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

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.

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

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

  2. SETI INSTITUTE DIRECTORS COLLOQUIUMFeb 20, 2008Hepatitis B Virus.Discovery, the Present, and the Future.Baruch S. BlumbergFox Chase Cancer Center, Philadelphia, PA

  3. HBV VACCINE AND CANCER PREVENTION 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

  4. Division of Clinical Research, 1980 Fox Chase Cancer Center, Philadelphia, PA USA

  5. Hepatitis BMorphology Characteristics 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 22 nm 42 nm HBsAg C HBV DNA HBcAg

  6. 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 1976: General agreement on identification of the Hepatitis B virus 1970’s: Taiwan, HBV carriers had more than 200 times higher risk of developing HCC versus non-carriers 1980’s: Report published on field testing of vaccine, followed by approval from FDA

  7. “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

  8. 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

  9. 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

  10. Hepatitis B infects and kills more than HIV in China Hepatitis B virus is 100 times more transmittable than HIV1 HBV • Kills 250,000–280,000 annually2 • 130 million carriers • 9.7% prevalence rate4 HIV • Killed 50,000–100,000 in 20033 • 840,000 infected3* • 0.12% prevalence rate3 *Official estimate of population aged 15–49 • 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

  11. 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 • 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

  12. PREVALENCE OF HBV CARRIERS BEFORE AND AFTER VACCINATION PROGRAMS (In Italy, the prevalence also decreased in the unvaccinated population.)

  13. 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

  14. 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 INCIDENCE OF PRIMARY CANCER OF THE LIVER (HEPATOCELLULAR CARCINOMA) BEFORE AND AFTER VACCINATION PROGRAMS • Wright TL. Hepatology Research 2007;37(s2):S294-S298

  15. 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 per PCR DNA Low(+) RR=1.8 (0.5-5.8) Survival Distribution Function DNA High(+) RR=9.9 (3.2-31.0) > 105 c/mL per PCR Survival Time (Years) Fig. 3 Tang B, et al, Journal of Medical Virology 2004;72:35–40

  16. Prospective studies conducted indicate high viral levels increase the risk of cirrhosis 40 36.2% Baseline HBV DNA level, copies/ml ≥106 (n=602) 105–<106 (n=333) 104–<105 ( n=628) 300–<104 ( n=1,150) <300 (n=869) 30 23.5% 20 Cumulative incidence of liver cirrhosis (% subjects) 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.

  17. Placebo (n = 215) Placebo (n = 215) YMDDm (n = 209) (49%) YMDDm (n = 209) (49%) 21% Wild Type (n = 221) Wild Type (n = 221) Placebo 13% YMDDm 5% Wild Type Prospective study demonstrated a reduction in disease progression with treatment 25 25 25 20 20 20 15 15 15 Disease Progression (% of patients) 10 10 10 5 5 5 0 0 0 0 0 0 6 6 6 12 12 12 18 18 18 24 24 24 30 30 30 36 36 36 Time (months) Fig. 5 Adapted from Liaw et al. N Engl J Med. 2004;351:1521-1531.

  18. Cost implications and the long term burden of disease progression in CHB Cost increases sharply with progression of disease Fig. 6 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

  19. Slide C VIRUSES AND CANCER Virus 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, HLA Genotype – – – HIV Infection HIV Infection HIV Infection 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

  20. Slide D VIRUSES AND CANCER Type HPV-16, -18, -33, -39 HPV-5, -8, -17 SV40, JC, BK HTLV-I HTLV-II Human Tumor Anogenital cancers and some upper airway cancers Skin cancer ? Brain tumors ? Insulinomas ? Mesotheliomas Adult T-cell leukemia/lymphoma Hairy cell leukemia Cofactors Smoking, ? other Factors EV, sunlight, immune suppression – _ _ Uncertain Unknown Virus Family Papillomaviruses Polyomaviruses Retroviruses 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

  21. 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

  22. Non-pathological interactions of HBV with populations

  23. Distribution of Australia Antigen (HBsAg) by Gender Total Number 243 226 495 430 334 764 138 59 197 45 44 89 Number Positive 19 14 33 27 10 37 6 3 9 10 6 16 Percent Positive 7.8 6.2 6.7 6.3 3.0 4.8 4.3 5.1 4.6 22.2 13.6 18.0 Marshall Islands, USTTPI Male Female Total Cebu, Philippines Male Female Total Manila, Philippines Male Female Total Cashinahua, Peru Male Female Total Blumberg, et al, Amer. J. Human Genetics 18, 594, 1966

  24. PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS ACCORDING TO THE RESPONSES TO HBV OF PARENTS Sex ratio 250 (161,429)* 146 (96,230)* 109 (91,131)* Live births Male Females 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 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) *In parentheses, the 5 percent confidence limits. Blumberg, B.S. Sex differences in response to Hepatitis B Virus, Arthritis and Rheumatism,22, 1261, 1979

  25. Hepatitis B and Sex Ratio: Individual Level Estimates Daughters 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 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

  26. SEX RATIO AND HEPATITIS, WORLD China 1.14 1.12 South Korea 1.1 Pakistan Belarus Sex Ratio at Birth 1.08 Spain Singapore Greece Ireland Turkey Bangladesh Poland Japan Malaysia Australia Israel 1.06 N. Amer & W. Europe Italy Brazil France 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

  27. 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

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