1. 1 Chronic HBV: Current Management Natalie Bzowej, MD, PhD, FRCPC Director Transplant Research Ochsner Medical Center New Orleans, LA

2. 2 Chronic HBV: Current Management Agenda ●Screening Guidelines ●Prevalence (global and in the US) ●Phases of Hepatitis B ●Natural History ●Overview of Treatment

3. 3 30 year-old white male in for routine check up Patient reports no problems with health No significant personal or family history Wife was recently found to be HBsAg+ O/E No stigmata of CLD Exam normal Would you screen the patient for hepatitis B? Case 1

4. 4 47-year-old woman born in the US comes in for a routine physical PMHx and Family Hx unremarkable Social hx - parents immigrated from Korea Would you screen this patient for hepatitis B? Case 2

5. 5 22-year-old Chinese woman born in China comes in for physical c/o fatigue and nausea PMHx and Family Hx unremarkable Social Hx: immigrated at the age of 2 Would you screen this patient for hepatitis B? Case 3

6. 6 Candidates for Screening for HBV Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. ●Household and sexual contacts of HBsAg-positive persons ●US born children of immigrants from high-risk areas ●Persons born in high endemic areas (>2% prevalence) ●Persons who have ever injected drugs ●Persons with multiple sexual partners, or history of STDs ●Men who have sex with men ●Inmates of correctional facilities ●Individuals infected with HIV or HCV ●Patients undergoing dialysis ●All pregnant women ●Individuals with chronically elevated ALT/AST

7. 7 Prevalence of HBV: Global Estimates HBsAg Prevalence High (>8%) Intermediate (2%-7%) Low (<2%) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

8. 8 HBV Infection in the United States ●Revised HBV prevalence in the United States taking into account recent estimates of foreign-born persons - 847,145 to 2,243,757 persons with chronic HBV - Average chronic HBV prevalence rate among foreign-born persons living in the United States is 2.0% to 5.4% Kowdley KV, et al. Hepatology. 2012;56:422-433.

9. 9 Estimated HBV Prevalence Among Foreign-Born Americans (2009) All Foreign Born (n=41,329,349) Asia (n=10,970,572) Foreign-Born Americans: 13.6% of General Population Chronic HBV Prevalence (%) Central America (n=16,068,537) Caribbean (n=3,588,352) South America (n=2,856,583) Africa (n=1,669,101) Europe (n=5,113,072) North America (n=888,318) 3.7% 7.9% 1.3% 2.3% 1.6% 11.8% 2.2% 0.3% Kowdley KV, et al. Hepatology. 2012;56:422-433.

10. 10 Upper Limit of Normal ALT Levels ●Updated upper limits - Males: 30 U/L (-25% from prior ULN) - Females: 19 U/L (-37% from prior ULN) ●Based on retrospective cohort study - 6835 first time blood donors 1995-1999 Anti-HCV negative and no contraindication to donation ●ALT activity independently related to - BMI - Abnormal lipid or carbohydrate metabolism Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Prati D, et al. Ann Intern Med. 2002;137:1-9.

11. 11 Labs HBsAg+, HBeAg+, Anti-HBe–, Anti-HBc (IgM)– HBV DNA: 1,263,500 IU/mL, ALT: 128 U/L In what phase is this patient? Is this patient a candidate for treatment? If treatment is indicated, what treatment would you choose? What clinical and laboratory markers will you assess to determine effectiveness and duration? CASE 1: 30 yr old male

12. 12 Labs HBsAg+, HBeAg-, Anti-Hbe+ HBV DNA: 1,300 IU/mL, ALT: 17 U/L In what phase is this patient? Is this patient a candidate for treatment? CASE 2 (47 yr old Asian female)

13. 13 Labs HBsAg+, HBeAg+, Anti-Hbe- HBV DNA: 33,000,000 IU/mL, ALT: 12 U/L In what phase is this patient? Is this patient a candidate for treatment? CASE 3 (22 yr old Asian female)

14. 14 4 Phases of Chronic HBV Infection 1.Immune tolerance phase - HBeAg positive; high HBV DNA (10 5-10 copies/mL); normal ALT 2.HBeAg-positive chronic hepatitis (immune clearance) - High HBV DNA (10 5-10 copies/mL); high or fluctuating ALT; active inflammation on liver biopsy 3.Inactive HBsAg carrier (low or non-replication) - HBeAg negative; low HBV DNA (<10 4 copies/mL); normal ALT - HBsAg may become undetectable 4.HBeAg-negative chronic hepatitis (precore/bcp mutant) - Intermediate to high HBV DNA (10 4-8 copies/mL); high or fluctuating ALT; active inflammation on liver biopsy Pungpapong S, et al. Mayo Clin Proc. 2007;82:967-975.

15. 15 Labs HBsAg+, HBeAg+, Anti-HBe–, Anti-HBc (IgM)– HBV DNA: 1,263,500 IU/mL, ALT: 128 U/L In what phase is this patient? HBeAg-positive chronic hepatitis (immune clearance) CASE 1: 30 yr old male

16. 16 Labs HBsAg+, HBeAg-, Anti-Hbe+ HBV DNA: 1,300 IU/mL, ALT: 17 U/L In what phase is this patient? Inactive HBsAg carrier (low or no replication) CASE 2 (47 yr old Asian female)

17. 17 Labs HBsAg+, HBeAg+, Anti-Hbe- HBV DNA: 33,000,000 IU/mL, ALT: 12 U/L In what phase is this patient? Immune tolerance phase CASE 3 (22 yr old Asian female)

18. 18 Chronic HBV Infection: Disease Progression Fattovich G, et al. Gastroenterology. 2004;127:S35-S50. Seef LB, et al. Hepatology. 2001;33:455-463. Torresi J, et al. Gastroenterology. 2000;118:S83-S103. Fattovich G, et al. Hepatology. 1995;21:77-82. Liver Cancer (HCC) Cirrhosis Liver Failure Liver Transplantation* Death Chronic HBV Infection 23% in 5 years 10%-15% in 5 years 30% 5%-10% Acute Flare *Chronic HBV infection is the 6 th leading cause for liver transplantation the United States. Disease Progression Occurs in 15% to 40% With Chronic HBV Infection

19. 19 Chronic HBV: Goals of Therapy ●Control disease (not cure) by limiting viral replication - Sustained suppression of HBV replication - Prevent cirrhosis, hepatic failure, and HCC ●Markers of treatment response - Decreased serum HBV DNA to low/undetectable levels Improved liver histology Decreased or normalized serum ALT ●Endpoints of treatment HBeAg loss or seroconversion (in HBeAg+ patients) HBsAg loss or seroconversion Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

20. 20 NIH Guidelines: Candidates for HBV Therapy ●HBV therapy indicated - Acute liver failure - Cirrhosis and clinical complications - Cirrhosis or advanced fibrosis and HBV DNA in serum - Receiving cancer chemotherapy or immunosuppressive therapy ●HBV therapy may be indicated - Chronic HBV (HBeAg positive or negative) without advanced fibrosis or cirrhosis Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

21. 21 NIH Guidelines: Immediate HBV Therapy Is Not Routinely Indicated ●Immune-tolerant phase - HBeAg positive, high HBV DNA levels, normal ALT or little activity on liver biopsy ●Inactive carrier phase - HBsAg positive, low or undetectable HBV DNA levels, persistently normal ALT ●Latent HBV infection - Detectable HBV DNA levels without HBsAg Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

22. 22 Approved Treatments for HBV Generic Name Manufacturer Year Approved for HBV Interferon alfa-2bSchering Corporation1991 LamivudineGlaxoSmithKline1998 Adefovir dipivoxilGilead Sciences2002 EntecavirBristol-Myers Squibb2005 Peginterferon alfa-2aHoffmann La-Roche2005 TelbivudineIdenix2006 Tenofovir DFGilead Sciences2008

23. 23 Candidates for HBV Treatment APASL (2008)EASL(2009) Keeffe et al (2008)AASLD(2009) HBV DNA threshold (IU/L) HBeAg positive HBeAg positive HBeAg negative HBeAg negative 20,000 2000 20,000 2000 20,000 2000-20,000 ALT: Normal range --Use revised, lower range (M: 30 U/L; F: 19 U/L) Use revised, lower range (M: 30 U/L; F: 19 U/L) When to treat: key factors HBV DNA and ALT HBV DNA and ALT HBV DNA and ALT HBV DNA and ALT BiopsyConsider in certain groups Consider in certain groups Consider in certain groups Consider in certain groups Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org/Pages/Default.aspx. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. EASL. J Hepatol. 2009:50:227-242. Liaw Y-F, et al. Hepatol Int. 2008;2:263-283.

24. 24 AASLD Guidelines: HBeAg-Positive Patients (non-cirrhotic) HBV DNA (IU/mL) ALT (x ULN) Management Recommendation Preferred Drugs >20,000<2<2 Observe Consider biopsy in persons >40 years of age, ALT persistently high normal, or with family history of hepatocellular carcinoma Consider treatment if biopsy shows moderate or severe inflammation or significant fibrosis >2 Observe for 3 to 6 months and treat if no spontaneous HBeAg loss Immediate treatment if icteric or clinical decompensation Consider liver biopsy prior to treatment if compensated Lamivudine and telbivudine not preferred due to high rate of resistance Tenofovir DF Entecavir Peginterferon Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL. Cobas TaqMan 48 HBV: 1 IU/mL=5.8 copies/mL. Case 1: ALT (128), HBV DNA (1,263,500 IU/mL)

25. 25 AASLD Guidelines: HBeAg-Negative Patients (non-cirrhotic) HBV DNA (IU/mL) ALT (x ULN) Management Recommendation Preferred Drugs >20,000>2>2 Treat Lamivudine and telbivudine not preferred due to high rate of resistance Tenofovir DF Entecavir Peginterferon 2000 to 20,000 1-2 Consider biopsy Treat if biopsy shows moderate/severe necroinflammation or significant fibrosis <2000<1 Observe Treat if HBV DNA or ALT becomes higher Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL. Cobas TaqMan 48 HBV: 1 IU/mL=5.8 copies/mL. Case 2: HBV DNA: 1,300 IU/mL, ALT: 17 U/L

26. 26 AASLD Guidelines: HBeAg-Positive or Negative Patients With Cirrhosis HBV DNA (IU/mL) ALT (x ULN) Management Recommendation Preferred Drugs DetectableCirrhosisCompensated Treat if HBV DNA >2000 IU/mL Consider treatment if HBV DNA is <2000 IU/mL and ALT is elevated Tenofovir DF Entecavir Decompensated Refer for transplantation Lamivudine (or telbivudine) + adefovir, tenofovir DF or entecavir UndetectableCirrhosisCompensated Observe Decompensated Refer for transplantation Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL. Cobas TaqMan 48 HBV: 1 IU/mL=5.8 copies/mL.

27. 27 Duration of HBV Treatment ●HBeAg-positive - An additional 12 months after HBeAg seroconversion to reduce relapse rate (non-cirrhotics) ●HBeAg-negative - Relapse common after cessation of therapy - Long-term treatment currently recommended ●Cirrhosis - Long-term therapy required or until HBsAg loss - Combination therapy may be considered Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

28. 28 30 year-old male, eAg+, high ALT, high HBV DNA liver biopsy: stage 2 fibrosis genotype A Treated with pegasys x 48 weeks finite treatement duration Check ALT, HBV DNA at 1, 3, 6 and 12 months Virus negative at 24, 48 and 72 weeks eAg- loss, eAb + at 2 years sAg loss at 5 years Case 1

29. 29 HBV Genotyping and Response to Therapy ●At least 8 genotypes have been identified ●Prevalence varies by geographic region - Type A: North America, northern Europe, India, and Africa - Types B and C: Asia - Type G: United States and Europe - Type H: Central America and California ●HBeAg-negative precore mutant seen more frequently in genotypes B, C, and D Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Peginterferon alfa 2a HBeAg Seroconversion (%) 52% 30% 22% 31% A (n=23) B (n=76) C (n=162) D (n=9)

30. 30 30 year-old male, eAg+, high ALT, high HBV DNA liver biopsy: stage 2 fibrosis Treated with tenofovir or entecavir Check ALT, HBV DNA at 1, 3, 6 and 12 months Monitor creatinine periodically Virus becomes negative at 24 wks HBeAg-, HBeAb+ at 4 yrs (treat for one more year) 6 mos off treatment HBV DNA 1500 IU/mL, ALT 33 HBeAg remains negative, HBeAb positive Monitor HBV DNA q 3mos x 1 yr, then q 6 mos Treat only if rising DNA and ALT Case 1 (Alternate Scenario)

31. 31 Cumulative Incidence of Drug Resistance During HBV Therapy Patients (%) 29% 73% 20% 25% 11% 1.2% 0% HBV Treatment-Naïve Patients (baseline wild-type virus) Lamivudine 5 Years Adefovir 5 Years Entecavir 6 Years Tenofovir DF 4 Years Telbivudine 2 Years Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. 0% HBeAg status Positive Negative Mixture of both

32. 32 Summary ●Chronic HBV infection is a common problem that leads to morbidity and mortality ●Understand the prevalence of your patient population ●A wide range of treatment options exist ●Treatment should be initiated and tailored to the individual based on - HBV DNA levels - Elevated ALT or abnormal liver biopsy - HBeAg status - HBV genotype ●Tenofovir DF, entecavir, and peginterferon are preferred first-line agents

33. 33 A 25-year-old Asian female who is HBsAg (+) and HBeAg (+) with serum HBV DNA of >170, 000, 000 int. unit/mL has a serum ALT of 17 int. unit/L. Initial evaluation of this patient with chronic hepatitis B should not include: A.History and physical examination B.Laboratory tests to assess liver disease - complete blood counts with platelets, hepatic panel, and prothrombin time C.Tests to rule out viral coinfections - anti-HCV, anti- HIV D.Liver biopsy to grade and stage liver disease 10

34. 34 A patient with HBV and decompensated cirrhosis can be treated with all of the following agents except: A.a) tenofovir B.b) lamivudine C.c) interferon D.d) entecavir 10

35. 35 Groups at high risk who should be screened for HBV include: A.) Household and sexual contacts of HBsAg-positive persons B.b) Persons needing immunosuppressive therapy C.c) Men who have sex with men D.d) Patients undergoing renal dialysis E.e) a, b, c and d 10