1. Steven-Huy Han, MD, AGAF Professor of Medicine and Surgery Department of Medicine Division of Digestive Diseases and Liver/Pancreas Transplantation David Geffen School of Medicine at UCLA Los Angeles, California The Role of HBV in the Burden of Hepatocellular Carcinoma Image: Professors Pietro M. Motta & Tomonori Naguro/Copyright©2010 Photo Researchers, Inc. All Rights Reserved This program is supported by educational grants from

2. Public Health Burden of HCC in the United States

3. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC HCC Is Common and Increasing  663,000 deaths from liver cancer yearly worldwide [1] –Expected to increase by 15% by 2015  Age-adjusted US incidence has increased 2-fold from 1985-1998  American Cancer Society statistics for liver cancer in 2010 [2] –Estimated new cases: 24,120 –Estimated deaths: 18,510 –5th leading cause of cancer deaths in males 1. Mathers CD, et al. PLoS Med. 2006;3:e442. 2. American Cancer Society. Cancer facts & figures 2010. http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed September 13, 2010. http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf

4. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Burden of HCC in the United States  Annual prevalence, incidence, and survival with HCC estimated from SEER database  Distribution of costs estimated from 392 HCC patients  Annual estimated cost of HCC in the United States: $454.9 million –Per-patient cost: $32,907  Healthcare costs accounted for 89.2% of cost  Lost productivity accounted for 10.8% of cost Lang K, et al. J Hepatol. 2009;50:89-99.

5. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Viral Hepatitis as a Risk Factor for HCC  Worldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%) Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16. Known Risk Factor in the US: Viral Hepatitis (N = 691) 5 15 33 47 0 20 40 60 80 100 HBV + HCVHBVHCVNeither Presence of Risk Factor Among HCC Patients (%)

6. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC: The National Academies Press; 2010. API Americans = 4.5% of the general US population...... but account for more than 50% of the 800,000 to 1.4 million Americans with chronic HBV infection Chronic HBV in Americans From Asia and the Pacific Islands (API)

7. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Chronic HBV Morbidity and Mortality  HBV and HCC represent the greatest health disparity between Asian and white Americans –HCC is the second leading cause of cancer death for Asian men living in the United States –HCC incidence is up to 9 times higher in Asian American men than white American men Asian Liver Center at Stanford University. 2007 Physician’s guide to hepatitis B: a silent killer. Stanford, CA. 2007: 3.

8. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Chronic Hepatitis B Immigration Trends to the United States HBsAg Prevalence ≥ 8% (high) 2% to 7% (intermediate) < 2% (low) Immigration numbers by continent: 2000-2009 ~ 3.57 million Asians ~ 876,000 South Americans ~ 804,000 Africans ~ 1.4 million Europeans Centers for Disease Control and Prevention. CDC health information for international travel 2010. http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849. Accessed September 14, 2010. http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849 United States. Department of Homeland Security. Yearbook of Immigration Statistics: 2009. Washington, D.C.: U.S. Department of Homeland Security, Office of Immigration Statistics, 2010. http://www.dhs.gov/xlibrary/assets/statistics/yearbook/2009/ois_yb_2009.pdf. Accessed September 14, 2010. http://www.dhs.gov/xlibrary/assets/statistics/yearbook/2009/ois_yb_2009.pdf

9. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC CHB: The Silent Killer  ~ 65% of API Americans infected with HBV are unaware of their infection status Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. 35% 65% Unaware Aware

10. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC CHB Morbidity and Mortality  Up to 4000 people die each year in the United States from CHB-related liver disease [1]  Highest incidence of HCC in the United States is among API Americans [2] 1. CDC Division of Viral Hepatitis. Chronic hepatitis B: Information on testing. http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFactSheet-BW.pdf. Accessed September 14, 2010. 2. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC: The National Academies Press; 2010. http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFactSheet-BW.pdf CHB Liver damage Cirrhosis Liver failure HCC

11. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Groups at High Risk Who Should Be Screened for CHB Infection  Individuals born in areas of high or intermediate prevalence rates (≥ 2%) for HBV –All countries in Asia, Africa, and the South Pacific Islands –Middle East: except Cyprus and Israel –European Mediterranean: Malta and Spain –The Arctic: indigenous people –Many countries in South America and the Caribbean –All countries in Eastern Europe except Hungary –Central America: Guatemala and Honduras Lok AS, et al. Hepatology. 2009;50:661-662.

12. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Other Groups Recommended for CHB Screening  US-born persons not vaccinated as infants whose parents were born in regions of high HBV endemicity (≥ 8%)  Household or sexual contacts of individuals with HBV  Injection drug users  Men who have sex with men  Persons with elevated ALT/AST of unknown etiology  Persons with selected medical conditions who require immunosuppressive therapy  Pregnant women  Persons who are the source of blood or body fluid exposures that might warrant postexposure prophylaxis  Persons infected with HCV or HIV Lok AS, et al. Hepatology. 2009;50:661-662.

13. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Who Should Be Vaccinated for HBV? CDC. HBV FAQs for Health Professionals. Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm. Accessed September 14, 2010. Infants  At birth Children  Who were not vaccinated as infants At-Risk Adults  Travelers to regions of intermediate/high endemicity  Susceptible sex partners and household contacts of HBsAg-positive persons  Persons seeking evaluation or treatment for an STD  Persons with behavioral or occupational exposures  Persons with end-stage renal disease, chronic liver disease, or HIV infection  Residents/staff in certain settings with clients with known HBV risk factors

14. HBV Treatment Indications and the Relationship to HCC

15. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Risk Factors for HCC in HBsAg-Positive Individuals  Host –Older age (> 40 yrs) –Male sex –Asian/African ancestry –HCC family history  Clinical –Cirrhosis –HCV coinfection  Viral –HBeAg positive –Higher HBV DNA –Genotype B, C –Precore mutation –Basal core promoter mutation  Other –Smoking, alcohol –Obesity, diabetes McClune AC, et al. Clin Liver Dis. 2010;14:461-476.

16. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Risk of HCC According to Baseline Factors  REVEAL: long-term follow-up (mean: 11.4 yrs) of untreated HBsAg-positive individuals in Taiwan (N = 3653) HBV DNA (copies/mL) HCC (% per Yr) Chen CJ, et al. JAMA. 2006;295:65-73. < 300 300-9999 10,000-99,999 100,000-999,999 ≥ 1 million 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 No cirrhosis Cirrhosis

17. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC REVEAL: Persistent HBV DNA Associated With Increased HCC Risk *Cox proportional hazards models. Risk is relative to < 10 4 copies/mL at entry/not tested at follow-up. Data adjusted for sex, age, cigarette smoking, and alcohol consumption. Adjusted Hazard Ratio* for HCC (95% CI) Low < 10 4 Mid 10 4 -10 5 High ≥ 10 5 HBV DNA (copies/mL) High ≥ 10 5 DNA at entry: DNA at follow-up: 10.1 7.3 3.8 0 4 8 12 16 n = 146120 537 Chen CJ, et al. JAMA. 2006;295:65-73.

18. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Effect of Therapy on Disease Progression in Bridging Fibrosis/Cirrhosis Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. Disease progression = increase of ≥ 2 points in CTP, spontaneous bacterial peritonitis with proven sepsis, renal insufficiency, bleeding gastric or esophageal varices, HCC, or liver-related death. 50 40 30 20 10 0 Lamivudine (n = 436) Placebo (n = 215) 7.8 17.7 Disease Progression at Follow-up P =.001 Patients(%)

19. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC What Is the Role of HCC Family History in Deciding to Treat HBV?  AASLD guidelines –HCC family history not consistent determinant in deciding whether to treat HBV –Family history can be indicator for biopsy, which may help in making treatment decisions Lok AS, et al. Hepatology. 2009;50:661-662.

20. Surveillance and Diagnosis Strategies for HCC in HBV Patients

21. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC HBV Patients for Whom HCC Surveillance Is Recommended SubgroupHCC Incidence per Yr Asian males HBV carriers > 40 yrs of age0.4% to 0.6% Asian female HBV carriers > 50 yrs of age0.3% to 0.6% Hep B carrier with HCC family historyHigher than no family history African/N American blacks with HBVHCC occurs at younger age Cirrhotic HBV carriers3% to 8% Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf. Accessed September 13, 2010. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf

22. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Surveillance for HCC  Objective: to reduce mortality from HCC  Single randomized controlled trial showed that surveillance of HBV carriers with semiannual AFP and ultrasound reduced HCC-related mortality by 37%  18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China, enrolled  Surveillance group: US and AFP every 6 mos (n = 9373)  Control group: no surveillance (n = 9443) Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422. 83.2 131.5 Total Mortality (per 100,000) 0 50 100 150 200 250 300 Rate ratio: 0.63 (95% CI: 0.41-0.98) ControlScreened

23. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Sensitivity of AFP Surveillance for HCC StudySensitivity, %Specificity, %PPV, % Case-control studies  Trevisani 2001 609125 Surveillance studies  Tanaka 1990 64  Pateron 1994 508633  Borzio 1995 47  Sherman 1995 64919  Solmi 1996 54  Zoli 1996 62  McMahon 2000 979531  Bolondi 2001 418246  Tong 2001 599111 Trevisani F, et al. J Hepatol. 2001;34:570-575. Tanaka S, et al. Cancer. 1990;66:2210-2214. Pateron D, et al. J Hepatol. 1994;20:65-71. Borzio M, et al. Gastroenterology. 1995;108:812-817. Sherman M, et al. Hepatology. 1995;22:432-438. Solmi L, et al. Am J Gastroenterol. 1996;91:1189-1194. Zoli M, et al. Cancer. 1996;78:977-985. McMahon BJ, et al. Hepatology. 2000;32:842-846. Bolondi L, et al. Gut. 2001;48:251-259. Tong MJ, et al. J Gastroenterol Hepatol. 2001;16:553-559. *5% prevalence of HCC.

24. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC HCC Surveillance by Ultrasound  Performance characteristics of ultrasound superior to any serologic test –Sensitivity: 65% to 80% –Specificity: > 90% Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf. Accessed September 13, 2010. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf

25. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC HCC Surveillance by CT Scan  No evidence to support the use of CT scanning for routine HCC surveillance –PPV and NPV unknown –Accurate use of CT requires 4-phase contrast CT –Radiation exposure is significant –In the absence of contrast CT, false-positive rate very high –Cannot distinguish small HCC from dysplastic nodules or arterialized cirrhotic nodules –Flow abnormalities create diagnostic difficulty

26. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Combination of AFP and Ultrasound for Surveillance  Combination increases detection, but increases false-positives and costs  False-positive rates –AFP alone: 5.0% –Ultrasound alone: 2.9% –AFP/ultrasound combined: 7.5%  Ultrasound costs $2000 per tumor found  AFP/ultrasound costs $3000 per tumor found Zhang B, et al. J Med Screen. 1999;6:108-110.

27. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Surveillance Interval: 6 vs 12 Mos  Trevisani et al [1] –Survival similar with 6-mo vs 12-mo surveillance  Santagostino et al [2] –Rate of detection of single nodules (vs multinodular HCC) similar with 6-mo vs 12-mo surveillance  Kim et al [3] –Survival improved with 6-mo vs 12-mo surveillance 1. Trevisani F, et al. Am J Gastroenterol. 2002;97:734-744. 2. Santagostino E, et al. Blood. 2003;102:78-82. 3. Kim DY, et al. AASLD 2007. Abstract 368.

28. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC AASLD Surveillance Guidelines  Surveillance recommended in at-risk groups –Specific hepatitis B carriers –Nonhepatitis B cirrhosis  HCC surveillance should be performed with ultrasound  Patients should be screened at 6-mo intervals –Increased surveillance interval in patients at higher risk not needed Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf. Accessed September 13, 2010. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf

29. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Tools for Diagnosis  AFP serology: no longer recommended due to challenges in distinguishing ICC from HCC  Radiology –HCC diagnosis possible with imaging alone if contrast-enhanced modalities used (CT, MR) –If < 1 cm on ultrasound, follow by ultrasound at 3-6 mo intervals –If > 1 cm on ultrasound, further screening with 4-phase multidetector CT scan or dynamic contrast-enhanced MRI  Biopsy –Small lesions require evaluation by expert pathologists –If the biopsy is negative for HCC, the lesion should be followed by imaging at 3- to 6-mo intervals Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf. Accessed September 13, 2010. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf

30. Staging and HCC Treatment Considerations

31. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Treatment for HCC Often Suboptimal  Proportion of patients receiving potentially curative therapy (N = 2963) –34.0% of patients with single lesions –34.0% of patients with lesions < 3 cm –19.2% of patients with lesions > 10 cm –4.9% of patients with metastatic disease  11.5% of patients ideal for transplantation received it  12.9% of patients ideal for surgical resection received it El-Serag HB, et al. J Hepatol. 2006;44:158-166.

32. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Treatment Options for HCC  Surgical –Resection –Liver transplantation  Locoregional –Percutaneous ethanol injection –Radiofrequency ablation –Transcatheter arterial chemoembolization –Yttrium 90  Systemic/targeted –Sorafenib

33. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC AASLD Guidelines: Staging Strategy and Treatment for Patients With HCC Liver transplant RFA/PEI Curative treatments TACE Single Increased Associated diseases Normal NoYes Terminal stage PST 0-2, Child-Pugh A-B Multinodular, PST 0 Sorafenib Portal pressure/bilirubin 3 nodules ≤ 3 cm N1, M1, PST 1-2≤ 3 cm, PST 0 Intermediate stage PST > 2, Child-Pugh C Very early stage Single < 2 cm Early stage Single or 3 nodules Advanced stage Portal invasion, PST 0, Child-Pugh A Resection Symptomatic HCC Palliative treatments Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects.Semin Liver Dis. 2010;30(1):61-74 (reprinted by permission).

34. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Liver Transplantation for HCC: Milan Criteria (Stage 1 and 2) + Absence of macroscopic vascular invasion, absence of extrahepatic spread Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

35. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Referral and Use of Multidisciplinary Approach  Patients with confirmed liver cancer should be referred to tertiary care center  Multidisciplinary team of specialists should include –Hepatologist –Pathologist –Interventional radiologist –Surgeon –Oncologists Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf. Accessed September 13, 2010. http://www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf

36. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Develop Patient and Family Teaching Plan  Discuss mode of transmission and prevention  Discuss importance of maintaining healthy lifestyle  Review signs and symptoms to look for potential disease progression  Review goals of treatment  Discuss importance of treatment adherence  Discuss HCC surveillance plan and importance of regular evaluation  Discuss results from surveillance and what they mean

37. HBV Management in Patients With HCC

38. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Antiviral Therapy Following HCC Treatment Shown to Reduce Recurrence  Lamivudine (n = 16) vs no therapy (n = 33) following resection or RFA for HCC [1] –Improved treatment eligibility following recurrence among those receiving lamivudine (P =.005)  Lamivudine after resection [2] –Significant improvement in tumor-free survival vs untreated controls (P =.0086)  Retrospective study (N = 103) [3] –Radiofrequency ablation for initial HCC –Multivariate analysis: high HBV DNA (HR: 2.67; 95% CI: 1.31-5.47; P =.007), absence of antiviral therapy (HR: 2.57; 95% CI: 1.34- 4.94; P =.005) independent risk factors for HCC recurrence 1. Kuzuya T, et al. J Gastroenterol Hepatol. 2007;22:1929-1935. 2. Kubo S, et al. Hepatol Res. 2007;37: 94-100. 3. Chuma M, et al. J Gastroenterol. 2009;44:991-999.

39. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Impact of HBV Therapy on Recurrence and Survival Following HCC Treatment  15 CHB patients with single nodule ≤ 4 cm received local ablation –All had complete response to therapy –No antiviral therapy prior to HCC diagnosis –9 patients received fully suppressive lamivudine ± tenofovir or adefovir following diagnosis –Recurrence in 2 patients –Median survival: 60 mos –Remaining patients served as untreated controls –Recurrence in all 6 patients –Median survival: 12.5 mos (P =.006 vs treated patients) Hann HW, et al. Int J Cancer. 2010;[Epub ahead of print].

40. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Management of HBV During Chemotherapy or Immunosuppression  Reactivation of HBV replication common during immunosuppression/chemotherapy (20% to 50%)  Prophylactic antiviral therapy recommended in HBV carriers at onset of cancer chemotherapy or immunosuppressive therapy –If baseline HBV DNA < 2000 IU/mL, continue treatment for 6 mos after –If baseline HBV DNA > 2000 IU/mL, continue treatment until they reach treatment endpoints for hepatitis B  Tenofovir or entecavir preferred if treatment for > 12 mos Lok AS, et al. Hepatology. 2009;50:661-662.

41. clinicaloptions.com/hepatitis Role of HBV in the Burden of HCC Summary and Conclusions  Hepatitis B is prevalent among Asian Americans  Important to screen for HBV infection in at-risk populations  Diagnosing hepatitis B carriers enables subsequent surveillance for HCC when indicated  Increasing data support the importance of HBV replication in the pathogenesis of HCC  AASLD guidelines recommend HCC screening among specific groups of patients with hepatitis B  Treatment for HCC is evolving; staging required prior to initiating therapy

42. Go Online for More From This Program! Interactive Virtual Presentation Downloadable Worksheet for Identifying HCC Risk and Developing Surveillance and Counseling Strategies in Hepatitis B Carriers clinicaloptions.com/HBVandHCC