Hepatitis viruses

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Hepatitis viruses
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Hepatitis viruses

• At least 6 viruses
• HAV
• HBV
• HCV
• HDV
• HEV
• HGV?

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Hepatitis viruses

• Target organ LIVER!!
• They differ greatly in
• Their structure
• Mode of replication
• Mode of transmission
• Course of the disease they cause

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Hepatitis viruses

• HAV HBV
• Non-A, non-B hepatitis viruses
• (C, G, E..)
• HDV, delta agent
• Other non-A, non-B viruses (HSV, CMV..)

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Hepatitis viruses /hepatitis

• Liver damage
• Icteric symptomes
• Jaundice
• Release of liver enzymes

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Hepatitis Viruses

• Hepatitis A, which is sometimes known as
  infectious hepatitis, (1) is caused by a
  picornavirus, a ribonucleic acid (RNA) virus (2)
  is spread by the fecal-oral route (3) has an
  incubation period of approximately 1 month, after
  which icteric symptoms start abruptly (4) does
  not cause chronic liver disease and (5) rarely
  causes fatal disease.

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Hepatitis A virus

• Cause infectious hepatitis
• Fecal-oral
• Consumption of contaminated water, shelfish, or
  other food
• Picornavirus enterovirus 72 Heparnavirus unique
  genome

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Hepatitis A virus/ structure replication

• Naked icosahedral capsid
• sense, ssRNA genome
• 7470 b
• Capsid more stable to acid and other treatments
  than other picornaviruses
• One serotype!

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Structure of hepatitis A virus
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Hepatitis A virus/Pathogenesis

• Ingestion oropharynx epithelial lining of
  intestines parenchymal cells of the
  liver bile stool (shedding into the stoo?oool)
  10 days before symptoms of jaundice

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Spread of HAV within the body
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Hepatitis A virus/Pathogenesis

• Replicates without producing apparent cytopathic
  effects
• Antibody protection against reinfection is
  lifelong
• The liver pathology caused by HAVHBV
  (indistinguishable) immunopathology, not
  virus-induced cytopathology
• HAV cannot initiate chronic infection

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Hepatitis A virus/Epidemiology

• 40 of acute cases of hepatitis
• Most infected people are contagious before
  symptoms spreads readily
• 90 of infected children,
• 25-50 of infected adults have inapparent (but
  productive) infection
• Virus is in high concentrations in stool
• spread via the fecal-oral route

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Hepatitis A virus/Epidemiology

• spread via the fecal-oral route
• Contaminated water
• Food
• Dirty hands
• Virus is resistant to
• Detergents
• Acid (pH of 1)
• 60oC
• Fresh water, salt water

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Hepatitis A virus/Epidemiology

• spread via contaminated shellfish
• Clams, oysters, mussels
• They concentrate the viral particles
• (In Shanghai, China, in 1988, 300 000 people are
  infected clams from a polluted river)

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Hepatitis A virus/Epidemiology

• Seropositivity rate of adults in various
  countries
• Sweden 13
• USA 41-44
• Yugoslavia 97
• Taiwan 88
• Turkey xx 70-90

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Hepatitis A virus/Clinical syndromes

• Symptomes very similar to those caused by HBV
• stem from immune-mediated damage to the liver
• Usually asymptomatic in children milder than
  adults
• Initial symptomes fever, fatigue, nausea, loss
  of appetite, abdominal pain
• Jaundice in 2/3 of adults, only in 1 or 2/10 of
  children

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Hepatitis A virus/Clinical syndromes

• 99 of time complete recovery
• 1-3/1000 fulminant hepatitis 80 mortality rate

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Time course of HAV infection
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Hepatitis A virus/Laboratory diagnosis

• Time course of the clinical symptomes
• Identification of a known infected source
• Specific serologic tests
• anti-HAV IgM by ELISA or RIA

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Hepatitis A virus/Treatment, Prevention control

• Fecal-oral spread
• Prophylaxis
• Immune serum globulin
• Before or early in the incubation period 80-90
  effective in preventing clinical illness
• Vaccine killed HAV vaccine (FDA appr)
• For use in children or adults at risk for
  infection

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Hepatitis B virus

• Hepadnaviruses
• Infect liver, kidneys, pancreas
• Only humans and chimpanzees

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Hepatitis B virus/Structure

• Small
• Envelopped
• DNA genome
• Several unusual properties
• Small (3200 bases) -circular-partly
  double-stranded DNA
• Encodes a reverse transcriptase
• Replicates through an RNA intermediate

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Hepatitis B

• previously known as serum hepatitis,
• (1) is caused by a hepadnavirus with a
  deoxyribonucleic acid (DNA) genome
• (2) is spread parenterally by blood or needles,
  by sexual contact, and perinatally
• (3) has a median incubation period of
  approximately 3 months, after which icteric
  symptoms start insidiously
• (4) is followed by chronic hepatitis in 5 to 10
  of patients and (5) is causally associated with
  primary hepatocellular carcinoma (PHC).
• More than one third of the world's population has
  been infected with HBV, resulting in 1 to 2
  million deaths per year.
• The incidence of HBV is decreasing, however,
  especially in infants, because of the development
  and use of the HBV subunit vaccine.

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Unique Features of Hepadnaviruses

• Virus has enveloped virion containing partially
  double-stranded, circular DNA genome.
• Replication is through a circular RNA
  intermediate.
• Virus encodes and carries a reverse
  transcriptase.
• Virus encodes several proteins (HBsAg L, M, S
  HBe/HBc) that share genetic sequences but with
  different in-frame start codons.
• HBV has a strict tissue tropism to the liver.
• HBV-infected cells produce and release large
  amounts of HBsAg particles lacking DNA.
• The HBV genome can integrate into the host
  chromosome.

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Hepatitis B virus/Structure

• Virion Dane particule, 42nm in diameter
• Unusually stable for an envelopped virus
• Resist treatment with
• ether,
• a low pH, transmission
• Freezing,
• Moderate heating

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Hepatitis B virus/Structure

• Virion Dane particule, 42nm in diameter include
• a polymerase
• Reverse transcriptase activity
• Ribonuclease activity
• HBcAg
• HBsAg, 3 forms
• LgtMgtS glycoproteins, contains a determinant
  (goup- specific), and d or y and w or r,
  type-specific determinants

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HBsAg and HBeAg

• are secreted into the blood during viral
  replication.
• The detection of HBeAg is the best correlate to
  the presence of infectious virus.
• HBcAg not present in sera.

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Hepatitis B virus/Replication

• Unique!
• Replicates through an RNA intermediate and
  produces and releases antigenic decoy particules
• (They used a girl hitch-hiker as the decoy to get
  him to stop)

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Hepatitis B virus

• A circular positive-strand RNA intermediate is
  first synthesized by
• cells DNA dependent RNA polymerase
• RNA-dependent DNA polymerase
• a negative strand DNA is formed
• positive RNA degragated
• Positive strand DNA is initiated but stops when
  the genome and the core enveloped
• RESULT partially double stranded DNA

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Hepatitis B virus/PathogenesisImmunity

• HBV can cause
• Acute or
• Chronic,
• Symptomatic or,
• Asymptomatic
• disease...

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Hepatitis B virus/PathogenesisImmunity

• Its determined by the persons immune response
  to the infection

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Hepatitis B virus/PathogenesisImmunity

• HBsAg and HBeAg in the blood ongoing active
  infection
• The major source of infectious virus is blood
• Semen
• Saliva
• Milk
• Vaginal menstrual secretions
• Amniotic fluid

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Hepatitis B virus/PathogenesisImmunity

• The virus replicates in hepatocytes with minimal
  cytopathic effect infection proceeds without
  causing liver damage or symptoms HBV genome
  integrate into hepatocyte chromatin remain
  latent filamentous forms of HBsAg
  hepatocyte cytopathology

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Hepatitis B virus/PathogenesisImmunity

• cell-mediated immunity and inflammation are
  responsible for causing the symptoms and
  effecting resolution of the HBV infection by
  eliminating the infected hepat?cyte
• antibody (vaccinated people) can protect against
  reinfection
• Large amount of HBsAg!!
• Immune complexes hypersensitivity

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Hepatitis B virus/PathogenesisImmunity

• Infants young childrens are less able to
  resolve the infection
• 90 infected perinatally become chronic carriers

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Hepatitis B virus/Epidemiology

• In US, 300 000 new infected people/year
• and 4000 death
• Underdeveloped nations
• 15 of the population infected during birth or
  chidhood

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Hepatitis B virus/Epidemiology

• Asymptomatic carriers foster the spread of the
  virus
• Routes of spread sexual, parenteral, and
  perinatal

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Hepatitis B virus/Epidemiology

• Transmission
• Contaminated blood, blood components
• Needle sharing
• Acupuncture
• Ear piercing
• Tattooing
• Very close personel contact
• The exchange of semen, saliva, vaginal secretions
  (e.g., sex, childbirth)

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Hepatitis B virus/Clinical syndronnes

• Acute infection
• Clinically apparent illness 25
• Long incubation
• Insidious onset
• Prodromal period fever, malaise, anorexia,
  nausea, vomiting, ...
• Icteric symptomes jaundice, dark urine, pale
  stools

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Hepatitis B virus/Clinical syndronnes

• Acute infection
• Fulminant hepatitis in 1 of icteric patients
• Hypersensitivity reactions
• Rash,
• polyarthritis,
• Fever
• Acute necrotizing vasculitis,
• Glomerulonephritis

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High-Risk Groups for Hepatitis B Virus Infection

• People from endemic regions (i.e., China, parts
  of Africa, Alaska, Pacific Islands)
• Babies of mothers with chronic hepatitis B virus
• Intravenous drug abusers
• People with multiple sex partners, homosexual and
  heterosexual
• Hemophiliacs and other patients requiring blood
  and blood product treatments
• Health care personnel who have contact with blood
  
• Residents and staff members of institutions for
  the mentally retarded
• Hemodialysis patients and blood and organ
  recipients

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Hepatitis B virus/Clinical syndronnes

• Chronic infection
• 5-10 of people with HBV infections

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Hepatitis B virus/Clinical syndronnes

• Primary hepatocellular carcinoma
• 80 of all cases of chronic HBV inf.
• One of the three most common cause of cancer
  mortality in the world
• May become the first vaccine-preventable human
  cancer
• Latency period 9 to 35 years

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Primary hepatocellular carcinoma

• HBV may induce PHC by
• - promoting continued liver repair and -cell
  growth in response to inflammation and
• -tissue damage or by
• -integrating into the host chromosome and
  stimulating cell growth directly..

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Primary hepatocellular carcinoma

• HBV may induce PHC by
• - Integration could stimulate genetic
  rearrangements or juxtapose viral promoters next
  to cellular growth-controlling genes.
• -Alternatively, a protein encoded by the HBV X
  gene may transactivate (turn on) the
  transcription of cellular proteins and stimulate
  cell growth..

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Primary hepatocellular carcinoma

• The presence of the HBV genome may allow a
  subsequent mutation to promote carcinogenesis.
• The latency period between HBV infection and PHC
  may be as short as 9 years or as long as 35
  years.

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Hepatitis B virus/Laboratory diagnosisInterpretat
ion of serologic markers of hepatitis B virus
infection
Serologic reactivity Disease state Healthy state Disease state Healthy state Disease state Healthy state Disease state Healthy state Disease state Healthy state Disease state Healthy state Disease state Healthy state
Serologic reactivity Early Early acute Acute Chronic Late acute Resolved vaccinated
Anti-HBc Anti-HBe Anti-HBs HBeAg HBsAg Infectious virus - - - - - - - - - - - - /- /- - - /- - - - - - - - -
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Hepatitis B virus/PreventionControl

• Screening donated blood
• HBsAg, anti-HBc
• Avoiding intimate personal contact with HBsAg
  ()s
• Avoiding the lifestyles that facilitate the
  spread of the virus
• (High risk groups )
• Vaccination

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Hepatitis B virus/PreventionControl

• Universal blood and body fluid precautions
• (refer to HIV and retroviruses lesson)

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Prevention, and Control

• Transmission of HBV in blood or blood products
  has been greatly reduced by screening donated
  blood for the presence of HBsAg and anti-HBc.
• Additional efforts to prevent transmission of HBV
  consist of avoiding sex with a carrier of HBV and
  avoiding the lifestyles that facilitate spread of
  the virus.
• Household contacts and sexual partners of HBV
  carriers are at increased risk, as are patients
  undergoing hemodialysis, recipients of pooled
  plasma products, health care workers exposed to
  blood, and babies born of HBV-carrier mothers.

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Prevention, and Control

• Vaccination is recommended for infants, children,
  and especially people in high-risk groups
• For newborns of HBsAg-positive mothers and
  people accidentally exposed either percutaneously
  or permucosally to blood or secretions from an
  HBsAg-positive person, vaccination is useful even
  after exposure. Immunization of mothers should
  decrease the incidence of transmission to babies
  and older children, also reducing the number of
  chronic HBV carriers. Prevention of chronic HBV
  will reduce the incidence of PHC

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The HBV vaccines

• subunit vaccines.
• The initial HBV vaccine was derived from the
  22-nm HBsAg particles in human plasma obtained
  from chronically infected people.
• The current vaccine was genetically engineered
  and is produced by the insertion of a plasmid
  containing the S gene for HBsAg into a yeast,
  Saccharomyces cerevisiae. The protein
  self-assembles into particles, which enhances its
  immunogenicity.

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The HBV vaccines

• The vaccine must be given in a series of three
  injections, with the second and third given 1 and
  6 months after the first.
• More than 95 of individuals receiving the full
  three-dose course will develop protective
  antibody.
• The single serotype and limited host range
  (humans) help ensure the success of an
  immunization program.

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Universal blood and body fluid precautions

• are used to limit exposure to HBV.
• It is assumed that all patients are infected.
• Gloves are required for handling blood and body
  fluids wearing protective clothing and eye
  protection may also be necessary.
• Special care should be taken with needles and
  sharp instruments.
• HBV-contaminated materials can be disinfected
  with 10 bleach solutions

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Treatment, Prevention

• Hepatitis B immune globulin within a week of
  exposure and to newborn infants of HBsAg-positive
  mothers to prevent and ameliorate disease.
• Chronic HBV infection
• lamivudine
• adefovir dipivoxil
• Famciclovir
• Interferon-a

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Hepatitis C and G viruses

• HCV
• was identified by molecular biologic means in
  1989
• Predominant cause of NANBH virus infections
• Major cause of post-transfusion hepatitis (before
  routine screening of the blood supply for HCV)

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Hepatitis C virus

• HCV
• gt 170 000 000 (17x 107) carriers in the world
• Transmission similar to HBV but
• Greater potential for establishing persistent,
  chronic hepatitis
• Cirrhosis HCC

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Hepatitis C virus/Structure Replication

• HCV has never been isolated
• Only member of the Hepaciviridae (family
  Flaviviridae)
• Enveloped
• Positive-sense RNA
• Encodes 10 proteins (2 glycoproteins, E1, E2)
• 6 groups of variants (clades), genotypes..

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Hepatitis C virus/Pathogenesis

• Cell-mediated immunopathology is responsible
  mainly for producing the tissue damage
• Antibody to HCV is not protective!
• Immunity to HCV may not be lifelong

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Hepatitis C virus/Epidemiology

• Is transmitted primarily in infected blood and
  sexually
• Almost all (gt90) HIV infected individuals who
  are/were IVDUs are infected with HCV
• Almost 20 of Egyptian blood donors are ()

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Hepatitis C virus/Clinical syndromes

• 3 types of diseases
• Acute hepatitis chronic persistant inf. Cirrhosis
• (15 recovery) (70) (15)

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Hepatitis C virus/Clinical syndromes

• Acute HCV infection similar to acute HAV/HBV,
• Inflammatory response is less intense
• Symptoms milder
• gt80 asymptomatic

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Hepatitis C virus/Laboratory diagnosis

• Anti-HCV with ELISA
• Seroconversion within 7 to 31 weeks of infection
• HCV RNA with molecular techniques
• RT-PCR
• Genotyping

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Treatment

• interferon-a or pegylated interferon (treated
  with polyethylene glycol to enhance its biologic
  lifetime)
• with ribavirin

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Hepatitis D virus

• 15 million people are infected with HDV in the
  world
• Cause of 40 of fulminant hepatitis infections
• Unique
• Uses HBV and target cell proteins to replicate
  and produce its one protein
• a viral parasite
• HBsAg is essential for packaging the virus

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Hepatitis D virus/StructureReplication

• ssRNA genome
• 1700 nucleotides
• Rod shaped (circular)
• Virion size HBV
• Delta Ag surrounded by HBsAg containing envelope

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The delta hepatitis virion
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Hepatitis D virus/Pathogenesis

• Similar to HBV
• Spread in blood, semen, and vaginal secretions
• It can replicate and cause disease only in people
  with active HBV infections
• A person can be coinfected with HBV HDV, or
• A HBV carrier can be superinfected with HDV
• Replication of HDV results in cytotoxicity and
  liver damage
• Unlike HBV, damage to the liver occurs as a
  result of the directc cytopathic effect of the
  delta agent combined with the underlying
  immunopathology of the HBV disease

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Hepatitis D virus/Epidemiology

• Worlwide distribution
• Endemic in southern Italy, the Amazon Basin,
  parts of Africa, and the Middle East
• Spread by the same routes as HBV

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Hepatitis D virus/Clinical syndromes

• Increases the severity of HBV infections
• gt fulminant hepatitis than other H. viruses

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Hepatitis D virus/Laboratory diagnosis

• Ag,
• Ab, with
• ELISA or RIA
• HDV RNA

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Hepatitis D virus/Tre-Pre-Co

• No known specific treatment
• Prevention of HBV
• HBV vaccine

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Hepatitis E virus

• E-NANBH
• Enteric/epidemic Non-A, Non-B hepatitis
• Predominently spread by the fecal-oral route,
  esp. in contaminated water
• Worlwide
• Problematic in developping countries

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Hepatitis E virus

• Epidemics in India, Pakistan, Nepal, Burma, North
  Africa, Mexico
• Symptoms and course similar to those of HAV
• Cause only acute disease
• Mortality rate associated with HEV disease is x10
  times that associated with HAV disease (1-2)

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Hepatitis E virus

• Mortality rate associated with HEV disease is x10
  times that associated with HAV disease (1-2)
• Serious in pregnant women
• Mortality rate of approximately 20

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Hepatitis G Virus

• HGV known as GB virus-C GBV-C
• resembles HCV in many ways.
• a flavivirus
• transmitted in blood
• a predilection for chronic hepatitis infection
• It is identified by detection of the genome by
  RT-PCR or other RNA detection methods.