HEPATITIS B

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HEPATITIS B

• Anna S. F. Lok, MD
• University of Michigan
• Ann Arbor, MI

2
What is Hepatitis B?

• Hepatitis B is an infection of the liver caused
  by the hepatitis B virus

3
How common is hepatitis B?

• Worldwide
• 400 million people are chronic carriers
• About 75 of HBV carriers live in Asia
• 0.5-1 million deaths per year due to HBV
• Asia
• Liver cancer is the 2nd cancer killer among Asian
  men and the 5th cancer killer among Asian women
• Roughly 40 of Asian men and 15 of Asian women
  with chronic hepatitis B die of a liver-related
  illness

4
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
?8 - High
2-7 - Intermediate
lt2 - Low
5
Hepatitis B and Asian Americans

• Less than 0.5 (1 in 200) Americans have chronic
  hepatitis B
• About 10-15 (1 in 8 to 10) Asian Americans have
  chronic hepatitis B
• About 50 (1 in 2) of the people in the US with
  chronic hepatitis B are Asian Americans
• A much higher percent of Asian Americans compared
  to Americans of other races have hepatitis B

6
Why is Hepatitis B so common among Asian
Americans?

• Hepatitis B is very common in Asia
• Many Asian Americans were infected with hepatitis
  B before they came to the US
• Asian Americans born in the US may be infected
  through their mother or other family members, who
  are HBV carriers

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Hepatitis B and Asian Americans

• National Health and Nutrition Examination Survey
  (NHANES)
• Survey on prevalence of various diseases in the
  US
• Sampled cohorts representative of US population
• African Americans and Hispanics over sampled to
  ensure sufficient number studied to permit
  conclusions on prevalence of diseases among those
  racial/ethnic groups
• Reliable data not available for Asian Americans
  because Asians not over sampled, number studied
  too small to be conclusive, and Asians lumped as
  other racial/ethnic groups

8
Hepatitis B and Asian Americans

• NHANES III 1988-1994
• Current and past HBV infection 4.9
• Chronic HBV infection 0.4
• Highest prevalence among blacks
• 5-15 among immigrants from Central and
  Southeast Asia, Middle East and Africa
• Prevalence data for Asians not available

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Why is it that hepatitis B gets so little
attention in the US?

• Federal and state governments public health
• Overall prevalence is low not a very common
  problem here
• Most of those affected by HBV are Asians who
  are politically silent (squeaky wheel gets the
  oil)
• NIH, CDC, Scientific organizations research and
  education
• Not a common problem
• With an effective vaccine, hepatitis B will be
  eradicated in the next generation.. we predicted
  that in the 1980s
• Competition for and attention from other more
  trendy diseases HIV, HCV, SARS, avian flu,
  cancers.

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How is HBV spread?

• HBV is more easily spread than HIV (virus that
  causes AIDS) and HCV
• HBV can live outside the human body for up to 7
  days
• People with chronic hepatitis B can have very
  large amounts of virus in their blood serum HBV
  DNA up to 11 log10 copies/mL (100 billion)

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How is HBV spread?

• Mainly through blood and bodily secretions
• Infected mother to babies at birth
• Contact with blood from carriers through wounds,
  contaminated household articles such as razors,
  toothbrushes, or contaminated needles used for
  tattoos and injecting drugs
• Sexual contact with carriers

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How is HBV spread?

• HBV is not spread by
• Hugging or kissing
• Coughing or sneezing
• Sharing eating utensils

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Outcome of Acute HBV Infection
Recovery
Acute Hepatitis
SubclinicalHepatitis
FulminantHepatitis
Death
Acute Infection
Chronic Infection
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What is Hepatitis B?

• Hepatitis B may be ACUTE
• Recent infection
• May have no symptoms, especially in children
• Common symptoms easily tired, poor appetite,
  nausea, abdominal discomfort, jaundice
• Roughly 95 recover, usually in 2-3 months
• About 1 severe hepatitis with acute liver
  failure
• About 5 go on to chronic infection, lasts longer
  than 6 months

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Risk of Chronic HBV Infection
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Outcome of Chronic HBV Infection
Chronic HBV Infection
Inactive Carrier State
Chronic Hepatitis
Cirrhosis
HCC
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What is Hepatitis B?

• Hepatitis B may be CHRONIC
• Long-lasting infection, persists for more than 6
  months
• Most people have no symptoms
• Common symptoms easily tired, poor appetite,
  nausea, abdominal discomfort
• Can go on to cirrhosis, liver failure, liver
  cancer, and death

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How can hepatitis B be diagnosed?

• The only way to know is to have a blood test
• Most people with hepatitis B have no symptoms
  until late stages of liver disease
• Tests for hepatitis B or liver enzymes are not
  included in most routine check-ups
• Hepatitis B may be present even if liver enzymes
  were tested and were normal

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Serological Markers of HBV Infection?????????????
?????

• HBsAg Acute/Chronic infection
• Anti-HBc IgM Recent infection
• HBeAg High infectivity
• Anti-HBe Low infectivity
• Anti-HBs Immunity
• Anti-HBc IgG HBsAg Chronic infection
• Anti-HBc IgG anti-HBs Resolved infection

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Acute HBV Infection
HBV DNA
HBeAg
Anti-HBe
Anti-HBe
Anti-HBs
Anti-HBc
HBsAg
Anti-HBc IgM
0 2
4 6

Months
Years
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Chronic HBV Infection
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Serum HBV DNA is the most reliable marker of HBV
replication and infectivity

• Fluctuating levels, serial tests important for
  clinical assessment
• Virus persists at low levels even after recovery
• Reactivation can occur spontaneously and more
  often when immune system is suppressed
• HBV DNA levels do not always correlate with ALT
  levels or histologic activity of liver disease
• Persistently high serum HBV DNA levels are
  associated with increased risk of cirrhosis and
  HCC

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Hepatitis B Vaccines

• Genetically engineered hepatitis B surface
  antigen only
• 3 doses month 0, 1, 6
• Immune response 50 after 1 dose
  95 after 3 doses
• Duration of protection gt15 years, dependent on
  initial antibody response
• Factors associated with poor response older age,
  chronic medical illness (cirrhosis, kidney
  failure, diabetes), decreased immune response,
  smoking, obesity, genetics

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Indications for HBV Vaccines

• Hepatitis B immune globulin and HB vaccine to
  infants of HBsAg mothers
• All infants
• All children and adolescents who were not
  vaccinated at birth
• Vaccination of adults at risk of infection
• Occupational
• Sexual / household contacts
• Injection drug users
• Long-term residence in high prevalence areas

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HBV Vaccine Safety

• Worldwide, more than 500 million individuals
  have received HB vaccine over the past 20 years
• Most common adverse event soreness and
  erythema at the injection site
• Systemic symptoms transient low-grade
  fever, headache, malaise and myalgia in 10

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Impact of HBV vaccination on HBV infection rates
in Taiwanese children
30
HBsAg
Anti-HBc
20

10
0
?
1984
1994
1999
Vaccination of infants born to HBsAg mother
Universal vaccination of infant/preschool children
Ni YH, Ann Intern Med 2001135796
27
Impact of HBV Vaccination on Incidence of HCC
in Taiwanese Children
?
Universal Vaccination of Newborns
Chang MH, NEJM 19973361855
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Hepatitis BFactors affecting disease activity
and progression
VIRUS Genotype Molecular Variants
HOST Gender Age Immune Response Genetics
ENVIRONMENT Alcohol HCV, HDV, HIV Carcinogens
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Stages of chronic HBV infection
Immune
Immune
Low replicative
Reactivation
tolerance
clearance
phase
phase
HBeAg - / anti-HBe (PC/CP variants)
HBeAg (wild)
lt
lt
gt
gt
gt105 cp/ml
HBV-DNA
lt105 cp/ml
109-1010 cp/ml
107-108 cp/ml
ALT
Normal / mild CH
moderate/severe CH
moderate/severe CH
Normal/mild CH
cirrhosis
cirrhosis
Inactive cirrhosis
Inactive-carrier state
HBeAg Chronic hepatitis
HBeAg Chronic hepatitis
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Unique Aspects of Hepatitis B among Asians

• Clinical Manifestations/Natural history
• Immune tolerant phase
• Frequent exacerbations and reactivations
• Increased risks of HCC

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Immune Tolerant Phase

• First 10-30 years of perinatally acquired HBV
  infection
• Asymptomatic
• High HBV DNA levels but normal ALT
• Very low rates of spontaneous/treatment-induced
  HBeAg seroconversion

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Immune Clearance Phase
HBeAg ? anti-HBe seroconversion Predictors
ALT, age, gender, HBV genotype Annual rate
5-15 Hepatitis Flares ? HBeAg seroconversion
preceded by flares ¼ flares followed by HBeAg
seroconversion More common in men Increased
risk of cirrhosis
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Stages of chronic HBV infection
Immune
Immune
Low replicative
Reactivation
tolerance
clearance
phase
phase
HBeAg - / anti-HBe (PC/CP variants)
HBeAg (wild)
lt
lt
gt
gt
gt105 cp/ml
HBV-DNA
lt105 cp/ml
109-1010 cp/ml
107-108 cp/ml
ALT
Normal / mild CH
moderate/severe CH
moderate/severe CH
Normal/mild CH
cirrhosis
cirrhosis
Inactive cirrhosis
Inactive-carrier state
HBeAg Chronic hepatitis
HBeAg Chronic hepatitis
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Inactive HBsAg Carrier State

• HBsAg gt 6 months
• HBeAg- , anti-HBe
• Serum HBV DNA lt 103 copies/ml
• Persistently normal ALT
• Outcome dependent on liver damage accrued prior
  to entering inactive carrier state and any
  subsequent reactivation

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HBeAg Chronic Hepatitis B

• HBsAg
• HBeAg
• Serum HBV DNA gt 104-5 copies/ml
• Elevated ALT / moderate-severe inflammation
  on biopsy
• Frequently associated with precore or core
  promoter mutations that prevent or decrease
  HBeAg production

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Risk factors for progression to cirrhosis
Viral factors Host Factors
External Factors

• Persistently high HBV DNA levels
• HBV precore/CP variant?
• HBV genotype (C gt B)

• Older age
• Male gender
• Advanced fibrosis
• Persistent ALT elevation
• Recurrent hepatitis flares
• HDV, HCV coinfections
• HIV coinfection

• Alcohol

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Risk factors for progression to HCC
Viral factors Host Factors
External Factors

• Persistently high HBV DNA levels
• HBV CP variant
• HBV genotype (C gt B)

• Older age
• Male gender
• Asians??
• Advanced fibrosis
• Persistent ALT elevation
• Recurrent hepatitis flares
• HDV, HCV coinfections
• HIV coinfection
• Family history of HCC

• Alcohol
• Aflatoxin
• Smoking

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What can patients do to protect their liver?

• Do not drink alcohol
• Do not take any herbal medicine that might hurt
  the liver
• Eat a balanced diet, exercise regularly, avoid
  getting overweight
• Hepatitis B is a chronic health problem, HBV
  levels and severity of liver damage can change
  with time, see their doctor and get tested at
  least once a year even if they have no symptoms

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Treatment of Chronic Hepatitis B

• Goals
• Suppression of HBV replication
• Decrease hepatic necroinflammation and fibrosis
• Prevent progression to cirrhosis, liver failure
  and HCC

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Treatment of Chronic Hepatitis BDefinition of
Response

• HBeAg patients
• Serum HBV DNA decrease to lt100,000 copies/ml
• Loss of HBeAg anti-HBe seroconversion
• Normalization of ALT level
• HBeAg- patients
• Serum HBV DNA decrease to undetectable by PCR
• Normalization of ALT level
• On-treatment response initial / maintained
• Off-treatment sustained response FU mo 6 or 12

Lok A et al., Gastro 20011201828
41
Randomized controlled trial of lamivudine in
patients with advanced liver disease HBeAg
and/or serum HBV DNA gt700,000 gEq/mL
with disease progression
21
Placebo
P0.001
9
Lamivudine
Time to disease progression (months)
Placebo (n215) ITT
population Lamivudine
(n436) p0.001
Liaw YF, NEJM 2004 3511521
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Licensed HBV therapies and those under
development


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Who Should be Treated?

• Not a question of who to treat but when treat
  now or monitor and treat when indicated
• All HBV carriers are potential treatment
  candidates
• A patient who is not a treatment candidate now
  can be a treatment candidate in the future
• Changes in HBV replication status and/or
  activity/stage of liver disease
• Availability of new and better treatments

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When to start treatment?
Benefits
Risks
Likelihood of sustained response cirrhosis
and HCC
Side effects Drug resistance
Patients age Co-morbid illness Costs
Likelihood of cirrhosis / HCC in the next 10-20
yrs Likelihood of sustained viral suppression
after a defined course of treatment
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What should be the primary treatment?
Long-term Benefits
Long-term Risks
Antiviral potency Durability of response
Side effects Drug resistance
Contraindications Ease of administration Duration
of Rx Costs of Rx monitoring Patient and
provider preference
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When can treatment be stopped?

• IFN treatment finite duration, 12 mos
• Nucleoside/tide analogues
• HBeAg patients 6-12 mos after HBeAg
  seroconversion (50 after 5 yr Rx)
• HBeAg- patients endpoint not defined,
  ?until HBsAg loss (5 after 5 yr)
• Cirrhosis patients endpoint not defined,
  ?life-long

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Hepatitis B can be a deadly diseaseBUTIt can be
prevented, and it can be treated

• GET TESTED