1. Natural History of Hepatitis B and Liver Cancer Screening Herbert H Lee, M.D., M.P.H., M.S.Ed.

2. HBV Disease Progression Acute Infection Chronic Infection Cirrhosis Death 1. Torresi J, et al. Gastroenterology. 2000;118 (2 suppl 1):S83-103. 2. Fattovich G, et al. Hepatology. 1995;21:77-82. 3. Moyer LA, et al. Am J Prev Med. 1994;10:45-55. 4. Perrillo R, et al. Hepatology. 2001;33:424-432. 5% - 10% 1,3 Liver Failure (Decompensation) 30% 1 >90% of children <5% of adults 1 23% in 5 yr 2 Liver Cancer (HCC) Chronic HBV is the 6th leading cause of liver transplantation in the US 4 Liver Transplantation

3. Complications of CHB Fibrosis – Consequence of ongoing liver injury and repair 1 Cirrhosis – Risk of progression to cirrhosis of untreated CHB is 2-6% per year 2 End-stage Liver Disease – Typically presents 3-5 years after a diagnosis of CHB with cirrhosis 2 Hepatocellular Carcinoma – 70% of deaths in patients with CHB are due to HCC, with or without cirrhosis 3 1.Lim YS and Kim WR. Clin Liver Dis. 2008;12:733-746. 2.Weisberg IS, et al. Clin Liver Dis. 2007;11:893-916. 3.Asian Liver Center. 2007 Physician’s Guide to Hepatitis B. http://liver.stanford.edu/Media/publications/Handbook/2007Handbook.pdf. Accessed January 9, 2009.

4. Hepatitis B: Annual Disease Progression Chronic HBV Infection Compensated Cirrhosis Decompensated Cirrhosis Chronic HBV Infection Inactive Carrier State Hepatocellular Carcinoma Death 2-6% for HBeAg(+) hepatitis B 8-10% for HBeAg(-) hepatitis B <0.2% <1.0% 2-3% 7-8% 20-50% 3-5% Yim JY and Lok AS-F. Hepatology 2006;43:S173-S181.

5. < <> > HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal/mild CH Moderate/severe CH Normal/mild CH Cirrhosis Immune Tolerance Immune Clearance Low Replicative Phase Reactivation Phase Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive cirrhosis 2 x 10 8 - 2 x 10 11 IU/mL Phases of Chronic HBV Infection Slide courtesy of A. S. F. Lok, MD. 200,000 - 2 x 10 9 IU/mL Inactive-carrier stateHBeAg- chronic hepatitis HBeAg+ chronic hepatitis

6. Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology. 2001:120:1828. Clinical Profiles of Chronic HBV Infection Immune Tolerant HBeAg+ CHBInactive HBsAg Carrier HBeAg- CHB (Precore Mutant) HBsAg++++ HBeAg++–– Anti-HBe––++ ALTNormal   HBV DNA > 20,000 IU/mL (> 10 5 copies/mL) < 200 IU/mL (< 10 3 copies/mL) > 2000 IU/mL (> 10 4 copies/mL*) HistologyNormal/mildActiveNormalActive *Expert opinions vary as to this value.

7. Natural History of HBV: Development of HBeAg-Negative CHB Hadziyannis SJ, Vassilopoulos D. Hepatology. 2001;34:617-624. Phases of HBV infection HBeAg positive HBeAg negative / anti-HBe positive Replicative or immune tolerance phase HBeAg clearance Low-replicative phase HBV reactivation Wild-type HBV Variant HBV CHB = chronic hepatitis B

8. Comparison of HBeAg-positive CHB with HBeAg-negative CHB HBeAg + CHBHBeAg - CHB Type of infectionWild typePre-C/C mutant Mean HBV loadHighLow Seroconversion2-15%/yearN/A Natural historyVariableMore active/severe Rx end pointHBeAg seroconversionN/A Rx durationMore definedLonger-term Rx Rx responseHigher response rate Lower relapse rate Lower response rate Higher relapse rate

9. Differentiating HBeAg-Negative Chronic Hepatitis B From Inactive Carrier State Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. StatusHBeAg-Negative DiseaseInactive Carrier HBsAg positive Anti-HBe positive Anti-HBc positive HBV DNAModerate, often fluctuating levels; serum HBV DNA > 2000 IU/mL Low or undetectable; serum HBV DNA negative or < 2000 IU/mL ALTElevated, often fluctuating levels Normal

10. HBV: Factors Associated With Increased Risks of Progression to Cirrhosis Host FactorsVirus Factors Environmental Factors Older age* (longer duration) Male* Immune Status High levels of HBV replication* Genotype (C > B)* HBV variant (core promoter) Concurrent infection (HCV,* HDV, HIV) Alcohol consumption* Diabetes mellitus † Obesity † * Supported by strong evidence. † Further studies needed. Yim JY, Lok AS-F. Hepatology. 2006;43:S173-S181.

11. Cumulative Incidence of Cirrhosis by Serum HBV DNA Level at Study Entry Iloeje UH, et al. Gastroenterology. 2006;130:678-686. Cumulative Incidence of Liver Cirrhosis (%) N = 3582 Taiwanese patients Log-rank P <.001 Yr of Follow-up 40 30 20 10 0 130123456789101112 Baseline HBV DNA Level, copies/mL ≥ 1.0 x 10 6 1.0 x 10 5 - 9.9 x 10 5 1.0 x 10 4 - 9.9 x 10 4 300-9.9 x 10 3 < 300

12. Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry Yr of Follow-up Cumulative Incidence of HCC (%) N = 3653 Taiwanese patients Chen CJ, et al. JAMA. 2006;295:65-73. 0 2 4 6 8 10 12 14 012345678910111213 Baseline HBV DNA Level, copies/mL ≥ 1 million 100,000-999,999 10,000-99,999 300-9999 < 300

13. Progression to Cirrhosis Decreased If HBeAg Seroconversion Before Age 40 Chu, C.-M., et al. J. Viral Hepat. 2007; 14(3): 147-152

14. Spontaneous Clearance of HBsAg and HBeAg HBsAg Clearance 0.5% of carriers per year; most develop anti-HBs HBeAg Clearance 8% to 12% of carriers per year –45% in 5 years –80% in 10 years More frequent in older carriers and with  ALT levels Up to 20% who clear HBeAg can have exacerbations of hepatitis May indicate emergence of precore mutant virus Lok ASF, McMahon BJ. Hepatology. 2001;34:1225-1241.

15. HBeAg Seroconversion Not Always Associated With Outcomes in Asians Chang Gung Memorial Hospital, Taiwan (N = 283) – Median age of seroconversion: 32 years – Patients without evidence for cirrhosis at time of HBeAg seroconversion 7.8% and 2.2% developed cirrhosis and HCC, respectively, over a median follow-up of 8.6 years Queen Mary Hospital, Hong Kong (N = 3233) – Median age of seroconversion: 35 years – Median age for the development of HCC and/or cirrhosis: 57 years 73.3% of patients with clinical complications were anti-HBe positive Hsu YS, et al. Hepatology. 2002;35:1522-1527. Yuen MF, et al. Gut. 2005;54:1610-1614.

16. Role of ALT in Assessment of HBV Patients ALT > 20 IU/L associated with increased risk for liver disease-related death [1] Patients with mildly elevated ALT (> 1 to 2 x ULN) may be at increased risk of developing complications or fibrosis progression [2,3] Up to 24% of patients with normal ALT have stage 2-4 fibrosis by biopsy [4,5] AASLD position statement on ALT measurements: [6] – Useful in identifying significant liver disease and need for treatment – Useful for gauging the future course of natural history of HBV infection – ALT values > 1- 2 x ULN at the highest risk of complications 1. Kim HC, et al. BMJ 2004;328:983-986. 2. Yuen MF, et al. Gut. 2005;54:1610-1614. 3. Lai M, et al. J Hepatol. 2007;47:760-767. 4. Lai M, et al. Hepatology 2005;42(suppl 1):720A. 5. Alberti A, et al. Ann Intern Med. 2002;137:961-964. 6. Kim WR, et al. Hepatology. 2008;47:1363-1370.

17. Monitoring CHB: The Role of ALT Upper limits of normal (ULN) for ALT are currently suggested to be 30 IU/mL for men and 19 IU/mL for women 1,3 1.Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 2.Yuen MF, et al. Gut. 2005;54:1610-1614. 3.Prati D, et al. Ann Intern Med. 2002;137:1-10. – Associated with increased risk of complications and disease progression 2 – Relevant in predicting a serologic response to antiviral treatment 1 Elevated ALT ALT level is an important criterion for identifying patients who are candidates for therapy 1 – However, relying solely on elevated ALT to determine candidacy for treatment has its limitations

18. The Importance of Monitoring Viral Load Over Time Hadziyannis SJ and Papatheodoridos GV. Semin Liver Dis. 2006;26:130-141. Severity of the disease would not be evident from infrequent testing (IU/mL) 8.9x10 6 7.1x10 6 5.4x10 6 3.6x10 6 1.8x10 6 Hypothetical HBeAg-negative patient ALT (U/L) 500 400 300 200 100 0 50x10 6 40x10 6 30x10 6 20x10 6 10x10 6 0 HBV DNA (copies/mL) ALT HBV DNA 3633302724211815129630 Months

19. Natural History Study of CHB Patients conducted in the USA 1989-1999: 369 patients enrolled in a prospective study Followed for a mean of 84 months (7 years) Baseline laboratory tests: HBeAg, albumin, ALT, Platelets, DNA HBV HCC surveillance: AFP and abdominal ultrasound Mean age at recruitment: 48 years; 79% Asian Mean follow-up 84 months: – 37 died non-HCC liver deaths – 30 developed HCC Tong MJ et al., Hepatology. 2008

20. Risk Factors for HCC in HBsAg-Positive Individuals Host – Older age (older that 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.

21. HCC Surveillance in Chronic Hepatitis B: AASLD Recommendations Asian men older than 40 yrs of age Asian women older than 50 yrs of age Patients with cirrhosis Patients with family history of HCC African Americans Those with other risk factors such as high HBV DNA, co-infection with HCV or HIV, or presence of other liver diseases Bruix J, et al. Hepatology. 2011;53:1020-1022.

22. Summary HBV infection causes chronic hepatitis B that can be associated with cirrhosis and HCC HBV infection can be divided into four phases: immune tolerance, immune clearance, low replicative, and reactivation phases HBeAg-positive CHB differs with HBeAg-negative CHB in clinical presentation Modified ALT should be used to assess HBV disease activity HCC surveillance is important in HBV-infected individuals