Transcript Slide 1

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
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HBV VACCINE AND CANCER PREVENTION
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2.
3.
4.
5.
6.
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8.
9.
HBV is a common infection
It s a causative agent of HCC worldwide (estimate 80%)
The vaccine is highly effective and in wide use
HBV carrier rates have been dramatically reduced
by vaccination
The vaccination program decreases the incidence
of HCC
There are many cancers whose cause is attributed to
infectious agents
There are probably others in which viruses contribute
to pathogenesis
The pathogenesis and etiology of cancer is complex
with multiple “causes”
A program for the identification and prevention of virus
related diseases should be a priority in the
cancer program
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4
Division of Clinical Research, 1980
Fox Chase Cancer Center, Philadelphia, PA USA
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Hepatitis B Morphology
Characteristics
22 nm
42 nm
Nucleic acid: DNA
Classification:
Hepadnavirus type 1
Serotypes: Multiple
In vivo replication: Reverse
transcription in liver and other
tissues
In vitro propagation:
Primary hepatocyte culture and
transfection by cloned HBV DNA
HBsAg
C
HBV DNA
HBcAg
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The Discovery of Hepatitis B Virus
1963 : Identification of the “Australia antigen”
1967: “Australia antigen “ recognized as part
of the Hepatitis B virus
1969: Invention of
the HBV vaccine,
Novel method
used in 1970’s to
manufacture
1969: Postulated
that HBV was
cause of primary
liver cancer
1970’s: Taiwan, HBV carriers had
more than 200 times higher risk
of developing HCC versus noncarriers
1976: General
agreement on
identification of the
Hepatitis B virus
1980’s: Report
published on field
testing of vaccine,
followed by approval
from FDA
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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 liver
and 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 Liver
– Worldwide:
• Third most common cause of death from cancer
in males
• Seventh most common cause of death from
cancer in females
• More than a million deaths per year
• Hepatitis B virus (about 80%) and hepatitis C
virus account for most of these cancers
• Many other factors involved in the pathogenesis
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12
Epidemiology 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
HIV in China
Hepatitis B virus is 100 times more transmittable than HIV1
HBV
HIV
• Kills 250,000–
• Killed 50,000–
280,000 annually2
• 130 million carriers
• 9.7% prevalence
rate4
100,000 in 20033
• 840,000 infected3*
• 0.12% prevalence
rate3
*Official estimate of population aged 15–49
1.
2.
3.
4.
WHO factsheet No.204; revised October 2000.
Datamonitor Healthcare. Commercial perspectives: Hepatitis B and C – The Chinese way? 2004
WHO HIV/AIDS in the Asia and Pacific region 2003.
Rosmawati M et al. J Gastroenterol Hepatol 2004;19:958–969
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The Burden of Liver Cancer
• Liver cancer has a very low survival rate
–
In developing countries, most people with liver cancer die
within months of diagnosis
– Usually develops between 35 and 65 years of age, when
people are maximally productive and with family
responsibilities.
• Fifth most common cause of death worldwide1
–
Around 0.5 million globally die of liver cancer each year2. Rising
incidence in the US1
– Liver cancer is the 2nd most common cause of cancer death in
China3. Incidence rates have doubled in Taiwan since 1980’s4
– Third major cause of death in Korea, with 65-75% of patients
positive for HBsAg5
1.
2.
3.
4.
5.
Wright TL. Hepatology Research 2007;37(s2):S294-S298
El-Serag HB. J Clin Gastroenterol 2002;35(5 Suppl 2):S72–78.
Tang Z-Y, et al. J Gastroenterol Hepatol 2004;19(Suppl 2): A1.
Chen DS. Hepatology Research 2007;37(s2):S101-S105
Han KH and Kim JK. Hepatology Research 2007;37(s2):S106-S109
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REGION
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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ACUTE HBV HEPATITIS CASES IN SELECTED
POPULATIONS BEFORE AND AFTER VACCINATION
PROGRAMS
• 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
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Liver cancer a consequence of CHB HBV
infection that may be prevented
• The most effective way to prevent HCC is to prevent viral
infection through immunization1
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
Cohort 370,285 m. 30+.
2) “natural” anti-HBs 0.34
35,934, vaccinated
INCIDENCE OF PRIMARY CANCER OF THE LIVER
(HEPATOCELLULAR CARCINOMA) BEFORE AND AFTER
VACCINATION PROGRAMS
1.
Wright TL. Hepatology Research 2007;37(s2):S294-S298
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Mortality from HCC increases with increasing
levels of HBV viral load
A Fox Chase Cancer Center Cohort Study
HCC Mortality by HBV Viral Load at Baseline
DNA(-)
< 105 c/mL
DNA Low(+) per PCR
RR=1.8 (0.5-5.8)
DNA High(+)
RR=9.9 (3.2-31.0)
> 105 c/mL
per PCR
Survival Time
(Years)
Tang B, et al, Journal of Medical Virology 2004;72:35–40
Fig. 3
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Prospective studies conducted indicate high
viral levels increase the risk of cirrhosis
Cumulative incidence of liver
cirrhosis (% subjects)
40
36.2%
Baseline HBV DNA level, copies/ml
≥106 (n=602)
105–<106 (n=333)
30
104–<105 ( n=628)
300–<104 ( n=1,150)
23.5%
<300 (n=869)
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Log rank test of trend
p<0.001
10
9.8%
5.9%
4.5%
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Years of follow-up
Iloeje UH, et al. Gastroenterology. 2006; 130;678–686.
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Disease Progression (% of patients)
Prospective study demonstrated a reduction in
disease progression with treatment
25
Placebo (n = 215)
YMDDm (n = 209) (49%)
Wild Type (n = 221)
20
21%
Placebo
15
13%
YMDDm
10
5%
5
Wild Type
0
0
6
12
18
24
30
36
Time (months)
Fig. 5
Adapted from Liaw et al. N Engl J Med. 2004;351:1521-1531.
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Cost implications and the long term burden of
disease progression in CHB
Cost increases sharply with progression of disease
CHB
Taiwan
UK
US
Compensated
Cirrhosis
Decompensated
Cirrhosis
HCC
Liver Transplant
$0
Fig. 6
$20,000
$40,000
$60,000
$80,000
$100,000
Annual Costs per Patient (US$)
Hsieh CR, Kuo CW. 2004. J Clin Gastroenterol; 38(Suppl 3):S148-S152
Brown RE et al. 2004. J Clin Gastroenterol; 38(Suppl 3):S169-S174
Lee TA et al. 2004. J Clin Gastroenterol; 38(Suppl 3):S144-S147
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Slide C
VIRUSES AND CANCER
Virus Family
Type
Human Tumor
Cofactors
Adenoviruses
Types 2,
5, 12
?None ?Mesothelioma
?Other
?Asbestos
?Other
Flaviviruses
HCV
Hepatocellular carcinoma
-
Hepadnavirus
HBV
Hepatocellular carcinoma
(? Cancer of the pancreas)
Aflatoxin, alcohol,
smoking
Herpesviruses
EBV
Burkitt’s lymphoma
Malaria
Immunoblastic lymphoma
Immunodeficiency
Nasopharyngeal carcinoma
Nitrosamines, HLA
Genotype
Hodgkin’s disease
–
Leiomyosarcomas
–
Gastric cancers
Kaposi’s sarcoma
–
HIV Infection
Body cavity-based lymphoma
HIV Infection
Castleman’s disease
HIV Infection
HHV-8
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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Slide D
VIRUSES AND CANCER
Virus Family
Type
Human Tumor
Cofactors
Papillomaviruses
HPV-16, -18,
-33, -39
Anogenital cancers and
some upper airway
cancers
Smoking, ? other
Factors
HPV-5, -8,
-17
Skin cancer
EV, sunlight, immune
suppression
SV40, JC, BK
? Brain tumors
–
? Insulinomas
_
? Mesotheliomas
_
Adult T-cell
leukemia/lymphoma
Uncertain
Hairy cell leukemia
Unknown
Polyomaviruses
Retroviruses
HTLV-I
HTLV-II
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
with populations
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Distribution of Australia Antigen (HBsAg)
by Gender
Marshall Islands, USTTPI
Male
Female
Total
Cebu, Philippines
Male
Female
Total
Manila, Philippines
Male
Female
Total
Cashinahua, Peru
Male
Female
Total
Total
Number
Number
Positive
Percent
Positive
243
226
495
19
14
33
7.8
6.2
6.7
430
334
764
27
10
37
6.3
3.0
4.8
138
59
197
6
3
9
4.3
5.1
4.6
45
44
89
10
6
16
22.2
13.6
18.0
Blumberg, et al, Amer. J. Human Genetics 18, 594, 1966
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PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS
ACCORDING TO THE RESPONSES TO HBV OF PARENTS
Parent’s response Couples
To HBV
Either parent HBsAg + :
(No.)
Live births
Male
Females
Sex ratio
33
60 (1.8 ± 0.2)
24 (0.7 ± 0.1)
250 (161,429)*
29
51 (1.8 ± 0.2)
35 (1.2 ± 0.2)
146 (96,230)*
154
24 (1.6 ± 0.1)
22 (1.4 ± 0.1)
109 (91,131)*
anti-HBs –
Both parents HBsAg - :
anti-HBs –
Both parents HBsAg - :
either parent anti-HBs +
*In parentheses, the 5 percent confidence limits.
Blumberg, B.S. Sex differences in response to Hepatitis B Virus,
Arthritis and Rheumatism,22, 1261, 1979
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Hepatitis B and Sex Ratio: Individual Level Estimates
Location
Greenland
Greenland
Kar Kar Island
Kar Kar Island
Greece 1
Greece 1
Philippines
Philippines
Greece 2
Greece 2
France
France
HBV Status
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Sons
64
174
63
163
85
287
66
304
52
1006
20
149
Daughters
60
194
54
206
46
255
41
301
30
955
12
122
Sex Ratio
1.07
0.90
1.17
0.79
1.85
1.13
1.61
1.01
1.73
1.05
1.66
1.22
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.
From Oster, E. 2004
SEX RATIO AND HEPATITIS, WORLD
China
Sex Ratio at Birth
1.14
1.12
South Korea
1.1
Pakistan
1.08
Belarus
Spain
Greece
Ireland
Japan Poland
Israel Australia
1.06N. Amer
&
Italy
W. Europe
Brazil
France
Singapore
Turkey
Bangladesh
Malaysia
1.04
Mexico
1.02
Iran
1
0
2
4
6
8
10
12
14
16
Hepatitis Rate (%)
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.
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
30
CHANGES IN SEX RATIO IN ALASKA BEFORE AND
DURING VACCINATION PROGRAM
1.16
Native American High HBV
Native American Low HBV
Non-Native American
1.14
1.12
1.1
1.08
1.06
1.04
1.02
1
1980-1985
1986-1990
1991-1995
1996-2002
Oster, E., Hepatitis B and the Case of the Missing Women, 2006
31