baruch s. blumberg, m.d., ph.d
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Baruch S. Blumberg, M.D., Ph.D.
Senior Advisor to the President
Fox Chase Cancer Center
2
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
3
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
4
5
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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7
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
8
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
9
“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
10
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
11
12
13
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
14
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
18
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
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
20
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
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
22
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
25
• 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
27
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
28
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
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
30
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
31
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
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