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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

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Hepatitis b l.jpg

HEPATITIS B

Anna S. F. Lok, MD

University of Michigan

Ann Arbor, MI


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What is Hepatitis B?

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


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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


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Geographic Distribution of

Chronic HBV Infection

HBsAg Prevalence

8% - High

2-7% - Intermediate

<2% - Low


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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


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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”


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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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100

80

60

%

Risk

40

20

0

Neonates

Infants

Children

Adults

Age at Infection

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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HBV DNA

HBeAg

Anti-HBe

HBsAg

Anti-HBc

Anti-HBc IgM

Months

Years

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 and infectivity

  • 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


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Indications for HBV Vaccines and infectivity

  • 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 and infectivity

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 2001;135:796


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Impact of HBV Vaccination on Incidence Taiwanese children

of HCC in Taiwanese Children

Universal Vaccination of Newborns

Chang MH, NEJM 1997;336:1855


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Hepatitis B Taiwanese childrenFactors 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 Taiwanese children

Immune

Immune

Low replicative

Reactivation

tolerance

clearance

phase

phase

HBeAg - / anti-HBe + (PC/CP variants)

HBeAg + (wild)

>

<

<

>

>105 cp/ml

HBV-DNA

<105 cp/ml

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

HBeAg +

Chronic hepatitis

Inactive-carrier state

HBeAg –

Chronic hepatitis


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Unique Aspects of Taiwanese childrenHepatitis 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 Taiwanese children

  • 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 Taiwanese children

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


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Stages of chronic HBV infection Taiwanese children

Immune

Immune

Low replicative

Reactivation

tolerance

clearance

phase

phase

HBeAg - / anti-HBe + (PC/CP variants)

HBeAg + (wild)

>

<

<

>

>105 cp/ml

HBV-DNA

<105 cp/ml

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

HBeAg +

Chronic hepatitis

Inactive-carrier state

HBeAg –

Chronic hepatitis


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Inactive HBsAg Carrier State Taiwanese children

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


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HBeAg – Chronic Hepatitis B Taiwanese children

  • 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


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Risk factors for progression to cirrhosis Taiwanese children

Viral factors Host Factors External Factors

  • Persistently high HBV DNA levels

  • HBV precore/CP variant?

  • HBV genotype (C > 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 Taiwanese children

Viral factors Host Factors External Factors

  • Persistently high HBV DNA levels

  • HBV CP variant

  • HBV genotype (C > 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? Taiwanese children

  • 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 Taiwanese children

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 B Taiwanese childrenDefinition 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


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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) ITT population

Lamivudine (n=436) p=0.001

Liaw YF, NEJM 2004; 351:1521


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Licensed HBV therapies advanced liver disease and those under development


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Who Should be Treated? advanced liver disease

  • 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? advanced liver disease

Benefits

Risks

Likelihood of

sustained response

cirrhosis and HCC

Side effects

Drug resistance

Patient’s 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? advanced liver disease

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? advanced liver disease

  • 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 disease advanced liver disease BUTIt can be prevented, and it can be treated

GET TESTED


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