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Hepatitis B Virus (PowerPoint)

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					Hepatitis B Virus

           Huamin Wang
               王华民

Department of Microbiology & Immunology
        Hainan Medical College
                  2007
        Statistics on HBV
• Most healthy adults (90%) who are
  infected will recover and develop
  protective antibodies against future
  hepatitis B infections
• 90% of infants and up to 50% of young
  children infected with hepatitis B will
  develop chronic infections.
    Hepatitis B In the World
• 2 billion people have been infected (1 out
  of 3 people).
• 400 million people are chronically infected.
• 10-30 million will become infected each
  year.
• An estimated 1 million people die each
  year from hepatitis B and its complications.
• Approximately 2 people die each minute
  from hepatitis B.
 Hepatitis B In the United States
• 12 million Americans have been infected (1 out
  of 20 people).
• More than one million people are chronically
  infected .
• Up to 100,000 new people will become infected
  each year.
• 5,000 people will die each year from hepatitis B
  and its complications.
• Approximately 1 health care worker dies each
  day from hepatitis B.
         Hepatitis B in China
• 1.3 billion people
• the world's largest population of hepatitis B
  patients, with nearly half a million people
  dieing of the liver disease every year
• 120 million Chinese have tested positive
  for hepatitis B, which has become a
  severe public health problem in the
  country
           General Concepts

• Hepatitis = 'inflammation of the liver'.
• six medically important viruses are commonly
  described as “hepatitis viruses”:
 HAV,HBV,HCV,HDV,HEV,HGV.
         Definitions for Hepatitises
• Acute(急性): Short term and/or severe.
• Chronic(慢性): Lingering or lasting - may or may not be
  severe
• Fulminant(爆发性): Developing quickly and lasting a
  short time, high mortality rate.
• Cirrhosis(硬化): Hardening: may be the result of infection
  or toxins (e.g. alcohol)
• Jaundice(黄疸): Yellowing of the skin, eyes, etc due to
  raised levels of bilirubin in the blood due to liver damage.
• Hepatocellular carcinoma(肝细胞癌): is closely
  associated with hepatitis B, and at least in some regions of
  the world with hepatitis C virus.
  Viral Hepatitis - Historical Perspectives

   “Infectious”   A              Enterically
                               E
                                 transmitted

Viral hepatitis       NANB


                                 Parenterally
      “Serum”     B D          C transmitted

                         F, G, TTV
                         ? other
Table 24.12
Hepatitis B Virus
       1、Properties of HBV
• a member of the hepadnavirus group
• Circular partially double-stranded DNA
  viruses
• Replication involves a reverse transcriptase.
• endemic in the human population and
  hyperendemic in many parts of the world.
• a number of variants
• It has not yet been possible to propogate the
  virus in cell culture
HBV : Structure
              HBV : Structure
• Virion also referred to as Dane particle (ds-tranded DNA)
• 42nm enveloped virus
• Core antigens located in the center (nucleocapsid)
    * Core antigen (HBcAg)
   * e antigen (HBeAg)- an indicator of transmissibility
  (minor component of the core- antigenically distinct from
  HBcAg)
• 22nm spheres and filaments other forms- no DNA in
  these forms so they are not infectious (composed of
  surface antigen)- these forms outnumber the actual
  virions
            HBV Structure & Antigens
   Dane particle




HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown
               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.
GENOME
              Open Reading Frames
There are 4 open reading frames derived from the same strand (the
incomplete + strand)
• S - the 3 polypeptides of the surface antigen (preS1, preS2 and
S - produced from alternative translation start sites.
• C - the core protein
• P - the polymerase
• X - a transactivator of viral transcription (and cellular genes?).
HBx is conserved in all mammalian (but not avian)
hepadnaviruses. Though not essential in transfected cells, it is
required for infection in vivo.
        2、HBV: Replication

• Reverse transcription: one of the mRNAs is
  replicated with a reverse transcriptase making the
  DNA that will eventually be the core of the
  progeny virion
• RNA intermediate: HBV replicates through an
  RNA intermediate and produces and release
  antigenic decoy particles.
• Integration: Some DNA integrates into host
  genome causing carrier state
Replication of HBV
   3、HBV: Modes of Transmission

 Parenteral - IV drug abusers, health workers are
  at increased risk.

 Sexual - sex workers and homosexuals are
  particular at risk.

 Perinatal(Vertical) - mother(HBeAg+) →infant.
Global Patterns of Chronic HBV Infection
 • High (>8%): 45% of global population
   – lifetime risk of infection >60%
   – early childhood infections common
 • Intermediate (2%-7%): 43% of global
   population
   – lifetime risk of infection 20%-60%
   – infections occur in all age groups
 • Low (<2%): 12% of global population
   – lifetime risk of infection <20%
   – most infections occur in adult risk groups
            4、Epidemiology
• 350,000,000 carriers worldwide
• 120,000,000 carriers in China
 - the carrier rate can exceed 10%
 -15 to 25% of chronically infected patients will die
 from chronic liver disease
• 500,000 deaths/year in China
• 982,297 liver disease in China 2005
• 50% of children born to mothers with chronic HBV in
  the US are Asian American
 Concentration of Hepatitis B Virus
      in Various Body Fluids
                                    Low/Not
     High        Moderate          Detectable

    blood          semen 精液          urine
    serum        vaginal fluid 阴道分泌液 feces
wound exudates      saliva 唾液        sweat
   伤口渗出液                             tears
                                   breastmilk
    High-risk groups for HBV infection
• 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
                            Outcome of Hepatitis B Virus Infection
                        100         by Age at Infection                                          100

                                                                                                  80
Chronic Infection (%)




                        80




                                                                                                        Symptomatic Infection (%)
                        60                                                                       60
                                                                 Chronic Infection

                        40     Chronic Infection (%)                                             40


                        20                                                                       20

                                           Symptomatic Infection
                         0                                                                        0
                             Birth       1-6 months        7-12 months     1-4 years   Older Children
                                                                                         and Adults
                                                       Age at Infection
 5、Pathogenesis & Immunity
• Virus enters hepatocytes via blood
• Immune response (cytotoxic T cell) to viral
  antigens expressed on hepatocyte cell surface
  responsible for clinical syndrome
• 5 % become chronic carriers (HBsAg> 6 months)
• Higher rate of hepatocellular ca in chronic
  carriers, especially those who are “e” antigen
  positive
• Hepatitis B surface antibody likely confers
  lifelong immunity (IgG anti-HBs)
• Hepatitis B e Ab indicates low transmissibility
            6、Clinical Features
Incubation period:                      Average 60-90 days
                                        Range 45-180 days
Insidious onset of symptoms.
                Tends to cause a more severe disease than Hepatitis A.
Clinical illness (jaundice):                       <5 yrs, <10%
                                         ≥ 5 yrs, 30%-50%
                                          1/3 adults-no symptoms
Clinical Illness at presentation           10 - 15%

Acute case-fatality rate:             0.5%-1%
Chronic infection:                                < 5 yrs, 30%-90%
                                        ≥ 5 yrs, 2%-10%
                                    More likely in ansymptomatic
   infections
Premature mortality from
   chronic liver disease:        15%-25%
Possible Outcomes of HBV Infection
                     Acute hepatitis B infection

    3-5% of adult-                                 95% of infant-
  acquired infections                            acquired infections
                           Chronic HBV infection



                           Chronic hepatitis

                                    12-25% in 5 years
                              Cirrhosis
        6-15% in 5 years                       20-23% in 5 years

        Hepatocellular                          Liver failure
         carcinoma
Death                      Liver transplant                 Death
Acute Hepatitis B Virus Infection with Recovery
           Typical Serologic Course
                    Symptoms
                HBeAg                        anti-HBe


                                             Total anti-HBc
Titre

        HBsAg                      IgM anti-HBc                anti-HBs




        0   4   8   12   16   20   24   28    32   36     52      100

                    Weeks after Exposure
 Acute HBV Infection with Progression to
Chronic Infection: Typical Serologic Course

           Acute                  Chronic
         (6 months)               (Years)
                         HBeAg                 Anti-HBe
                                      HBsAg

                                         Total anti-HBc


                        IgM anti-HBc



  0 4   8 12 16 20 24 28 32 36   52           Years
                   Weeks after Exposure
7、Laboratory Diagnosis
8-1、Current Treatment Options

• Interferon alfa (Intron A) (干扰素)
  Response rate is 30 to 40%.
• Lamivudine (Epivir HBV) (拉米呋啶)
   (relapse ,drug resistance)
• Adefovir dipivoxil (Hepsera)(阿德福韦酯)
            8-2、Prevention
• Vaccination
  - highly effective recombinant vaccines
• Hepatitis B Immunoglobulin (HBIG)
  -exposed within 48 hours of the incident/ neonates
  whose mothers are HBsAg and HBeAg positive.
• Other measures
  -screening of blood donors, blood and body fluid
  precautions.
          Hepatitis B Vaccine
• Infants: several options that depend on status of
  the mother
  – If mother HBsAg negative: birth, 1-2m,6-18m
  – If mother HBsAg positive: vaccine and Hep B immune
    globulin within 12 hours of birth, 1-2m, <6m
• Adults
  * 0,1, 6 months
• Vaccine recommended in
  – All those aged 0-18
  – Those at high risk
                    summary
•   General concepts for hepatitis
•   Types of hepatitis
•   Properties of HBV : Structure\ ORF\Replication
•   Transmission \Epidemiology
•   Pathogenesis & Immunity
•   Clinical Features
•   Laboratory Diagnosis
•   Treatment \Prevention
                Questions
• What is hepatitis B?
• What are the properties of HBV?
• How many ORFs of HBV?
• How is HBV spread?
• How does the HBV curse the liver diseases?
• How do you interpret serological lab results
  for HBV?
• How to treat and prevent hepatitis B?
              Review Quiz
• Following transmission of HBV from mother to
  infant, which of the following is the most
  common medical problem for the infant?
  A. Liver failure.
  B. Chronic HBV carrier state
  C. Development of lymphoma.
  D. Opportunistic infections.
  E. Development of CNS disease.
  Why are the Chinese at greater
     risk than Westerners?
• Because there are more Asian people already
  infected with hepatitis B than Westerners.
  Although hepatitis B is not an "Asian disease", it
  affects hundreds of millions of Asians. Since the
  Asian community starts with such a large
  number of infected people, there are more
  people who can pass the hepatitis B virus on to
  others. This increases the risk that you could get
  infected. Since there is a smaller number of
  Westerners who are infected, this group has a
  lower risk of infection
     How is hepatitis B spread
  differently among the Chinese?
• Asians and Westerners can both get hepatitis B through contact with
  blood, unprotected sex, shared needles, and from an infected
  mother to newborn baby during delivery.
• Jobs and lifestyle choices can create an equal risk for both groups.
  However, hepatitis B is often spread differently among Asians.
• Asians are most commonly infected as newborns - from a mother
  who unknowingly passes the virus on during delivery.
• Young children are also at risk if they live in close daily contact with
  an infected family member.
• Babies and children are more likely to develop a chronic hepatitis B
  infection because their young immune systems have trouble getting
  rid of the virus.
• Westerners are most commonly infected as young adults through
  unprotected sex. As adults, their immune systems can usually get
  rid of the virus and they "recover" from an infection.
    What does it mean to be a
 "chronic carrier" of hepatitis B?
• People who are unable to get rid of the hepatitis B
  virus are diagnosed as being a "chronic carrier".
• The virus can stay in their blood and liver for a
  long time.
• They can unknowingly pass the virus on to other
  people.
• Chronic hepatitis B can also lead to serious liver
  diseases, such as cirrhosis or liver cancer. Not
  every chronic carrier will develop serious liver
  disease.
• However, they have a greater chance than
  someone who is not infected.
   Why should Chinese people be
  worried about chronic hepatitis B
            infections?
• Because chronic hepatitis B can lead to cirrhosis or liver
  cancer.
• It's important to get tested because early diagnosis can
  lead to early treatment which can save your life.
• Also, chronic carriers can spread the virus to others.
  Since most chronic carriers don't know they are infected,
  they are unknowingly spreading it to many other people.
• If people are not tested, hepatitis B can pass through
  several generations in one family and throughout the
  community.
   How can I stop the spread of
          hepatitis B?
• The good news is that you can break the cycle of
  infection in your family and in the Chinese
  community.
• Get tested for hepatitis B.
• Make sure everyone in your family is vaccinated
  against hepatitis B.
• Get the vaccine yourself.
• Look for good medical care.
• Discuss treatment options with your family doctor
  or a liver specialist if you already have chronic
  hepatitis B.
Are there any treatments if I have
      chronic hepatitis B?
• Currently, there are five approved drugs in the
  United States for people who have chronic hepatitis
  B infections. These drugs are also available in China:
• 1、Epivir-HBV or Zeffix (lamivudine) is a pill that is
  taken orally
• 2、Hepsera (adefovir dipivoxil) is a pill that is taken
  orally
• 3、Baraclude (entecavir) is a pill that is taken orally
• 4、Intron A (interferon alpha) is a drug given by
  injection
• 5、Pegasys (pegylated interferon) is a drug that is
  give by injection
Are there any treatments if I have
      chronic hepatitis B?
• It is important to know, not every chronic hepatitis B
  patient needs to be on medication.
• Some patients only need to be monitored by their doctor
  on a regular basis (at least once a year, or more).
• Other patients with active signs of liver disease may
  benefit the most from treatment.
• Be sure to talk to your doctor about whether you could
  benefit from treatment and discuss the treatment options.
• In addition, there are promising new drugs in clinical
  trials and in the research pipeline.
• However, it is vital that all people with chronic
  hepatitis B visit their doctor on a regular basis,
  whether they receive treatment or not!

				
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