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Baruch S. Blumberg, M.D., Ph.D. Senior Advisor to the President Fox Chase Cancer Center

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Baruch S. Blumberg, M.D., Ph.D. Senior Advisor to the President Fox Chase Cancer Center. SETI INSTITUTE DIRECTORS COLLOQUIUM Feb 20, 2008 Hepatitis B Virus.Discovery, the Present, and the Future. Baruch S. Blumberg Fox Chase Cancer Center, Philadelphia, PA. HBV VACCINE AND CANCER PREVENTION. - PowerPoint PPT Presentation

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Page 1: Baruch S. Blumberg, M.D., Ph.D

Baruch S. Blumberg, M.D., Ph.D.

Senior Advisor to the President

Fox Chase Cancer Center

Page 2: Baruch S. Blumberg, M.D., Ph.D

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SETI INSTITUTE DIRECTORS SETI INSTITUTE DIRECTORS COLLOQUIUMCOLLOQUIUM

Feb 20, 2008Feb 20, 2008

Hepatitis B Virus.Discovery, the Hepatitis B Virus.Discovery, the Present, and the Future.Present, and the Future.

Baruch S. BlumbergBaruch S. BlumbergFox Chase Cancer Center, Philadelphia, PAFox Chase Cancer Center, Philadelphia, PA

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1. HBV is a common infection2. It s a causative agent of HCC worldwide (estimate 80%)3. The vaccine is highly effective and in wide use4. HBV carrier rates have been dramatically reduced

by vaccination5. The vaccination program decreases the incidence

of HCC6. There are many cancers whose cause is attributed to

infectious agents7. There are probably others in which viruses contribute

to pathogenesis8. The pathogenesis and etiology of cancer is complex

with multiple “causes”9. A program for the identification and prevention of virus

related diseases should be a priority in the cancer program

HBV VACCINE AND CANCER PREVENTION

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Division of Clinical Research, 1980Division of Clinical Research, 1980

Fox Chase Cancer Center, Philadelphia, PA USAFox Chase Cancer Center, Philadelphia, PA USA

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Hepatitis BHepatitis B MorphologyMorphology

CharacteristicsCharacteristicsNucleic acid: DNAClassification:Hepadnavirus type 1Serotypes: MultipleIn vivo replication: Reverse transcription in liver and other tissues In vitro propagation:Primary hepatocyte culture and transfection by cloned HBV DNA

42 nm

22 nm

C

HBsAg

HBcAgHBV DNA

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The Discovery of Hepatitis B VirusThe Discovery of Hepatitis B Virus

1976: General 1976: General agreement on agreement on

identification of the identification of the Hepatitis B virusHepatitis B virus

1969: Postulated 1969: Postulated that HBV was that HBV was

cause of primary cause of primary liver cancerliver cancer

1970’s: Taiwan, HBV carriers had 1970’s: Taiwan, HBV carriers had more than more than 200 times higher200 times higher risk risk of developing HCC versus non-of developing HCC versus non-

carrierscarriers

1969: Invention of 1969: Invention of the the HBV vaccineHBV vaccine, ,

Novel method Novel method used in 1970’s to used in 1970’s to

manufacturemanufacture

1980’s: Report 1980’s: Report published on field published on field testing of vaccine, testing of vaccine,

followed by approval followed by approval from FDAfrom FDA

1963 : Identification of the “Australia antigen” 1963 : Identification of the “Australia antigen”

19671967: “Australia antigen “ recognized as part : “Australia antigen “ recognized as part of the Hepatitis B virusof the Hepatitis B virus

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“Hepatitis B is a viral infection of the liver. More than two thousand million (2 billion) people alive today have been infected with the hepatitis B virus. Approximately 350 million are chronically infected and are at high risk of serious illness and death from cirrhosis of the liverand primary liver cancer. Hepatitis B is preventable with a safe and effective vaccine — the first vaccine against cancer.” WHO website, 2004

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Primary Cancer of the LiverPrimary Cancer of the Liver

– Worldwide:Worldwide:

• Third most common cause of death from cancer Third most common cause of death from cancer in malesin males

• Seventh most common cause of death from Seventh most common cause of death from cancer in femalescancer in females

• More than a million deaths per yearMore than a million deaths per year

• Hepatitis B virus (about 80%) and hepatitis C Hepatitis B virus (about 80%) and hepatitis C virus account for most of these cancersvirus account for most of these cancers

• Many other factors involved in the pathogenesisMany other factors involved in the pathogenesis

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Epidemiology of HBV in the United StatesEpidemiology of HBV in the United States

1.25 to 2 million persons in the US are estimated to be chronically infected with high levels in some immigrant groups.

Gish RG, et al. J Viral Hepat. 2006, 13:787-798.McQuillan GM, et al. AM J Public Health. 1999, 89:14-18.CDC. MMWR. 2005, 54(RR-16):1-23.CDC.MMWR Weekly. 2006, 55:505-509

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Hepatitis B infects and kills more than Hepatitis B infects and kills more than HIV in ChinaHIV in China

HBVHBV

• Kills 250,000–Kills 250,000–280,000 annually280,000 annually22

• 130 million carriers 130 million carriers

• 9.7% prevalence 9.7% prevalence raterate44

1. WHO factsheet No.204; revised October 2000.2. Datamonitor Healthcare. Commercial perspectives: Hepatitis B and C – The Chinese way? 20043. WHO HIV/AIDS in the Asia and Pacific region 2003.4. Rosmawati M et al. J Gastroenterol Hepatol 2004;19:958–969

HIVHIV

• Killed 50,000–Killed 50,000–100,000 in 2003100,000 in 200333

• 840,000 infected840,000 infected33* *

• 0.12% prevalence 0.12% prevalence raterate33

*Official estimate of population aged 15–49

Hepatitis B virus is 100 times more transmittable than HIV1

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The Burden of Liver CancerThe Burden of Liver Cancer

• Liver cancer has a very low survival rateLiver cancer has a very low survival rate– In developing countries, most people with liver cancer die In developing countries, most people with liver cancer die

within months of diagnosiswithin months of diagnosis– Usually develops between 35 and 65 years of age, when Usually develops between 35 and 65 years of age, when

people are maximally productive and with family people are maximally productive and with family responsibilities. responsibilities.

• Fifth most common cause of death worldwideFifth most common cause of death worldwide11 – Around 0.5 million globally die of liver cancer each yearAround 0.5 million globally die of liver cancer each year2. 2. Rising Rising

incidence in the USincidence in the US11

– Liver cancer is the 2Liver cancer is the 2ndnd most common cause of cancer death in most common cause of cancer death in ChinaChina3. 3. Incidence rates have doubled in Taiwan since 1980’sIncidence rates have doubled in Taiwan since 1980’s44

– Third major cause of death in Korea, with 65-75% of patients Third major cause of death in Korea, with 65-75% of patients positive for HBsAgpositive for HBsAg55

1. Wright TL. Hepatology Research 2007;37(s2):S294-S2982. El-Serag HB. J Clin Gastroenterol 2002;35(5 Suppl 2):S72–78. 3. Tang Z-Y, et al. J Gastroenterol Hepatol 2004;19(Suppl 2): A1.4. Chen DS. Hepatology Research 2007;37(s2):S101-S1055. Han KH and Kim JK. Hepatology Research 2007;37(s2):S106-S109

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REGIONREGION BEFORE AFTER NOTES

China, regional study 16.0 % 1.4 Carriers, Population

Gambia, W. Africa 10.0% 0.6 Carriers, Population

Italy, Afragola, 10.5% 0.8 Males <12 y Carriers.

Italy, Afragola, no vaccine 18.0% 5.5 M. 13–60. Carriers

Japan 2.7% 0.9 Carriers, Population

Japan ~4.0% 0.04 Carriers, Children <6 y

Saudi Arabia** 6.7% 0.3 Carriers, Population

Spain, Catalonia 9.3% 0.9 Carriers, 15-24 y.

USA, Hawaii 1.6% 0.04 Carriers, Elementary school

PREVALENCE OF HBV CARRIERS BEFORE AND AFTER VACCINATION PROGRAMS

(In Italy, the prevalence also decreased in the unvaccinated population.)

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• Total acute HBV cases in the USA population dropped from 260,000 before vaccination to 78,000 afterwards.

• Total acute HBV cases in Native Americans in Alaska, USA dropped from 215 to zero cases.

• Total cases in Hawaii, USA dropped from 4.5/100,00 to 0.0/100,000

ACUTE HBV HEPATITIS CASES IN SELECTED ACUTE HBV HEPATITIS CASES IN SELECTED POPULATIONS BEFORE AND AFTER VACCINATION POPULATIONS BEFORE AND AFTER VACCINATION

PROGRAMSPROGRAMS

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Liver cancer a consequence of CHB HBV Liver cancer a consequence of CHB HBV infection that may be prevented infection that may be prevented

• The most effective way to prevent HCC is to prevent viral The most effective way to prevent HCC is to prevent viral infection through immunizationinfection through immunization11

INCIDENCE OF PRIMARY CANCER OF THE LIVER (HEPATOCELLULAR CARCINOMA) BEFORE AND AFTER

VACCINATION PROGRAMS

1. Wright TL. Hepatology Research 2007;37(s2):S294-S298

LOCATION BEFORE AFTER NOTES

Taiwan 0.70 0.36 Ages 6-14

“ 0.52 0.13 Ages 6-9

Korea 18.1 1) Vaccinated 0.58

2) “natural” anti-HBs 0.34

Cohort 370,285 m. 30+.

35,934, vaccinated

Page 19: Baruch S. Blumberg, M.D., Ph.D

19Tang B, et al, Journal of Medical Virology 2004;72:35–40

DNA Low(+)

RR=1.8 (0.5-5.8)

DNA High(+)

RR=9.9 (3.2-31.0)

DNA(-)Survival Distribution Function

Survival Time (Years)

HCC Mortality by HBV Viral Load at Baseline

< 105 c/mLper PCR

> 105 c/mLper PCR

Mortality from HCC increases with increasing Mortality from HCC increases with increasing levels of HBV viral load levels of HBV viral load

A Fox Chase Cancer Center Cohort StudyA Fox Chase Cancer Center Cohort Study

Fig. 3

Page 20: Baruch S. Blumberg, M.D., Ph.D

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Years of follow-up

Cu

mu

lati

ve in

cid

ence

of

liver

ci

rrh

osi

s (%

su

bje

cts)

Baseline HBV DNA level, copies/ml

Log rank test of trendp<0.001

≥106 (n=602)

105–<106 (n=333)

104–<105 ( n=628)

300–<104 ( n=1,150)

<300 (n=869)20

10

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

0

40

30

4.5%5.9%

9.8%

23.5%

36.2%

Iloeje UH, et al. Gastroenterology. 2006; 130;678–686.

Prospective studies conducted indicate high Prospective studies conducted indicate high viral levels increase the risk of cirrhosis viral levels increase the risk of cirrhosis

Page 21: Baruch S. Blumberg, M.D., Ph.D

21Adapted from Liaw et al. N Engl J Med. 2004;351:1521-1531.

0

5

10

15

20

25

0 6 12 18 24 30 36

Time (months)

0

5

10

15

20

25

0 6 12 18 24 30 360

5

10

15

20

25

0 6 12 18 24 30 36

Dis

ease

Pro

gre

ssio

n (

% o

f p

atie

nts

)

Wild Type (n = 221)YMDDm (n = 209) (49%)Placebo (n = 215)

Wild Type (n = 221)YMDDm (n = 209) (49%)Placebo (n = 215)

Wild Type

5%

13%

21%

YMDDm

Placebo

Fig. 5

Prospective study demonstrated a reduction in Prospective study demonstrated a reduction in disease progression with treatmentdisease progression with treatment

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Cost implications and the long term burden of Cost implications and the long term burden of disease progression in CHB disease progression in CHB

Cost increases sharply with progression of diseaseCost increases sharply with progression of disease

Hsieh CR, Kuo CW. 2004. J Clin Gastroenterol; 38(Suppl 3):S148-S152Brown RE et al. 2004. J Clin Gastroenterol; 38(Suppl 3):S169-S174Lee TA et al. 2004. J Clin Gastroenterol; 38(Suppl 3):S144-S147

$0 $20,000 $40,000 $60,000 $80,000 $100,000

Liver Transplant

HCC

Decompensated

Cirrhosis

Compensated

Cirrhosis

CHB

Annual Costs per Patient (US$)

Taiwan

UK

US

Fig. 6

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VIRUSES AND CANCERVIRUSES AND CANCERVirus Family

Adenoviruses

Flaviviruses

Hepadnavirus

Herpesviruses

Type

Types 2,5, 12

HCV

HBV

EBV

HHV-8

Human Tumor

?None ?Mesothelioma?Other

Hepatocellular carcinoma

Hepatocellular carcinoma(? Cancer of the pancreas)

Burkitt’s lymphoma

Immunoblastic lymphoma

Nasopharyngeal carcinoma

Hodgkin’s disease

Leiomyosarcomas

Gastric cancers

Kaposi’s sarcoma

Body cavity-based lymphoma

Castleman’s disease

Cofactors

?Asbestos?Other

-

Aflatoxin, alcohol,smoking

Malaria

Immunodeficiency

Nitrosamines, HLAGenotype

–HIV Infection

HIV Infection

HIV Infection

Slide C

EBV, Epstein-Barr virus; EV, epidermodysplasia verruciformis; HBV, hepatitis B virus; HCV,hepatitis C virus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HPV,human papillomavirus; HTLV, human T-cell leukemia virus; SV40, simian vacuolating virus 40.

From: Cancer: Principles & Practice of Oncology (7th Edition)Editors: DeVita, Vincent T., Hellman, Samuel, Rosenberg, Steven A.Publisher: Lippincott Williams & Wilkins, 2005

Chapter: SECTION 2: DNA Viruses

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VIRUSES AND CANCERVIRUSES AND CANCER

Virus Family

Papillomaviruses

Polyomaviruses

Retroviruses

Type

HPV-16, -18, -33, -39

HPV-5, -8, -17

SV40, JC, BK

HTLV-I

HTLV-II

Human Tumor

Anogenital cancers andsome upper airwaycancers

Skin cancer

? Brain tumors

? Insulinomas

? Mesotheliomas

Adult T-cellleukemia/lymphoma

Hairy cell leukemia

Cofactors

Smoking, ? otherFactors

EV, sunlight, immunesuppression

_

_

Uncertain

Unknown

Slide D

EBV, Epstein-Barr virus; EV, epidermodysplasia verruciformis; HBV, hepatitis B virus; HCV,hepatitis C virus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HPV,human papillomavirus; HTLV, human T-cell leukemia virus; SV40, simian vacuolating virus 40.

From: Cancer: Principles & Practice of Oncology (7th Edition)Editors: DeVita, Vincent T., Hellman, Samuel, Rosenberg, Steven A.Publisher: Lippincott Williams & Wilkins, 2005

Chapter: SECTION 2: DNA Viruses

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• 15% of all human cancers are caused by viruses. In others viruses are involved in pathogenesis

• Prevention by vaccination, or “Treatment by Delay” of infected but asymptomatic individuals can prevent the development of cancer or chronic disease

• There is an imperative to focus on this rich possibility for cancer control

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Non-pathological interactions of HBV Non-pathological interactions of HBV with populationswith populations

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Distribution of Australia Antigen (HBsAg) Distribution of Australia Antigen (HBsAg) by Genderby Gender

Marshall Islands, USTTPI Male Female TotalCebu, Philippines Male Female TotalManila, Philippines Male Female TotalCashinahua, Peru Male Female Total

Total Number

243226495

430334764

13859197

454489

NumberPositive

191433

271037

639

106

16

PercentPositive

7.86.26.7

6.33.04.8

4.35.14.6

22.213.618.0

Blumberg, et al, Amer. J. Human Genetics 18, 594, 1966

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Parent’s response

To HBV

Either parent HBsAg + :

anti-HBs –

Both parents HBsAg - :

anti-HBs –

Both parents HBsAg - :

either parent anti-HBs +

Couples

(No.)

33

29

154

Live births

Male Females

60 (1.8 ± 0.2)

51 (1.8 ± 0.2)

24 (1.6 ± 0.1)

24 (0.7 ± 0.1)

35 (1.2 ± 0.2)

22 (1.4 ± 0.1)

Sex ratio

250 (161,429)*

146 (96,230)*

109 (91,131)*

PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS ACCORDING TO THE RESPONSES TO HBV OF PARENTSACCORDING TO THE RESPONSES TO HBV OF PARENTS

*In parentheses, the 5 percent confidence limits.Blumberg, B.S. Sex differences in response to Hepatitis B Virus, Arthritis and Rheumatism,22, 1261, 1979

Page 29: Baruch S. Blumberg, M.D., Ph.D

Hepatitis B and Sex Ratio: Individual Level EstimatesHepatitis B and Sex Ratio: Individual Level Estimates

Notes: This table shows sex ratios among the children of carrier and non-carrier parents in four regions. Data were collected by testing married women and, in all cases except for Greenland, their husbands for HBV. Detailed reproductive histories were also collected. The table represents all births to women in those samples, with generally more than one birth to each women. The last two studies (Greece 2 and France) were designed specifically to test the hypothesis that HBV affects offspring sex ratio, and were run after the original theory was expressed.

LocationGreenlandGreenlandKar Kar IslandKar Kar IslandGreece 1Greece 1PhilippinesPhilippinesGreece 2Greece 2FranceFrance

HBV StatusPositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegative

Sons64

17463

16385

28766

30452

100620

149

60

19454

20646

25541

30130

95512

122

Sex Ratio1.070.901.170.791.851.131.611.011.731.051.661.22

Daughters

From Oster, E. 2004

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Notes: Sex ratio is number of boys for each girl. Only countries with more than 15,000 people used to caclulate HBV pravalence are included. Citations for each country are in Appendix B.

Se

x R

atio

at B

irth

SEX RATIO AND HEPATITIS, WORLDSEX RATIO AND HEPATITIS, WORLD

Hepatitis Rate (%)

Brazil

Belarus

Bangladesh

Iran

Malaysia

Singapore

Israel

Pakistan

China

Mexico

Turkey

France

IrelandGreece

South Korea

Spain

AustraliaItaly

PolandJapan

1.14

1.12

1.1

1.08

1.06

1.04

1.02

10 2 4 6 8 10 12 14 16

Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004

N. Amer &W. Europe

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1996-20021991-19951986-19901980-1985

CHANGES IN SEX RATIO IN ALASKA BEFORE AND CHANGES IN SEX RATIO IN ALASKA BEFORE AND DURING VACCINATION PROGRAMDURING VACCINATION PROGRAM

1.16

1.14

1.12

1.1

1.08

1.06

1.04

1.02

1

Native American High HBVNative American Low HBVNon-Native American

Oster, E., Hepatitis B and the Case of the Missing Women, 2006