HEPATITIS B

Anna S. F. Lok, MD

University of Michigan

Ann Arbor, MI

• Hepatitis B is an infection of the Hepatitis B is an infection of the

liver caused by the hepatitis B virus liver caused by the hepatitis B virus

What is Hepatitis B?What is Hepatitis B?

WorldwideWorldwide

• 400 million people are chronic carriers 400 million people are chronic carriers

• About 75% of HBV carriers live in AsiaAbout 75% of HBV carriers live in Asia

• 0.5-1 million deaths per year due to HBV0.5-1 million deaths per year due to HBV

AsiaAsia

• Liver cancer is the 2Liver cancer is the 2ndnd cancer killer among Asian cancer killer among Asian men and the 5men and the 5thth cancer killer among Asian women cancer killer among Asian women

• Roughly 40% of Asian men and 15% of Asian Roughly 40% of Asian men and 15% of Asian women with chronic hepatitis B die of a liver-women with chronic hepatitis B die of a liver-related illnessrelated illness

How common is hepatitis B? How common is hepatitis B?

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence

8% - High

2-7% - Intermediate

<2% - Low

• Less than 0.5% (1 in 200) Americans have Less than 0.5% (1 in 200) Americans have chronic hepatitis Bchronic hepatitis B

• About 10-15% (1 in 8 to 10) Asian Americans About 10-15% (1 in 8 to 10) Asian Americans have chronic hepatitis Bhave chronic hepatitis B

• About 50% (1 in 2) of the people in the US with About 50% (1 in 2) of the people in the US with chronic hepatitis B are Asian Americanschronic hepatitis B are Asian Americans

• A much higher percent of Asian Americans A much higher percent of Asian Americans compared to Americans of other races have compared to Americans of other races have hepatitis Bhepatitis B

Hepatitis B and Asian Americans Hepatitis B and Asian Americans

• Hepatitis B is very common in AsiaHepatitis B is very common in Asia

• Many Asian Americans were infected with Many Asian Americans were infected with hepatitis B before they came to the UShepatitis B before they came to the US

• Asian Americans born in the US may be Asian Americans born in the US may be infected through their mother or other family infected through their mother or other family members, who are HBV carriersmembers, who are HBV carriers

Why is Hepatitis B so common among Why is Hepatitis B so common among Asian Americans? Asian Americans?

National Health and Nutrition Examination Survey National Health and Nutrition Examination Survey (NHANES) (NHANES)

• Survey on prevalence of various diseases in the USSurvey on prevalence of various diseases in the US

• Sampled cohorts representative of US populationSampled cohorts representative of US population

• African Americans and Hispanics over sampled to ensure African Americans and Hispanics over sampled to ensure sufficient number studied to permit conclusions on sufficient number studied to permit conclusions on prevalence of diseases among those racial/ethnic groupsprevalence of diseases among those racial/ethnic groups

• Reliable data not available for Asian Americans because Reliable data not available for Asian Americans because Asians not over sampled, number studied too small to be Asians not over sampled, number studied too small to be conclusive, and Asians lumped as “other racial/ethnic conclusive, and Asians lumped as “other racial/ethnic groups”groups”

Hepatitis B and Asian AmericansHepatitis B and Asian Americans

• NHANES III – 1988-1994NHANES III – 1988-1994

– Current and past HBV infection: 4.9%Current and past HBV infection: 4.9%

– Chronic HBV infection: 0.4%Chronic HBV infection: 0.4%

• Highest prevalence among blacks Highest prevalence among blacks

• 5%-15% among immigrants from Central and 5%-15% among immigrants from Central and Southeast Asia, Middle East and AfricaSoutheast Asia, Middle East and Africa

• Prevalence data for Asians not availablePrevalence data for Asians not available

Hepatitis B and Asian AmericansHepatitis B and Asian Americans

Federal and state governments – public healthFederal and state governments – public health

• Overall prevalence is low: not a very common problem Overall prevalence is low: not a very common problem herehere

• Most of those affected by HBV are Asians – who are Most of those affected by HBV are Asians – who are politically silent (squeaky wheel gets the oil)politically silent (squeaky wheel gets the oil)

NIH, CDC, Scientific organizations – research and NIH, CDC, Scientific organizations – research and educationeducation

• Not a common problemNot a common problem

• With an effective vaccine, hepatitis B will be eradicated in With an effective vaccine, hepatitis B will be eradicated in the next generation.. we predicted that in the 1980sthe next generation.. we predicted that in the 1980s

• Competition for $$ and attention from other more trendy Competition for $$ and attention from other more trendy diseases: HIV, HCV, SARS, avian ‘flu, cancers….diseases: HIV, HCV, SARS, avian ‘flu, cancers….

Why is it that hepatitis B gets so Why is it that hepatitis B gets so

little attention in the US?little attention in the US?

• HBV is more easily spread than HIV (virus that HBV is more easily spread than HIV (virus that causes AIDS) and HCVcauses AIDS) and HCV

• HBV can live outside the human body for up to 7 HBV can live outside the human body for up to 7 daysdays

• People with chronic hepatitis B can have very People with chronic hepatitis B can have very large amounts of virus in their blood – serum large amounts of virus in their blood – serum HBV DNA up to 11 logHBV DNA up to 11 log1010 copies/mL (100 billion) copies/mL (100 billion)

How is HBV spread? How is HBV spread?

Mainly through blood and bodily secretionsMainly through blood and bodily secretions

• Infected mother to babies at birth Infected mother to babies at birth

• Contact with blood from carriers through Contact with blood from carriers through wounds, contaminated household articles such wounds, contaminated household articles such as razors, toothbrushes, or contaminated as razors, toothbrushes, or contaminated needles used for tattoos and injecting drugsneedles used for tattoos and injecting drugs

• Sexual contact with carriersSexual contact with carriers

How is HBV spread? How is HBV spread?

HBV is not spread by:HBV is not spread by:

• Hugging or kissingHugging or kissing

• Coughing or sneezingCoughing or sneezing

• Sharing eating utensilsSharing eating utensils

How is HBV spread? How is HBV spread?

Outcome of Acute HBV Infection

Acute HepatitisSubclinicalHepatitis

FulminantHepatitis

Death

Acute Infection

Chronic Infection

Recovery

Hepatitis B may be Hepatitis B may be ACUTEACUTE

• Recent infectionRecent infection

• May have no symptoms, especially in childrenMay have no symptoms, especially in children

• Common symptoms: easily tired, poor appetite, Common symptoms: easily tired, poor appetite, nausea, abdominal discomfort, jaundicenausea, abdominal discomfort, jaundice

• Roughly 95% recover, usually in 2-3 monthsRoughly 95% recover, usually in 2-3 months

• About 1% severe hepatitis with acute liver failureAbout 1% severe hepatitis with acute liver failure

• About 5% go on to chronic infection, lasts longer About 5% go on to chronic infection, lasts longer than 6 months than 6 months

What is Hepatitis B? What is Hepatitis B?

Risk of Chronic HBV InfectionRisk of Chronic HBV Infection

Age at InfectionAge at Infection

00

2020

4040

6060

8080

100100

NeonatesNeonates InfantsInfants ChildrenChildren AdultsAdults

%Risk%

Risk

Outcome of Chronic HBV Infection

Chronic HBV Infection

Inactive Carrier State

Cirrhosis

HCC

Chronic Hepatitis

Hepatitis B may be Hepatitis B may be CHRONICCHRONIC

• Long-lasting infection, persists for more than 6 Long-lasting infection, persists for more than 6 monthsmonths

• Most people have no symptomsMost people have no symptoms

• Common symptoms: easily tired, poor appetite, Common symptoms: easily tired, poor appetite, nausea, abdominal discomfortnausea, abdominal discomfort

• Can go on to cirrhosis, liver failure, liver cancer, Can go on to cirrhosis, liver failure, liver cancer, and deathand death

What is Hepatitis B? What is Hepatitis B?

• The only way to know is to have a blood testThe only way to know is to have a blood test

• Most people with hepatitis B have no symptoms Most people with hepatitis B have no symptoms until late stages of liver disease until late stages of liver disease

• Tests for hepatitis B or liver enzymes are not Tests for hepatitis B or liver enzymes are not included in most routine check-upsincluded in most routine check-ups

• Hepatitis B may be present even if liver enzymes Hepatitis B may be present even if liver enzymes were tested and were normalwere tested and were normal

How can hepatitis B be diagnosed?How can hepatitis B be diagnosed?

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 InfectionAcute HBV Infection

0 2 4 6 0 2 4 6

HBsAg

Anti-HBsAnti-HBs

Anti-HBcAnti-HBc

Anti-HBc IgMAnti-HBc IgM

Months YearsMonths Years

HBeAg Anti-HBe

HBV DNA

Anti-HBeAnti-HBe

Chronic HBV InfectionChronic HBV Infection

HBV DNA

HBeAg

MonthsMonths YearsYears

Anti-HBc IgMAnti-HBc IgM

Anti-HBcAnti-HBc

Anti-HBeAnti-HBe

HBsAgHBsAg

• 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

Serum HBV DNA is the most reliable Serum HBV DNA is the most reliable marker of HBV replication and infectivitymarker of HBV replication 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

Hepatitis B Vaccines Hepatitis B 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

Indications for HBV Vaccines Indications for HBV Vaccines

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

%%

00

1010

2020

3030

19841984 19941994 19991999

Vaccination of infants born to HBsAg+ mother

Vaccination of infants born to HBsAg+ mother

HBsAg+HBsAg+

Anti-HBc+Anti-HBc+

Universal vaccination of infant/preschool children

Universal vaccination of infant/preschool children

Ni YH, Ann Intern Med 2001;135:796 Ni YH, Ann Intern Med 2001;135:796

Impact of HBV Vaccination on Incidence of HCC in Taiwanese Children

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

1981-1986 1986-1990 1990-1994

Avg

Ann

ual I

ncid

ence

of H

CC

(per

100

,000

)

Universal Vaccination of Newborns

Chang MH, NEJM 1997;336:1855

Hepatitis BFactors affecting disease activity and progression

VIRUSGenotype

Molecular Variants

HOSTGender

AgeImmune Response

Genetics

ENVIRONMENTAlcohol

HCV, HDV, HIVCarcinogens

< <> >HBeAg + (wild) HBeAg - / anti-HBe + (PC/CP variants)

ALT

HBV-DNA

Normal /mild CH

moderate/severe CH moderate/severe CHNormal/mild CH

cirrhosis

Inactive-carrier state HBeAg – Chronic hepatitis

HBeAg + Chronic hepatitis

Immune tolerance

Immune clearance

Low replicative phase

Reactivation phase

cirrhosis

109-1010 cp/ml107-108 cp/ml

<105 cp/ml

>105 cp/ml

Inactive cirrhosis

Stages of chronic HBV infection

Clinical Manifestations/Natural historyClinical Manifestations/Natural history

• Immune tolerant phase

• Frequent exacerbations and reactivations

• Increased risks of HCC

Unique Aspects of Unique Aspects of Hepatitis B among AsiansHepatitis B among Asians

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

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

< <> >HBeAg + (wild) HBeAg - / anti-HBe + (PC/CP variants)

ALT

HBV-DNA

Normal /mild CH

moderate/severe CH moderate/severe CHNormal/mild CH

cirrhosis

Inactive-carrier state HBeAg – Chronic hepatitis

HBeAg + Chronic hepatitis

Immune tolerance

Immune clearance

Low replicative phase

Reactivation phase

cirrhosis

109-1010 cp/ml107-108 cp/ml

<105 cp/ml

>105 cp/ml

Inactive cirrhosis

Stages of chronic HBV infection

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

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

Risk factors for progression to cirrhosis

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

Risk factors for progression to HCC

• Do not drink alcoholDo not drink alcohol

• Do not take any herbal medicine that might hurt Do not take any herbal medicine that might hurt the liverthe liver

• Eat a balanced diet, exercise regularly, avoid Eat a balanced diet, exercise regularly, avoid getting overweightgetting overweight

Hepatitis B is a chronic health problem, HBV levels Hepatitis B is a chronic health problem, HBV levels and severity of liver damage can change with time, and severity of liver damage can change with time, see their doctor and get tested at least once a year see their doctor and get tested at least once a year even if they have no symptomseven if they have no symptoms

What can patients do to protect their liver?What can patients do to protect their liver?

Goals

• Suppression of HBV replication

• Decrease hepatic necroinflammation and

fibrosis

• Prevent progression to cirrhosis, liver

failure and HCC

Treatment of Chronic Hepatitis B

Treatment of Chronic Hepatitis BDefinition 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

Time to disease progression (months)

Placebo (n=215) ITT population Lamivudine (n=436) p=0.001

Lamivudine

Placebo

P=0.001

21%

9%

Liaw YF, NEJM 2004; 351:1521

Licensed HBV therapies and those under development

Licensed Phase III Phase II Phase IInterferon -2b

Lamivudine

Adefovir

Entecavir

Peg IFN -2a

Emtricitabine (FTC)*

Tenofovir (TFV)*

FTC+ TFV*

Emtricitabine

PegIFN -2b

Telbivudine (LdT)

Clevudine

Tenofovir

Pradefovir

Valtorcitabine (LdC)

LB80380

Remofovir (MB06866)

Elvucitabine (Fd4C)

BAM 205

IL-12

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?

BenefitsRisks

Patient’s age Co-morbid illnessCosts

Likelihood of sustained response cirrhosis and HCC

Side effects

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

ContraindicationsEase of administration

Duration of RxCosts of Rx & monitoring

Patient and provider preference

Antiviral potency

Durability of responseSide effects

Drug resistance

Long-term Risks

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. LAM-R mutants

Activity vs. LAM-R mutants lower

No resistant mutants

Resistant mutants

15-30% yr 1

70% yr 5

Resistant mutants

0 yr 1, 29% yr 5

~15-20% yr 2 (LAM-R pts

switched to ADV only)

Resistant mutants

0 yr 1, <1% yr 2

~10% yr 2 (LAM-R pts)

Frequent side effects

(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

BUTIt can be prevented, and it can be treated

GET TESTED