Hepatitis virus

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Hepatitis virus
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Overview of Hepatitis Virus
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Viral Hepatitis - Overview

Type of Hepatitis
A
B
C
D
E
Source of
feces
blood/
blood/
blood/
feces
virus
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
permucosal
permucosal
permucosal
Chronic
no
yes
yes
yes
no
infection
Prevention
pre/post-
pre/post-
blood donor
pre/post-
ensure safe
exposure
exposure
screening
exposure
drinking
immunization
immunization
risk behavior
immunization
water
modification
risk behavior
modification
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• Human cytomegalovirus
• Epstein-Barr virus
• Herpes simplex virus
• Yellow fever virus
• Rubella.

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Hepatitis A virus
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Structure

• Small, non-enveloped icosahedral particle,
• 27 nm in diameter
• ssRNA

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Replication

• Unlike other picornaviruses, however, HAV is not
  cytolytic and is released by exocytosis.
• Laboratory isolates of HAV have been adapted to
  growth in primary and continuous monkey kidney
  cell lines, but clinical isolates are very
  difficult to grow in cell culture.

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Resistance
Stable to acid at pH 3 Solvents(ether,chlorofor
m) detergents saltwater,groundwater(months) dry
ing(stable) temperature 4? weeks 56?for
30minutes stable 61?for 20minutes partial
inactivation
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Resistance
Inactivated by chlorine treatment of drinking
water formalin(0.35,37?,72hours) acetic
acid(2,4hours) B-propiolactone???(0.25,1hours)
Ultraviolet radiation(2µW/?2/min)
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Hepatitis A Virus Transmission

• Virus can be transmitted via fecal-oral
  routeingestion of contaminated food and water
  can cause infection
• HAV in shellfish is from sewage-contaminated
  water
• Virus can be transmitted by food handlers,
  day-care workers, and children.

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Concentration of Hepatitis A Virusin Various
Body Fluids
Feces
Body Fluid
Serum
Saliva
Urine
100
102
104
106
108
1010
Infectious Doses per ml
Source Viral Hepatitis and Liver Disease
19849-22 J Infect Dis 1989160887-890
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Geographic Distribution of HAV Infection
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
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Age-specific Mortality Due to Hepatitis A

Age group
Case-Fatality
(years)
(per 1000)
lt5
3.0
5-14
1.6
15-29
1.6
30-49
3.8
gt49
17.5
Total
4.1
Source Viral Hepatitis Surveillance Program,
1983-1989
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Hepatitis A - Clinical Features

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Hepatitis A - Clinical Features

• Milder disease than Hepatitis B
• asymptomatic infections are very common,
  especially in children.
• Adults, especially pregnant women, may develop
  more severe disease
• no chronic form of the disease.
• Complications Fulminant hepatitis is rare 0.1
  of cases

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Pathogenesis
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Pathogenesis of HAV

• HAV replicates slowly in the liver without
  producing apparent cytopathological effects
  (CEPs). In the absence of cytolysis, the virus
  readily establishes a persistent infection.
• Jaundice, resulting from damage to the liver
• Antibody is detected and cell-mediated immune
  responses to the virus

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For example

• An epidemic of HAV that occurred in Shanghai,
  China, in 1988 in which 300,000 people were
  infected with the virus resulted from eating
  Anadara subcrenata obtained from a polluted
  river.

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Time course of HAV infection
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Immunity

• Antibody protection against reinfection is
  lifelong

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Laboratory Diagnosis

• Viral particles in the stool, by electron
  microscopy
• Specific IgM in serum
• PCR HAV-specific sequences in stool

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Treatment, Prevention and Control

• Prophylaxis with immune serum globulin given
  before or early in the incubation period
• A killed HAV vaccine has been approved and is
  available for use in children and adults at high
  risk for infection.
• A live HAV vaccine has been developed in China.

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Hepatitis B virus
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Introduction

• approximately 350 million people are infected
  globally with HBV.

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Structure

• Small, enveloped DNA
• The genome a small, circular, partly
  double-stranded DNA of 3200 base
• Although a DNA virus, it encodes a reverse
  transcriptase and replicates through an RNA
  intermediate.

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Structure

• Dane particle, is 42 nm in diameter.
• Resist to treatment with ether, a low pH,
  freezing, and moderate heating. This helps
  transmission from one person to another.

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Decoy Particles

• HBsAg-containing particles are released into the
  serum of infected people and outnumber the actual
  virions.
• Spherical or filamentous
• They are immunogenic and were processed into the
  first commercial vaccine against HBV.

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Structure

• HBcAg HBsAg HBeAg

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15-25nm
42nm
2020200nm
HBsAg
28nm
HBcAg
DNA
HBeAg
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Replication

• HBV has a very defined tropism for the liver.
• Its small genome also necessitates economy, as
  illustrated by the pattern of its transcription
  and translation.
• In addition, HBV replicates through an RNA
  intermediate and produces and release antigenic
  decoy particles.

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Replication

• The entire genome can also be integrated into the
  host cell chromatin.
• HBsAg, but not other proteins, can often be
  detected in the cytoplasm of cells containing
  integrated HBV DNA.
• The significance of the integrated DNA in the
  replication of the virus is not known, but
  integrated viral DNA has been found in
  hepatocellular carcinomas.

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Global Patterns of Chronic HBV Infection

• High (gt8) 45 of global population
• lifetime risk of infection gt60
• early childhood infections common
• Intermediate (2-7) 43 of global population
• lifetime risk of infection 20-60
• infections occur in all age groups
• Low (lt2) 12 of global population
• lifetime risk of infection lt20
• most infections occur in adult risk groups

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High-risk groups for HBVinfection

• People from endemic regions
• Babies of mothers with chronic HBV
• Intravenous drug abusers
• People with multiple sex partners
• Hemophiliacs and other patients requiting blood
  and blood product treatments
• Health care personnel who have contact with blood
• Residents and staff members of institutions for
  the mentally retarded

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Concentration of Hepatitis B Virus in Various
Body Fluids

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What determines the development of chronic vs.
acute infection

• Age (chronic infections decrease with increasing
  age)
• Sex Syndrome Males Females
• Chronic Infection 1.5 1
• Cirrhosis 3 1
• PHC 6 1
• Route of infection (oral/sexual infections give
  rise to less chronic cases than serum infection

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Hepatitis B - Clinical Features

• Incubation period Average 60-90 days
• Range 45-180 days
• Clinical illness (jaundice) lt5 yrs,
  lt10 gt5 yrs, 30-50
• Acute case-fatality rate 0.5-1
• Chronic infection lt5 yrs, 30-90 gt5
  yrs, 2-10
• Premature mortality fromchronic liver
  disease 15-25

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Outcome of Hepatitis B Virus Infection by Age at
Infection
100
100
80
80
60
60
Chronic Infection
Symptomatic Infection ()
Chronic Infection ()
40
40
20
20
Symptomatic Infection
0
0
1-6 months
7-12 months
Older Children and Adults
Birth
1-4 years
Age at Infection
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Pathogenesis(1)

• The virus starts to replicate within 3 days of
  its acquisition,
• Symptoms may not be observed for 45 days of
  longer, depending on the infectious dose, the
  route of infection, and the person.

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Pathogenesis(2)

• Hypoimmune response.
• IFN?,HLA-I??CTL?(An insufficient T-cell
  response )
• Cell mediated immunopathogenic damage.
• CTL ?acute hepatitis/chronic hepatitis

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Pathogenesis (3)

• Immune complexes formed between HBsAg and
  anti-HBs contribute to the development of
  hypersensitivity reactions, leading to problems
  such as vasculitis???, arthralgia???, rash, and
  renal damage.

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Pathogenesis(4)

• Pathogenic damage caused by autoimmunity
• liver specific protein(LSP)
• Viral variation
• HBeAg

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Clinical Syndromes
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Major eterminants of acute and chronic HBV
infection
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Acute Infection
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Symptoms of Acute Infection
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Clinical outcomes of acute hepatitis B infection
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The serological events associated with the
typical course of acute HBV disease
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Typical Serologic Course Acute Hepatitis B Virus
Infection with Recovery
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titer
anti-HBs
IgM anti-HBc
HBsAg
0
4
8
12
16
24
28
32
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100
20
36
Weeks after Exposure
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Chronic Infection

• Chronic hepatitis occurs in 5 to 10 of people
  with HBV infections, usually after mild or
  inapparent initial disease.
• Detected by the finding of elevated liver enzyme
  levels

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Development of the chronic HBV carrier state
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Typical Serologic Course Progression to Chronic
HBV Infection
Acute (6 months)
Chronic (Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
IgM anti-HBc
Years
0
4
8
16
20
24
28
36
12
32
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Weeks after Exposure
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Primary Hepatocellular Carcinoma

• The WHO estimates that 80 of all cases of PHC
  can be attributed to chronic HBV infections.
• HBV may induce PHC by promoting continued liver
  repair and cell growth in response to tissue
  damage or by integrating into the host chromosome
  and stimulating cell growth directly.

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Lab. Diagnosis

• The initial diagnosis of hepatitis can be made on
  the basis of the clinical symptoms and the
  presence of liver enzymes in the blood.
• The serology of infection describes the course
  and the nature of the disease.
• Acute and chronic HBV infect. Can be
  distinguished by the presence of HBsAg and HBeAg
  in the serum and the pattern of Ab to the
  individual HBV antigens.

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Diagnosis

• During the symptomatic phase of infection,
  detection of antibodies to HBeAg and HBsAg is
  obscured because the antibody is complexed with
  antigen in the serum.
• The best way to diagnose a recent acute
  infection, especially during the period when
  neither HBsAg nor anti-HBs can be detected, is to
  measure IgM anti-HBc.

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Diagnosis

• Detection of serum HBVDNA nucleic hybridization
  PCR.
• Detection of viral DNA polymerase.

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Treatment

• Interferon-alpha may be effective for treating a
  chronic HBV infection.
• Hepatitis B immune globulin may be administered
  within a week of exposure and to newborn infants
  of HBsAg-positive mothers.

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Elimination of Hepatitis B Virus Transmission
Objectives

• Prevent chronic HBV Infection
• Prevent chronic liver disease
• Prevent primary hepatocellular carcinoma
• Prevent acute symptomatic HBV infection

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Elimination of Hepatitis B Virus Transmission
Strategy

• Prevent perinatal????HBV transmission
• Routine vaccination of all infants
• Vaccination of children in high-risk groups
• Vaccination of adolescents
• all unvaccinated children at 11-12 years of age
• high-risk adolescents at all ages
• Vaccination of adults in high-risk groups

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Hepatitis C Virus
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Introduction

• The major cause of parenterally transmitted non A
  non B hepatitis. It eluded identification for
  many years. In 1989, the genome was cloned from
  the serum of an infected chimpanzee.

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Features of Hepatitis C Virus Infection

Incubation period Average 6-7 weeks Range 2-26
weeks Acute illness (jaundice) Mild (lt20) Case
fatality rate Low Chronic infection 75-85 Chroni
c hepatitis 70 (most asx) Cirrhosis 10-20 Morta
lity from CLD 1-5 (chronic liver
disease )
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Common characteristics

• Putative Togavirus related to the Flavi and Pesti
  viruses.Thus probably enveloped.
• Has a ssRNA genome
• Does not grow in cell culture, but can infect
  Chimpanzees

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Transmission

• Blood transfusions, blood products
• organ donation
• Intravenous drug abusers
• community acquired mechanism unclear. ?
• Vertical transmission ?
• sexual intercourse

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Epidemiology

• Causes a milder form of acute hepatitis than does
  hepatitis B
• But 50 individuals develop chronic infection,
  following exposure.
• Incidence endemic world-wide high incidence in
  Japan, Italy and Spain

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Clinical syndromes

• HCV can cause acute infections but is more likely
  to establish chronic infections.
• Viremia
• Chronic persistent hepatitis
• Chronic active hepatitiw
• Cirrhosis
• Liver failure

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Chronic Hepatitis C Factors Promoting
Progression or Severity

• Increased alcohol intake
• Age gt 40 years at time of infection
• HIV co-infection
• ?Other
• Male gender
• Other co-infections (e.g., HBV)

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Serologic Pattern of Acute HCV Infection with
Recovery
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
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Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
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HCV Prevalence by Selected GroupsUnited States
Hemophilia
Injecting drug users
Hemodialysis
STD clients
Gen population adults
Surgeons, PSWs
Pregnant women
Military personnel

Average Percent Anti-HCV Positive
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Laboratory diagnosis

• 1) SerologyReliable serological tests have only
  recently become available.HCV-specific IgG
  indicates exposure, not infectivity
• 2) PCR detects viral genome in patient's serum

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Treatment, Prevention, and Control

• Recombinant interferon-alpha is the only known
  effective treatment for HCV.
• Illicit drug abuse and transfusion are the most
  identifiable sources of HCV viruses.

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Hepatitis D virus

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Introduction

• Defective virus which requires Hepatitis B virus
  as a helper virus in order to replicate.
  Infection only occurs in patients who are
  already infected with Hepatitis B.

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Structure

• Virus particle 36 nm in diameterencapsulated
  with HBsAg, derived from HBV
• Delta antigen is associated with virus
  particlesssRNA genome

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Hepatitis D (Delta) Virus
d antigen
HBsAg
RNA
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Replication

• Transcription and replication of the HDV genome
  are unusual. Specifically, the host cells RNA
  polymerase II makes an RNA copy, replicates the
  genome, and makes mRNA.

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Geographic Distribution of HDV Infection
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Pathogenesis

• Spread in blood, semen, and vaginal secretion.
• It can replicate and cause disease only in people
  with active HBV infections.
• Replication of the delta agent results in
  cytotoxicity and liver damage.

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Clinical Syndromes

• Increases the severity of HBV infections.
• Fulminant hepatitis

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Hepatitis D - Clinical Features

• Coinfection
• severe acute disease
• low risk of chronic infection
• Superinfection
• usually develop chronic HDV infection
• high risk of severe chronic liver disease

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HBV - HDV Coinfection
Typical Serologic Course
Symptoms
ALT Elevated
anti-HBs
Titer
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure
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HBV - HDV Superinfection
Typical Serologic Course
Jaundice
Symptoms
Total anti-HDV
ALT
Titer
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure
100
Laboratory Diagnosis

• Detect the delta antigen of antibodies
• ELISA and RIA

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Hepatitis D - Prevention

• HBV-HDV Coinfection
• Pre or postexposure prophylaxis to prevent HBV
  infection
• HBV-HDV Superinfection
• Education to reduce risk behaviors among persons
  with chronic HBV infection

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Hepatitis E Virus

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Structure and Genome

• 30-32nm non-enveloped particle
• s/s ()sense RNA genome , 7.5Kb.
• Genetic organization similar (not identical) to
  Caliciviruses

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Hepatitis E - Clinical Features

• Incubation period Average 40 days
• Range 15-60 days
• Case-fatality rate Overall, 1-3 Pregnant
  women, 15-25
• Illness severity Increased with age
• Chronic sequelae None identified

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Geographic Distribution of Hepatitis E
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Hepatitis E - Epidemiologic Features

• Most outbreaks associated withfecally
  contaminated drinking water
• Minimal person-to-person transmission

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Prevention and Control Measures for Travelers to
HEV-Endemic Regions

• Avoid drinking water (and beverages with ice) of
  unknown purity, uncooked shellfish, and uncooked
  fruit/vegetables not peeled or prepared by
  traveler
• IG prepared from donors in Western countries does
  not prevent infection
• Unknown efficacy of IG prepared from donors in
  endemic areas
• Vaccine?

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Epidemiology

• The delta agent infects children and adults with
  underlying HBV infection, and people who are
  persistently infected with both HBV and HDV are a
  source for the virus.