1. Hepatitis B: Impeding Liver Cancer through Prevention and Management Hepatitis B: Impeding Liver Cancer through Prevention and Management Raymond S. Koff, M.D. Clinical Professor of Medicine University of Connecticut Health Science Center Farmington, Connecticut Raymond S. Koff, M.D. Clinical Professor of Medicine University of Connecticut Health Science Center Farmington, Connecticut

2. 900,000 900,000 888,000 410,000 346,000 30,000 400,000 5,000 5,000 < 1,000 Global Mortality from Vaccine Preventable Diseases Global Mortality from Vaccine Preventable Diseases Diseases Estimated annual deaths (1999)

3. Hepatocellular Carcinoma ● ● Among solid tumors, 5 th highest incidence worldwide and 3 rd most common cause of cancer deaths ● ● In the U.S. in 2007, 13 th most common cancer and increasing faster than all others from 1995 to 2004; 8 th most common cause of cancer deaths ● ● Despite advancing technology and available treatments, 5-year survival rates are generally less than 5%

4. Geographic Prevalence of Chronic Hepatitis B: Impact of Migration World Health Organization. Available at: http://www.who.int/vaccines- surveillance/graphics/htmls/hepbprev.htm. Accessed July 8, 2005. 2002 Yearbook of Immigration Statistics. Available at: http://uscis.gov/graphics/shared/aboutus/statistics/yearbook/2002.pdf. Accessed July 8, 2005. Mahoney FJ. Clin Microbiol Rev. 1999;12:351–366. Immigration Numbers Summed by Continent From 1996–2002

5. Chronic Hepatitis B Morbidity and Mortality, U.S. Previously infected individuals: ~10 million Previously infected individuals: ~10 million Actively infected individuals: ~1-1.25 million Actively infected individuals: ~1-1.25 million Annual cirrhosis deaths: ~4,000 Annual cirrhosis deaths: ~4,000 Annual HCC deaths: ~1,000-1,500 Annual HCC deaths: ~1,000-1,500

6. HBV Disease Progression 1. Torresi J. Gastroenterology. 2000;118(2 suppl 1):S83–S103. 2. Fattovich G. Hepatology. 1995;21:77–82. 3. Moyer LA. Am J Prev Med. 1994;10:45–55. 4. Perrillo R. Hepatology. 2001;33:424–432. Acute infection Chronic infection infection Cirrhosis Death 5–10% 1,3 Liver failure 30% 1 25% in 5 years Liver Cancer (HCC) Cancer (HCC) Chronic HBV is the 6 th leading cause of liver transplantation in the US 4 Liver transplant- ation

7. Age at Infection 0 0 20 40 60 80 100 Neonates Infants Children Adults % Risk % Risk Risk of Chronic HBV Infection

8. Chronic HBV Infection Years after clinical presentation 0 0 20 40 60 80 100 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 1010 101011 1212 1212 1313 1313 % Probability % Probability Fattovich G, Gut 1991; 32:294 Overall Risk of Progression to Cirrhosis

9. Fattovich, et al., Hepatology 1995; 21:77 Cumulative Probability of Developing HCC in Patients with HBV-Related Cirrhosis 0 0 10 0 0 9 9 8 8 7 7 6 6 5 5 4 4 3 3 2 2 1 1 % % Year 20 25 15 Chronic HBV Infection

10. Natural History of HBeAg-positive Disease in a 30-year old Asian Disease in a 30-year old Asian Health state Lifetime risk Cirrhosis: ~42% Cirrhosis: ~42% Decompensation: ~14% Decompensation: ~14% Hepatocellular carcinoma: ~25% Hepatocellular carcinoma: ~25% Liver-related death: ~37% Liver-related death: ~37% Chronic Hepatitis B

11.  Higher HBV DNA levels (>10 4 copies/mL)  HBeAg-positivity  Persistent ALT elevation  HIV, alcohol, immunosuppression  Higher HBV DNA levels (>10 4 copies/mL)  HBeAg-positivity  Persistent ALT elevation  HIV, alcohol, immunosuppression Chronic Hepatitis B Factors Influencing Risk of Cirrhosis Factors Influencing Risk of Cirrhosis

12. Cumulative Incidence of Cirrhosis for Five HBV DNA Categories (n=3,774) Iloeje UH et al, Gastroenterology 2006;130:678-86: The Taiwan Natural History Study 2.5 1.4 1.0 5.6 6.5 P value for log-rank test, <0.001 6 5 4 3

13. Serum HBV DNA Incidence Adj. Rel Risk p (copies/mL) (per 100,000) >1.0 x 10 6 1150 11.6 1.0 x 10 6 1150 11.6 <.001 >1.0 x 10 5 - 1.0 x 10 5 - <1.0 x 10 6 952 7.2 <.001 >1.0 x 10 4 - 1.0 x 10 4 - <1.0 x 10 5 315 2.4 <.008 >300 - 300 - <1.0 x 10 4 112 0.9 NS <300 145 1.0 --- Serum HBV DNA Incidence Adj. Rel Risk p (copies/mL) (per 100,000) >1.0 x 10 6 1150 11.6 1.0 x 10 6 1150 11.6 <.001 >1.0 x 10 5 - 1.0 x 10 5 - <1.0 x 10 6 952 7.2 <.001 >1.0 x 10 4 - 1.0 x 10 4 - <1.0 x 10 5 315 2.4 <.008 >300 - 300 - <1.0 x 10 4 112 0.9 NS <300 145 1.0 --- HBV DNA Levels and Risk of Hepatocellular Carcinoma: The Taiwan Natural History Study * HBV DNA Levels and Risk of Hepatocellular Carcinoma: The Taiwan Natural History Study * * Chen C-J et al. JAMA, 2006

14. HBV Vaccination in Taiwan % % 0 0 10 20 30 1984 1994 1999 Vaccination of infants born to HBsAg+ mother   HBsAg+ Anti-HBc+ Universal vaccination of infants/preschool children   Ni YH, Ann Intern Med 2001;135:796 Impact on HBV Infection in Children

15. HBV Vaccination in Taiwan 0 0 2 2 4 4 6 6 8 8 1981-1986 1986-1990 1990-1994 Annual incidence of HCC (per 1,000,000) Annual incidence of HCC (per 1,000,000)   Universal Vaccination of Newborns Chang MH, N Engl J Med 1997;336:1855 Impact on Incidence of HCC in Children

16. Epidemiology of HBV

17. Hepatitis B Virus Estimates of Infectivity in Body Fluids Estimates of Infectivity in Body Fluids Blood Semen CSF Semen Blood Lowest Infectivity Most Lowest Infectivity Most Urine Breastmilk Saliva Saliva Cervicovaginalsecretions Tears

18. Epidemiologic Characteristics of Patients With Hepatitis B — US, 2005* More than 70% of newly acquired infections in 2005 were attributable to high-risk sexual activity or injection drug use *Values total >100% because multiple risk factors could be reported for a single case. CDC. MMWR. 2007;56(SS-3):1-25.

19. Hepatitis B Factors Associated with Sexual Transmission Factors Associated with Sexual Transmission Multiple sexual partners, unprotected sex Multiple sexual partners, unprotected sex Injecting drug user as sexual partner Injecting drug user as sexual partner Duration of sexual activity Duration of sexual activity Male to female,male to male,female to male Male to female,male to male,female to male History or serologic evidence of other History or serologic evidence of other sexually transmitted diseases sexually transmitted diseases

20. Prevention of Hepatitis B

21. Hepatitis B Prevention Strategies Reducing the Risk of Infection Decreasing exposure opportunities Decreasing exposure opportunities Decreasing susceptibility Decreasing susceptibility - immunization with hepatitis B vaccines - immunization with hepatitis B vaccines

22. Non-vaccine Prevention of HBV ● Screening of blood donors for HBsAg, anti-HBc (future screening for HBV DNA) ● Screening of organ and tissue donors ● Safe-sex practices ● Reduction in sharing equipment for IV drug use ● Needle-exchange programs and education about cleaning equipment ● Avoidance of intranasal cocaine use ● Inspection of tattoo and body-piercing shops ● Sterilization of manicure/pedicure equipment ● Avoidance of multidose vial misuse

23. Vaccine-based Strategies for Vaccine-based Strategies for Eliminating HBV Transmission in the U.S. Eliminating HBV Transmission in the U.S. Maternal screening for HBsAg: providing post- exposure prophylaxis to infants of HBsAg-positive womenMaternal screening for HBsAg: providing post- exposure prophylaxis to infants of HBsAg-positive women - HBIG within 12 hours of birth and first of 3 - HBIG within 12 hours of birth and first of 3 doses of HBV vaccine doses of HBV vaccine Routine vaccination of all newborn infantsRoutine vaccination of all newborn infants Catch-up vaccination: for children aged <19 yrsCatch-up vaccination: for children aged <19 yrs Targeting high risk: children, adolescents, adultsTargeting high risk: children, adolescents, adults Screening and vaccination: household and family members of HBsAg-positive personsScreening and vaccination: household and family members of HBsAg-positive persons

24. 0–11 years old 95% decline 71% decline 94% decline 20+ years old 12–19 years old Source: CDC, National Notifiable Diseases Surveillance System (NNDSS). Incidence of Acute Hepatitis B United States by Age (1990–2004)

25. 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

26. 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 acknowledge a risk factor

27. Treatment of Chronic Hepatitis B

28.  Suppression of viral replication  Improvement in hepatic necroinflammatory disease  Reduction in long-term sequelae: HBV-associated cirrhosis, hepatocellular carcinoma  Reduction of infectivity Chronic Hepatitis B Management Goals

29. Effect of Lamivudine on Incidence of HCC in Chronic HBV with Advanced Fibrosis Liaw YF, et al. N Engl J Med 2004;351:1521–1531. Length of Therapy (months) Lamivudine Placebo Diagnosis of HCC (%) 0 10 601218243036 P = 0.047

30. Chronic Hepatitis B Chronic Hepatitis B Patients with: Elevated or normal ALT levels and : Elevated or normal ALT levels and :  HBeAg-positive and HBV DNA ≥10 4-5 copies/mL by PCR by PCR  HBeAg-negative and HBV DNA ≥ 10 4 copies/mL by PCR  +/- liver biopsy evidence of disease Cirrhosis with detectable HBV DNA Cirrhosis with detectable HBV DNA Candidates for Treatment Candidates for Treatment

31. HBV Treatment Options in 2008 ● Pegylated interferon alfa-2a ● Interferon alfa-2b ● Nucleoside analogs – Entecavir – Lamivudine – Telbivudine ● Nucleotide analogs – Adefovir – Tenofovir (likely to be FDA-approved soon)

32. Chronic Hepatitis B Comparing Oral Antivirals and Interferon Comparing Oral Antivirals and Interferon Orals IFN Oral administration: Yes No Oral administration: Yes No Side effects: Minimal Frequent Side effects: Minimal Frequent Duration of treatment: Prolonged Finite Duration of treatment: Prolonged Finite Flares during treatment: Rare Yes Flares during treatment: Rare Yes Resistant mutant Yes No Resistant mutant Yes No Rate of HBsAg clearance: Low Higher Rate of HBsAg clearance: Low Higher Improved outcomes: Yes Yes Improved outcomes: Yes Yes

33. Treatment of HBV Patients: Now and in the Future ● Focus on HBV DNA suppression ● Treatment decisions based on HBV DNA levels, disease severity, drug efficacy and resistance patterns (for oral agents) ● Combination oral therapy emerging ● New agents with prolonged activity after end- of-treatment, e.g. clevudine

34. Other Management Strategies Other Management Strategies ● Immunization against HAV, other infections ● Avoidance of alcohol, hepatotoxic herbals ● Screening for hepatocellular carcinoma - imaging studies, AFP, others - imaging studies, AFP, others - appropriate timing - appropriate timing ● Case-finding (family, non-family contacts) for vaccination vaccination

35. 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