity (> 8%) Injection drug users

    Men who have sex with men

    Persons with elevated alanine aminotransferase/aspartate aminotransferase of unknown etiology

    Donors of blood, plasma, organs, tissues, or semen Hemodialysis patients

    All pregnant women

    Persons needing immunosuppressive therapy Infants born to HBsAg-positive mothers

    Household, needle-sharing, or sex contacts of persons known to be HBsAg positive

    HIV-positive persons

    Persons who are the sources of blood or body fluids for exposures the might require postexposure prophylaxis (e.g., needlestick, sexual assault)

    Diagnosis

    A number of serologic markers (viral antigens and antibodies to the viral antigens) and nucleic acid testing are available to diagnose acute and chronic HBV infection. Cases of suspected acute HBV infection are diagnosed by the detection of HBsAg, HBeAg, IgM anti-HBc, and HBV DNA in serum in the appropriate clinical setting. Although anti- HBc IgM is detected during acute HBV infection, it is not specific for acute hepatitis B and may be seen during reactivation of chronic HBV infection.

    Chronic infection is defined as persistence of HBsAg for greater than 6 months in serum. If HBsAg is present, it is advised to check HBeAg, anti-HBe, HBV DNA, and serum ALT to determine the phase of infection.

    Treatment

    Acute HBV infection in an adult is associated with a high rate of spontaneous recovery, and antiviral treatment is rarely required. Supportive care is advised. For persons with evidence of acute liver failure, prompt institution of antiviral therapy with a potent nucleos(t)ide analog and referral to a transplant center is recommended. Peginterferon is contraindicated in persons with acute liver failure.

    The goals of treatment of chronic HBV are sustained suppression of HBV DNA to prevent the development of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Cure of chronic HBV infection is currently not possible because of persistence of covalently closed circular DNA within the hepatocyte nucleus. Treatment recommendations differ among regional guidelines, but treatment is generally indicated for HBeAg-positive subjects with confirmed HBV DNA greater than 2000 to 20,000 IU/mL and serum ALT two or more times the upper limit of normal, and for HBeAg-negative patients with HBV DNA greater than or equal to 2000 IU/mL with serum ALT two or more times the upper limit of normal and severe liver disease with liver biopsy–proven moderate to severe inflammation and/or moderate fibrosis. The decision to treat persons outside these parameters should be individualized based on their risk for complications and risk of therapy. Eight agents are approved for the treatment of chronic HBV infection: two interferon preparations, interferon alfa-2b (Intron A) and peginterferon alfa-2a (Pegasys), and six nucleos(t)ide analogs: lamivudine (Epivir HBV), adefovir (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka), tenofovir disoproxil fumarate (Viread), and tenofovir alafenamide (Vemlidy).

    Four agents are considered first line—peginterferon, entecavir, tenofovir, and tenofovir alafenamide—based on their safety, effectiveness, and low rates of antiviral resistance. Peginterferon is generally recommended in persons who would prefer a finite course of treatment and who have clinical and laboratory features predictive of a response to peginterferon (high ALT, low HBV DNA, young age, female gender, and HBV genotype A or B). Peginterferon is contraindicated in persons with decompensated cirrhosis, autoimmune illnesses, or active psychiatric illness. Nucleos(t)ide analogs are more potent inhibitors of HBV DNA replication and generally better tolerated than peginterferon. They are usually administered long term. The ideal endpoint of treatment is HBsAg loss, but this is rarely observed with any therapy (< 10% with interferon and after 5 years of therapy with nucleos(t)ide analogs).

    Prevention

    An effective vaccine against HBV has been available since 1981. In the United States, the Advisory Committee on Immunization Practices has recommended that all children complete the series of three vaccinations by 18 months of age with the first dose administered within 24 hours of birth. Infants whose mothers are HBsAg positive or whose HBsAg status is unknown should receive the last dose by 6 months of age. Hepatitis B immune globulin and HBV vaccination is recommended at birth for infants whose mothers are HBsAg positive to prevent maternal–infant transmission of HBV. In mothers with viral loads greater than 200,000 IU/mL, antiviral therapy with tenofovir, telbivudine (Tyzeka), or lamivudine in the third trimester of pregnancy can be considered.

  6. 6
    Hepatitis D

    Introduction

    Hepatitis D virus (HDV) is a viroid that is dependent on HBV for its lifecycle. The genome consists of a negative-sense, single-stranded circular RNA virus of ~ 1600 bases. The virus has an outer lipoprotein envelope HBsAg derived from HBV and is attached to a single structural protein, the HDV antigen (HDAg). There are eight known genotypes. Immunity to HBV prevents HDV infection.

    Natural History

    HDV is a cause of acute hepatitis, acute liver failure, and chronic hepatitis (see Table 1). HDV infection can occur either simultaneously with HBV (referred to as coinfection) or as an infection in a patient with chronic HBV infection (referred to as superinfection). The outcome of HBV/HDV coinfection depends on the course of acute hepatitis B infection and is generally self-limiting with a low risk of chronicity (~ 5%). In contrast, HDV superinfection of a chronic HBV carrier results in chronic HDV infection in more than 90% of cases.

    Acute liver failure is observed more commonly with coinfection than superinfection. Chronic HDV infection has a variable course, from an asymptomatic carrier to cirrhosis and decompensated liver disease. In general, HDV infection is associated with more rapid progression to cirrhosis and decompensated liver disease and a higher rate of hepatocellular carcinoma as compared with HBV monoinfection.

    Epidemiology

    In developed countries, the prevalence of HDV has declined as a consequence of widespread vaccination against hepatitis B. Chronic HDV infection is predominately seen in intravenous drug users or hemophiliacs requiring frequent transfusions. HDV is prevalent in the Amazon basin, Africa, the Mediterranean basin, Central Asia, Mongolia, and Russia (Figure 5). HDV genotype 1 can be found worldwide, but all other genotypes are restricted to specific geographic areas.

    FIGURE 5    Global prevalence of hepatitis D virus. Hepatitis D is  found globally but prevalence varies among geographic regions. The highest prevalence is observed in Central Africa, Central Asia, and the Amazon. Intermediate-prevalence regions include West Africa and Eastern Europe. Low-prevalence regions include North America, most of Western Europe, and Australia.

    HDV is spread by the same routes as HBV infection and is efficiently transmitted by parenteral and sexual exposure. In contrast to HBV, vertical transmission is not a common mode of transmission. Transmission cannot occur in the absence of HBsAg.

    Diagnosis

    Testing for hepatitis D should be considered in persons presenting with acute hepatitis B who have additional risk factors for HDV, including a history of injection drug use; persons from endemic regions who present with a severe or protracted hepatitis; patients with chronic hepatitis B who develop an acute hepatitis of undetermined origin; and persons with HBsAg-positive chronic hepatitis B from endemic regions. Total (IgM and IgG) and anti-HDV IgM are the only commercially available assays in the United States. Initial testing for HDV should be with total anti-HDV. Chronic infection should be confirmed by a reverse transcriptase polymerase chain reaction assay for HDV RNA.

    Treatment

    The goals of treatment are long-term suppression of both HDV and HBV to prevent the development of cirrhosis, hepatocellular carcinoma, and liver-related death. There is no effective treatment for HDV. Interferon alfa has been used for treatment of HDV. The most effective dose and duration of treatment have not been established.

    Peginterferon administered for 48 to 72 weeks results in sustained HDV RNA suppression after 6 months off therapy in 17% to 43% of patients. Liver transplantation with the use of hepatitis B immune globulin is an option for patients with decompensated liver disease. Novel agents blocking viral entry and posttranslational prenylation are currently being investigated in clinical studies.

    Financial Disclosure: The authors are employees of the U.S. government and have no financial conflicts of interest to disclose.

    Acknowledgments: This work is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

  7. 7
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    Hughes S.A., Wedemeyer H., Harrison P.M. Hepatitis delta virus. Lancet. 2011;378(9785):73–85.

    Matheny S.C., Kingery J.E. Hepatitis A. Am Fam Physician.

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    Trépo C., Chan H.L., Lok A. Hepatitis B virus infection. Lancet.

    2014;384(9959):2053–2063.

    2  Not available in the United  States.

    1  Not FDA approved for this  indication.

    2  Not available in the United  States.

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