Hepatitis B: Impeding Liver Hepatitis B: Impeding Liver

Cancer through Prevention and Cancer through Prevention and ManagementManagement

Raymond S. Koff, M.D.Raymond S. Koff, M.D.Clinical Professor of MedicineClinical Professor of Medicine

University of Connecticut University of Connecticut Health Science CenterHealth Science Center

Farmington, ConnecticutFarmington, Connecticut

Raymond S. Koff, M.D.Raymond S. Koff, M.D.Clinical Professor of MedicineClinical Professor of Medicine

University of Connecticut University of Connecticut Health Science CenterHealth Science Center

Farmington, ConnecticutFarmington, Connecticut

Hepatitis B

Measles

Tetanus

Hib

Pertussis

Yellow Fever

Diphtheria

Polio

900,000900,000

888,000888,000

410,000410,000

346,00346,0000

30,00030,000

400,00400,0000

5,005,0000

<<1,001,0000

Global Mortality from Vaccine Preventable DiseasesGlobal Mortality from Vaccine Preventable DiseasesD

i seases

Di s

eases

Estimated annual deaths (1999)Estimated annual deaths (1999)

Hepatocellular CarcinomaHepatocellular Carcinoma

● Among solid tumors, 5th highest incidence worldwide and 3rd most common cause of cancer deaths

● In the U.S. in 2007, 13th most common cancer and increasing faster than all others from 1995 to 2004; 8th most common cause of cancer deaths

● Despite advancing technology and available treatments, 5-year survival rates are generally less than 5%

Geographic Prevalence of Chronic Geographic Prevalence of Chronic Hepatitis B: Impact of MigrationHepatitis B: Impact of Migration

World Health Organization. Available at: World Health Organization. Available at: http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm. Accessed July 8, http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm. Accessed July 8, 2005.2005.2002 Yearbook of Immigration Statistics. 2002 Yearbook of Immigration Statistics. Available at:Available at: http://uscis.gov/graphics/shared/aboutus/statistics/yearbook/2002.pdf. Accessed July 8, 2005.http://uscis.gov/graphics/shared/aboutus/statistics/yearbook/2002.pdf. Accessed July 8, 2005.Mahoney FJ. Mahoney FJ. Clin Microbiol RevClin Microbiol Rev. 1999;12:351–366.. 1999;12:351–366.

Immigration Numbers Summed by Continent From 1996–2002Immigration Numbers Summed by Continent From 1996–2002

HBsAg PrevalenceHBsAg PrevalenceHigh (>8%)

Intermediate (2–8%)

Low (<2%)

~2 million Asians~2 million Asians

~400,000~400,000South AmericansSouth Americans

~350,000 ~350,000 AfricansAfricans

~930, 000 ~930, 000 EuropeansEuropeans

Chronic Hepatitis Chronic Hepatitis B B

Morbidity and Mortality, U.S. Morbidity and Mortality, U.S.

Previously infected individuals: ~10 millionPreviously infected individuals: ~10 million

Actively infected individuals: ~1-1.25 millionActively infected individuals: ~1-1.25 million

Annual cirrhosis deaths: ~4,000Annual cirrhosis deaths: ~4,000

Annual HCC deaths: ~1,000-1,500Annual HCC deaths: ~1,000-1,500

HBV Disease Progression

1. Torresi J. 1. Torresi J. GastroenterologyGastroenterology. 2000;118(2 suppl 1):S83. 2000;118(2 suppl 1):S83–S–S103.103.2. Fattovich G. 2. Fattovich G. HepatologyHepatology. 1995;21:77–82.. 1995;21:77–82.3. Moyer LA. 3. Moyer LA. Am J Prev MedAm J Prev Med. 1994;10:45. 1994;10:45––55.55.4. Perrillo R. 4. Perrillo R. HepatologyHepatology. 2001;33:424–432.. 2001;33:424–432.

Acute Acute infectioninfection

ChronicChronic infectioninfection CirrhosisCirrhosis Death

55––10%10%1,31,3

Liver failure

30%30%11

25% in 5 years

Liver Liver Cancer Cancer (HCC)(HCC)

Chronic HBV is the Chronic HBV is the 66thth leading cause of leading cause of liver transplantation liver transplantation

in the USin the US44

Liver Liver transplant-transplant-ationation

Age at InfectionAge at InfectionAge at InfectionAge at Infection

00

2020

4040

6060

8080

100100

NeonatesNeonates InfantsInfants ChildrenChildren AdultsAdults

%Risk%

Risk

Risk of Chronic HBV Infection

Chronic HBV InfectionChronic HBV Infection Chronic HBV InfectionChronic HBV Infection

Years after clinical presentationYears after clinical presentation

00

2020

4040

6060

8080

100100

00 11 22 33 44 55 66 77 88 991010

1111

1212

1313

% Probability

% Probability

Fattovich G, Gut 1991; 32:294Fattovich G, Gut 1991; 32:294

Overall Risk of Progression to Overall Risk of Progression to CirrhosisCirrhosis

Overall Risk of Progression to Overall Risk of Progression to CirrhosisCirrhosis

Fattovich, et al., Hepatology 1995; 21:77Fattovich, et al., Hepatology 1995; 21:77

Cumulative Probability of Developing Cumulative Probability of Developing HCC in Patients with HBV-Related HCC in Patients with HBV-Related CirrhosisCirrhosis

Cumulative Probability of Developing Cumulative Probability of Developing HCC in Patients with HBV-Related HCC in Patients with HBV-Related CirrhosisCirrhosis

00101000 998877665544332211

%%

YearYear

2020

2525

1515

Chronic HBV Chronic HBV InfectionInfection

Natural History of HBeAg-positive Natural History of HBeAg-positive Disease in a 30-year old AsianDisease in a 30-year old Asian

Health stateHealth state Lifetime Lifetime riskrisk

• Cirrhosis: ~42%Cirrhosis: ~42%

• Decompensation: ~14%Decompensation: ~14%

• Hepatocellular carcinoma: Hepatocellular carcinoma: ~25% ~25%

• Liver-related death: ~37%Liver-related death: ~37%

Chronic Hepatitis BChronic Hepatitis B

Higher HBV DNA levels (>10Higher HBV DNA levels (>104 4

copies/mL)copies/mL)

HBeAg-positivityHBeAg-positivity

Persistent ALT elevationPersistent ALT elevation

HIV, alcohol, immunosuppressionHIV, alcohol, immunosuppression

Higher HBV DNA levels (>10Higher HBV DNA levels (>104 4

copies/mL)copies/mL)

HBeAg-positivityHBeAg-positivity

Persistent ALT elevationPersistent ALT elevation

HIV, alcohol, immunosuppressionHIV, alcohol, immunosuppression

Chronic Hepatitis B Chronic Hepatitis B

Factors Influencing Risk of Factors Influencing Risk of CirrhosisCirrhosis

Cumulative Incidence of Cirrhosis for Five HBV DNA

Categories (n=3,774)Multivariate adjusted HR

0

0.1

0.2

0.3

0.4

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Year of Follow-up

Cu

mu

lati

ve In

cid

ence

of

Liv

er C

irrh

osi

s

≥ 1.0 x 101.0 - 9.9 x 101.0 - 9.9 x 10300 - 9.9 x 10< 300

Iloeje UH et al, Iloeje UH et al, Gastroenterology 2006;Gastroenterology 2006;130:678-86: The Taiwan Natural History Study130:678-86: The Taiwan Natural History Study

2.5 1.41.0

5.6

6.5

P value for log-rank test, <0.001

65

43

Serum HBV DNA Incidence Adj. Rel Risk Serum HBV DNA Incidence Adj. Rel Risk

pp(copies/mL) (per 100,000)(copies/mL) (per 100,000)

>>1.0 x 101.0 x 106 6 1150 11.6 1150 11.6 <.001<.001

>>1.0 x 101.0 x 1055 - <1.0 x 10 - <1.0 x 106 6 952 7.2 952 7.2

<.001<.001

>>1.0 x 101.0 x 1044 - <1.0 x 10 - <1.0 x 105 5 315 2.4315 2.4

<.008<.008

>300 - <1.0 x 10>300 - <1.0 x 104 4 112 0.9 112 0.9

NSNS

<300 145 1.0 <300 145 1.0

------

Serum HBV DNA Incidence Adj. Rel Risk Serum HBV DNA Incidence Adj. Rel Risk

pp(copies/mL) (per 100,000)(copies/mL) (per 100,000)

>>1.0 x 101.0 x 106 6 1150 11.6 1150 11.6 <.001<.001

>>1.0 x 101.0 x 1055 - <1.0 x 10 - <1.0 x 106 6 952 7.2 952 7.2

<.001<.001

>>1.0 x 101.0 x 1044 - <1.0 x 10 - <1.0 x 105 5 315 2.4315 2.4

<.008<.008

>300 - <1.0 x 10>300 - <1.0 x 104 4 112 0.9 112 0.9

NSNS

<300 145 1.0 <300 145 1.0

------

HBV DNA Levels and Risk of HBV DNA Levels and Risk of Hepatocellular Hepatocellular Carcinoma: The Taiwan Natural Carcinoma: The Taiwan Natural History History Study Study**

* Chen C-J et al. JAMA, 2006* Chen C-J et al. JAMA, 2006

HBV Vaccination in TaiwanHBV Vaccination in Taiwan

%%

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 infants/preschool children

Universal vaccination of infants/preschool children

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

Impact on HBV Infection in Children

HBV Vaccination in TaiwanHBV Vaccination in Taiwan

00

22

44

66

88

1981-19861981-1986 1986-19901986-1990 1990-19941990-1994

Annual Annual incidence of incidence of

HCCHCC(per (per

1,000,000)1,000,000)

Annual Annual incidence of incidence of

HCCHCC(per (per

1,000,000)1,000,000)

Universal Vaccination of Universal Vaccination of

NewbornsNewbornsUniversal Vaccination of Universal Vaccination of

NewbornsNewbornsChang MH, N Engl J Med 1997;336:1855Chang MH, N Engl J Med 1997;336:1855

Impact on Incidence of HCC in Children

Epidemiology of HBV

Hepatitis B VirusHepatitis B Virus

Estimates of Infectivity in Body Estimates of Infectivity in Body FluidsFluids

BloodBlood

SemenSemen

CSFCSF

SemenSemen

BloodBlood

Lowest Infectivity Lowest Infectivity

MostMost

UrineUrine

BreastBreastmilkmilk

SalivaSaliva

CervicovaginalCervicovaginalsecretionssecretions

TearsTears

Epidemiologic Characteristics of Epidemiologic Characteristics of Patients With Hepatitis B — US, Patients With Hepatitis B — US,

2005*2005*More than 70% of newly acquired infections in 2005 were

attributable to high-risk sexual activity or injection drug use

58%

15%10%

14%

32%

9%6% No risk factor identified

Injection drug use

Sexual contact withhepatitis B patient

Homosexual activity (male)

>1 sex partner

Surgery

Other

*Values total >100% because multiple risk factors could be reported for a single case.CDC. MMWR. 2007;56(SS-3):1-25.

Hepatitis BHepatitis B

Factors Associated with Sexual Factors Associated with Sexual TransmissionTransmission

• Multiple sexual partners, unprotected Multiple sexual partners, unprotected

sexsex

• Injecting drug user as sexual partnerInjecting drug user as sexual partner

• Duration of sexual activityDuration of sexual activity

• Male to female,male to male,female to Male to female,male to male,female to

malemale

• History or serologic evidence of otherHistory or serologic evidence of other sexually transmitted diseasessexually transmitted diseases

Prevention of Hepatitis B

Hepatitis B Prevention StrategiesHepatitis B Prevention Strategies

Reducing the Risk of InfectionReducing the Risk of Infection

• Decreasing exposure Decreasing exposure

opportunitiesopportunities

• Decreasing susceptibilityDecreasing susceptibility

- immunization with hepatitis B - immunization with hepatitis B

vaccinesvaccines

Non-vaccine Prevention of HBV

● Screening of blood donors for HBsAg, anti-Screening of blood donors for HBsAg, anti-HBc (future screening for HBV DNA)HBc (future screening for HBV DNA)

● Screening of organ and tissue donorsScreening of organ and tissue donors● Safe-sex practicesSafe-sex practices● Reduction in sharing equipment for IV drug Reduction in sharing equipment for IV drug

useuse● Needle-exchange programs and education Needle-exchange programs and education

about cleaning equipmentabout cleaning equipment● Avoidance of intranasal cocaine useAvoidance of intranasal cocaine use● Inspection of tattoo and body-piercing Inspection of tattoo and body-piercing

shopsshops● Sterilization of manicure/pedicure Sterilization of manicure/pedicure

equipment equipment ● Avoidance of multidose vial misuseAvoidance of multidose vial misuse

Vaccine-based Strategies for Vaccine-based Strategies for Eliminating HBV Transmission in the Eliminating HBV Transmission in the U.S.U.S.• Maternal screening for HBsAg:Maternal screening for HBsAg: providing providing

post-exposure prophylaxis to infants of post-exposure prophylaxis to infants of HBsAg-positive womenHBsAg-positive women

- HBIG within 12 hours of birth and first of - HBIG within 12 hours of birth and first of

3 3 doses of HBV vaccinedoses of HBV vaccine

• Routine vaccination of all newborn infantsRoutine vaccination of all newborn infants

• Catch-up vaccination:Catch-up vaccination: for children aged <19 for children aged <19

yrs yrs

• Targeting high risk:Targeting high risk: children, adolescents, children, adolescents,

adultsadults

• Screening and vaccination:Screening and vaccination: household and household and

family members of HBsAg-positive personsfamily members of HBsAg-positive persons

0

0.5

1

1.5

1990 1992 1994 1996 1998 2000 2002 2004

0

2

4

6

8

10

1990 1992 1994 1996 1998 2000 2002 2004

Year

Cas

es/1

00,0

00

0–11 years old

95% decline95% decline

71% decline71% decline

94% decline94% decline

20+ years old20+ years old

12–19 years old12–19 years old

Source: CDC, National Notifiable Diseases Surveillance System (NNDSS).Source: CDC, National Notifiable Diseases Surveillance System (NNDSS).

Incidence of Acute Hepatitis B Incidence of Acute Hepatitis B United States by Age (1990–United States by Age (1990–

2004)2004)

2007 Vaccine-based Strategies to Eliminate Hepatitis B Transmission in the Young

● Establish standing orders for first dose of HBV vaccine at birth

● Improve identification of and immunization of infants born to HBsAg-positive mothers and those in whom the maternal HBsAg status is unknown

● Develop HBV vaccination record reviews of all children aged 11 to 12 years and for individuals <19 years of age born in endemic regions

● Make hepatitis B vaccination a requirement for school entry● Incorporate HBV vaccine delivery into adolescent care

services

2007 Vaccine-based Strategies to Eliminate Hepatitis B Transmission in Adults

● Vaccinate high-risk adults attending facilities for individuals with high risks for sexual or parenteral exposure

● Educate adults in primary or specialty care settings about risks of infection, benefits of vaccination, and current recommendations; vaccinate those who report risks

● Vaccinate any individual requesting protection● Establish standing orders by health-care workers to

identify those recommended for vaccination and to vaccinate as part of routine care

● Initiate vaccination in individuals who fail to Initiate vaccination in individuals who fail to acknowledge a risk factoracknowledge a risk factor

Treatment of Chronic Treatment of Chronic Hepatitis B Hepatitis B

Suppression of viral replicationSuppression of viral replication

Improvement in hepatic necroinflammatory Improvement in hepatic necroinflammatory diseasedisease

Reduction in long-term sequelae: HBV-Reduction in long-term sequelae: HBV-associated cirrhosis, hepatocellular associated cirrhosis, hepatocellular carcinomacarcinoma

Reduction of infectivityReduction of infectivity

Chronic Hepatitis B Management Chronic Hepatitis B Management GoalsGoals

Effect of Lamivudine on Incidence Effect of Lamivudine on Incidence of HCC in Chronic HBV with of HCC in Chronic HBV with

Advanced FibrosisAdvanced Fibrosis

Liaw YF, et al.Liaw YF, et al. N Engl J Med N Engl J Med 2004;351:1521–1531. 2004;351:1521–1531.

Length of Therapy (months)

Lamivudine

Placebo

Dia

gn

osi

s o

f H

CC

(%

)

0

10

60 12 18 24 30 36

P = 0.047

Chronic Hepatitis BChronic Hepatitis B

Patients with:Patients with:

Elevated or normal ALT levelsElevated or normal ALT levels andand::

HBeAg-positive and HBV DNA HBeAg-positive and HBV DNA ≥≥10104-54-5 copies/mL copies/mL

by PCRby PCR

HBeAg-negative and HBV DNA HBeAg-negative and HBV DNA ≥≥101044 copies/mL by PCRcopies/mL by PCR

+/- liver biopsy evidence of disease +/- liver biopsy evidence of disease

Cirrhosis with detectable HBV DNACirrhosis with detectable HBV DNA

Candidates for TreatmentCandidates for Treatment

HBV Treatment Options in 2008HBV Treatment Options in 2008

● Pegylated interferon alfa-2aPegylated interferon alfa-2a● Interferon alfa-2bInterferon alfa-2b

● Nucleoside analogsNucleoside analogs– EntecavirEntecavir– LamivudineLamivudine– TelbivudineTelbivudine

● Nucleotide analogsNucleotide analogs– AdefovirAdefovir– Tenofovir (likely to be FDA-approved Tenofovir (likely to be FDA-approved

soon)soon)

Chronic Hepatitis BChronic Hepatitis B

Comparing Oral Antivirals and Comparing Oral Antivirals and InterferonInterferon

Orals IFNOrals IFN Oral administration: Yes NoOral administration: Yes No

Side effects:Side effects: Minimal Frequent Minimal Frequent

Duration of treatment: Prolonged Finite Duration of treatment: Prolonged Finite

Flares during treatment: Rare YesFlares during treatment: Rare Yes

Resistant mutant Yes NoResistant mutant Yes No

Rate of HBsAg clearance: Low HigherRate of HBsAg clearance: Low Higher

Improved outcomes: Yes YesImproved outcomes: Yes Yes

Treatment of HBV Patients:Treatment of HBV Patients: Now Now and and

in the Futurein the Future

● Focus on HBV DNA suppressionFocus on HBV DNA suppression● Treatment decisions based on HBV DNA Treatment decisions based on HBV DNA

levels, disease severity, drug efficacy and levels, disease severity, drug efficacy and resistance patterns (for oral agents)resistance patterns (for oral agents)

● Combination oral therapy emergingCombination oral therapy emerging

● New agents with prolonged activity after New agents with prolonged activity after end-of-treatment, e.g. clevudineend-of-treatment, e.g. clevudine

Other Management Other Management StrategiesStrategies

● Immunization against HAV, other infectionsImmunization against HAV, other infections● Avoidance of alcohol, hepatotoxic herbalsAvoidance of alcohol, hepatotoxic herbals

● Screening for hepatocellular carcinomaScreening for hepatocellular carcinoma

- imaging studies, AFP, others- imaging studies, AFP, others

- appropriate timing- appropriate timing

● Case-finding (family, non-family contacts) Case-finding (family, non-family contacts) for for

vaccinationvaccination

Summary

● Hepatitis B is the major global cause of HCC

● Safe and effective vaccines: result in dramatic declines of HBV infection in children and HCC

● Many at-risk individuals remain unvaccinated; a large reservoir of infected persons exists

● Treatment should reduce HBV transmission and improves outcomes but is expensive and long-term for most patients

● Concomitantly with increasing vaccine coverage, education on reducing high-risk lifestyles must be a continuing focus