Transcript Slide 1

HEPATITIS B
Anna S. F. Lok, MD
University of Michigan
Ann Arbor, MI
What is Hepatitis B?
•
Hepatitis B is an infection of the
liver caused by the hepatitis B virus
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 liverrelated illness
Geographic Distribution of
Chronic HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
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
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
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”
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
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….
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)
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
How is HBV spread?
HBV is not spread by:
•
Hugging or kissing
•
Coughing or sneezing
•
Sharing eating utensils
Outcome of Acute HBV Infection
Recovery
Subclinical
Hepatitis
Acute Hepatitis
Acute Infection
Chronic Infection
Fulminant
Hepatitis
Death
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
Risk of Chronic HBV Infection
100
80
%
60
Risk 40
20
0
Neonates
Infants
Children
Age at Infection
Adults
Outcome of Chronic HBV Infection
Chronic HBV Infection
Inactive Carrier
State
Chronic Hepatitis
Cirrhosis
HCC
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
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
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
Acute HBV Infection
HBV
DNA
HBeAg
Anti-HBe
Anti-HBe
Anti-HBs
AntiHBc
HBsAg
0
Anti-HBc
IgM
2
Months
4
6
Years
Chronic HBV Infection
HBV DNA
HBeAg
Anti-HBe
HBsAg
Anti-HBc
Anti-HBc IgM
Months
Years
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
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: >15 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
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
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%
Impact of HBV vaccination on HBV
infection rates in Taiwanese children
30
HBsAg+
Anti-HBc+
20
%
10
0
1984
Vaccination of infants
born to HBsAg+ mother

Universal vaccination
1994
of infant/preschool
children
Ni YH, Ann Intern Med 2001;135:796
1999
Impact of HBV Vaccination on Incidence
of HCC in Taiwanese Children
Avg Annual Incidence of HCC
(per 100,000)
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
1981-1986

1986-1990
Universal Vaccination of Newborns
Chang MH, NEJM 1997;336:1855
1990-1994
Hepatitis B
Factors affecting disease activity and progression
VIRUS
Genotype
Molecular Variants
HOST
Gender
Age
Immune Response
Genetics
ENVIRONMENT
Alcohol
HCV, HDV, HIV
Carcinogens
Stages of chronic HBV infection
Immune
tolerance
<
Immune
clearance
HBeAg + (wild)
Low replicative
phase
><
Reactivation
phase
HBeAg - / anti-HBe + (PC/CP variants)
>105
cp/ml
<105 cp/ml
HBV-DNA
109-1010 cp/ml
>
107-108 cp/ml
ALT
Normal /
mild CH
moderate/severe CH
Normal/mild CH
moderate/severe CH
cirrhosis
Inactive cirrhosis
cirrhosis
Inactive-carrier state
HBeAg –
Chronic hepatitis
HBeAg +
Chronic hepatitis
Unique Aspects of
Hepatitis B among Asians
Clinical Manifestations/Natural history
• Immune tolerant phase
• Frequent exacerbations and
reactivations
• Increased risks of HCC
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/treatmentinduced HBeAg seroconversion
Immune Clearance Phase
HBeAg → anti-HBe seroconversion
Predictors : ALT, age, gender, HBV genotype
Annual rate = 5-15%
Hepatitis Flares
⅔ HBeAg seroconversion preceded by flares
¼ flares followed by HBeAg seroconversion
More common in men
Increased risk of cirrhosis
Stages of chronic HBV infection
Immune
tolerance
<
Immune
clearance
HBeAg + (wild)
Low replicative
phase
><
Reactivation
phase
HBeAg - / anti-HBe + (PC/CP variants)
>105
cp/ml
<105 cp/ml
HBV-DNA
109-1010 cp/ml
>
107-108 cp/ml
ALT
Normal /
mild CH
moderate/severe CH
Normal/mild CH
moderate/severe CH
cirrhosis
Inactive cirrhosis
cirrhosis
Inactive-carrier state
HBeAg –
Chronic hepatitis
HBeAg +
Chronic hepatitis
Inactive HBsAg Carrier State
• HBsAg+
> 6 months
• HBeAg- , anti-HBe+
• Serum HBV DNA < 103 copies/ml
• Persistently normal ALT
• Outcome dependent on liver damage accrued
prior to entering inactive carrier state and any
subsequent reactivation
HBeAg – Chronic Hepatitis B
• HBsAg +
• HBeAg –
• Serum HBV DNA > 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
Risk factors for progression to cirrhosis
Viral factors
● Persistently high HBV
DNA levels
Host Factors
External Factors
● Older age
● Male gender
● HBV precore/CP variant?
● Advanced fibrosis
● HBV genotype (C > B)
● Persistent ALT elevation
● Recurrent hepatitis flares
● HDV, HCV coinfections
● HIV coinfection
● Alcohol
Risk factors for progression to HCC
Viral factors
● Persistently high HBV
Host Factors
External Factors
● Older age
● Alcohol
● Male gender
● Aflatoxin
● HBV CP variant
● Asians??
● Smoking
● HBV genotype (C > B)
● Advanced fibrosis
DNA levels
● Persistent ALT elevation
● Recurrent hepatitis flares
● HDV, HCV coinfections
● HIV coinfection
● Family history of HCC
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
Treatment of Chronic Hepatitis B
Goals
• Suppression of HBV replication
• Decrease hepatic necroinflammation and
fibrosis
• Prevent progression to cirrhosis, liver
failure and HCC
Treatment of Chronic Hepatitis B
Definition of Response
HBeAg+ patients
• Serum HBV DNA decrease to <100,000 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 2001;120:1828
Randomized controlled trial of lamivudine in
patients with advanced liver disease
HBeAg+ and/or serum HBV DNA >700,000 gEq/mL
% with disease
progression
21%
Placebo
P=0.001
9%
Lamivudine
Time to disease progression (months)
Placebo (n=215)
Lamivudine (n=436)
ITT population
p=0.001
Liaw YF, NEJM 2004; 351:1521
Licensed HBV therapies
and those under development
Licensed
Phase III
Interferon -2b
Emtricitabine
Lamivudine
PegIFN -2b
Phase II
Pradefovir
Entecavir
Valtorcitabine
Telbivudine (LdT) (LdC)
LB80380
Clevudine
Peg IFN -2a
Tenofovir
Adefovir
Emtricitabine
(FTC)*
Tenofovir
(TFV)*
FTC+ TFV*
Remofovir
(MB06866)
Elvucitabine
(Fd4C)
BAM 205
IL-12
Phase I
MCC 478
FLG
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
When to start treatment?
Benefits
Likelihood of
sustained response
cirrhosis and HCC
Risks
Side effects
Patient’s age
Co-morbid illness
Costs
Drug resistance
Likelihood of cirrhosis / HCC in the next 10-20 yrs
Likelihood of sustained viral suppression after a defined
course of treatment
What should be the primary treatment?
Long-term Benefits
Antiviral potency
Durability of response
Long-term
Risks
Side effects
Contraindications
Drug resistance
Ease of administration
Duration of Rx
Costs of Rx & monitoring
Patient and provider preference
IFN
Lamivudine
Adefovir
Entecavir
Parenteral
Oral
Oral
Oral
Finite duration
Long duration
Long duration
Long duration
More durable
response
Primary
nonresponse
in 25%
More potent than
LAM
Higher rate of
HBsAg loss
Effective vs. LAMR mutants
Activity vs. LAM-R
mutants lower
Resistant mutants Resistant mutants
Resistant mutants
No resistant
mutants
Frequent side
effects
15-30% yr 1
0 yr 1, 29% yr 5
0 yr 1, <1% yr 2
70% yr 5
~15-20% yr 2
(LAM-R pts
switched to ADV
only)
~10% yr 2 (LAM-R
pts)
(Nephrotoxic at
high doses)
(Limited track
record)
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
Hepatitis B can be a deadly
disease
BUT
It can be prevented,
and it can be treated
GET TESTED