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Welcome and Program Introduction

Welcome and Program Introduction. Program Chair Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Leonard Miller Professor of Medicine Director, Schiff Liver Institute Director, Center for Liver Diseases Division of Hepatology Miami, FL. Disclosures.

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Welcome and Program Introduction

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  1. Welcome and Program Introduction Program Chair Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Leonard Miller Professor of Medicine Director, Schiff Liver Institute Director, Center for Liver Diseases Division of Hepatology Miami, FL

  2. Disclosures Consulting Fees: Bayer; Bristol-Myers Squibb; Conatus; Evivar; Gilead Sciences, Inc; GlobeImmune, Inc; Johnson & Johnson; Merck & Co; Novartis/Idenix; Roche Molecular; Vertex Pharmaceuticals Data and Safety Monitoring Board: Daiichi-Sankyo; Johnson & Johnson; Pfizer; Salix Pharmaceuticals; Merck; Sanofi Aventis Contracted Research: Abbott; Bristol-Myers Squibb; Conatus; Debiopharm; Gilead Sciences, Inc; GlobeImmune, Inc; Idenix; Merck & Co; Novartis/Idenix; Roche Diagnostics; Roche Molecular; Roche Pharmaceuticals; Salix Pharmaceuticals, Inc; Sanofi Aventis; Vertex Pharmaceuticals; Pfizer

  3. Educational Objectives • Upon completing this program, participants will be better able to: • Integrate the 2009 AASLD guidelines into clinical practice with respect to screening at-risk patients, treatment timing, selection of agents, and duration of treatment • Develop treatment strategies for the management of pregnant women with CHB and for the prevention of perinatal infection in newborns • Develop management strategies for HBV carriers undergoing immunosuppressive or cytotoxic therapy

  4. Program Agenda

  5. Faculty

  6. Accreditation Statements PHYSICIAN CONTINUING MEDICAL EDUCATION Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and HealthmattersCME. PIM is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Postgraduate Institute for Medicine designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

  7. Housekeeping Notes • To receive Continuing Education Credit for this program, please complete the evaluation in your meeting folder and return to the meeting organizer in the back of the room. • We will be using an Audience Response System to present a series of questions during the meeting. • Press firmly and hold your answer choice until a green light on the keypad confirms your selection has been recorded (less than a second) • You may change your answer by selecting a different key. Only your last selection will be recorded • Please leave the keypad on the table when you exit • Questions? • There are Question Cards in your meeting folder • There will be a Q&A after each presentation, so please jot down your questions and the staff will pick them up during the course of the meeting

  8. Program Sponsorship This activity is jointly sponsored by Postgraduate Institute for Medicine and HealthmattersCME.

  9. Financial Support This activity is supported by an independent educational grant from Gilead Sciences Medical Affairs.

  10. Case 1: Initiating Treatment in Patients with HBV Robert G. Gish, MD Professor of Clinical Medicine Co-director, CHAT Chief of Clinical Hepatology University of California, San Diego Medical Center San Diego, CA

  11. Relevant Disclosures Consulting Fees: Bristol-Myers Squibb; Genentech/F. Hoffman LaRoche Ltd; Gilead Sciences, Inc Contracted Research: Bristol-Myers Squibb; Genentech/F. Hoffman LaRoche Ltd; Gilead Sciences, Inc

  12. Candidates for Screening for HBV • Persons born in mid to high endemic areas (≥2% prevalence) • US-born children of immigrants from high-risk areas (>8% prevalence) • Household and sexual contacts of HBsAg-positive persons • Persons who have ever injected drugs • Persons with multiple sexual partners or a history of STIs/STDs • MSM • Inmates of correctional facilities • Persons with chronically elevated ALT/AST levels • Persons infected with HIV or HCV • Patients undergoing dialysis • All pregnant women ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; MSM, men who have sex with other men; STDs, sexually transmitted diseases; STIs, sexually transmitted infections. Weinbaum CM et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

  13. Immigration Patterns to the United States: The Impact on HBV Approximately 315,000 emigrate from Asiaa Approximately 130,000 emigrate from Europea(predominantly Eastern Europe) 33.5 Million FB Residents in the United States (11.7% of the US Population) Approximately 60,000 emigrate from Central Americaa Approximately 63,000 emigrate from Africaa Approximately 69,000 emigrate from South Americaa Approximately 82,000 emigrate from the Caribbeana Approximately 174,000 emigrate from Mexicoa a Annual emigration to the United States. FB, foreign born. The United States Citizenship and Immigration Services. http://www.uscis.gov. Accessed April 5, 2006.

  14. Prevalence of CHB Foreign Born Population and CHB Prevalence in the United States by Place of Birth: SUMMARY 2008 CHB Prevalence Rate (%) CHB Prevalence in the US Place of Birth Population Low Mid High Low Mid High FB from all regions 41,329,349 2.0 3.7 5.4 847,145 1,522,798 2,243,757 Asia 10,970,572 4.8 7.9 10.6 521,244 862,779 1,163,700 Central America 16,068,537 0.4 1.3 2.5 71,902 208,804 398,598 Caribbean 3,588,352 1.1 2.3 3.9 38,902 82,000 140,074 South America 2,856,583 1.0 1.6 2.4 28,258 46,614 69,783 Africa 1,669,101 7.8 11.8 16.8 130,722 196,338 280,196 Europe 5,113,072 0.9 2.2 3.4 48,073 114,174 174,361 Oceania 174,814 4.1 5.4 7.7 7156 9424 13,490 North America 888,318 0.1 0.3 0.4 888 2665 3553 Data for 93 countries grouped by world region (US Census regions). Welch S et al., 59th AASLD; San Francisco, CA; October 31-November 1, 2008. Poster 853.

  15. Prevalence of CHB: Risks of CHB in Different Sub-populations Published CHB Rates in Different Subpopulations in Country/Region of Origin • Sample may not be representative of general population in country/region of origin • Quality of data varies (sampling method, assay used, lab skills) • Most rates based on presence of HBsAg, which includes chronic and acute HBV • Percentage of HBsAg+ with chronic disease varies with HBV endemicity (<90%-95%) • Sample may not be representative of emigrants to the United States • Race, ethnicity, socioeconomic differences • Location within country/region (urban or rural area, high or low endemicity) Lower-risk Groups General Population Higher-risk Groups Blood donors who are screened for risk factors as well as “Healthy” self-selected Pregnant women Community surveys “Random” samples Indigenous peoples Marginalized minorities Sex workers IDUs, MSM Prisoners Hemophiliacs Orphans (Eastern Europe) CHB, chronic hepatitis B; IDUs, injection drug users. Welch S et al., 59th AASLD; San Francisco, CA; October 31-November 1, 2008. Poster 853.

  16. Prevalence of CHBFB Population and CHB Prevalence in the United States by Place of Birth: Asia CHB Prevalence Rate (%) CHB Prevalence in the US Asia 10,970,572 4.8 7.9 10.6 521,244 862,779 1,163,700 Place of Birth Population Eastern Asia 3,490,940 7.5 10.6 13.5 261,579 368,783 472,293 Low Mid High Low Mid High South Central Asia 2,748,463 1.7 3.5 6.1 45,411 95,556 168,467 Western Asia 863,542 1.9 3.6 5.5 16,589 31,093 47,456 Asia n.e.c.a 50,554 1.0 2.5 3.0 506 1264 1517 South Eastern Asia 3,817,072 5.2 9.6 12.4 197,160 366,083 473,966 a Asia n.e.c. Bahrain, Cyprus, Oman, Qatar, United Arab Emirate. Welch S et al., 59th AASLD; San Francisco, CA; October 31-November 1, 2008. Poster 853.

  17. Evaluation of Patients for CHB • History and physical examination • HTN • High BMI • Otherwise normal physical exam • Laboratory tests BMI, body mass index; HTN, hypertension. Lok AS and McMahon BJ. Hepatology. 2009;50(3):661-662; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):1315-1341.

  18. Patient X Laboratory Testing Reveals • HBV DNA of 106 IU/mL • ALT 39 IU/L (normal for lab <45 IU/L) • Platelet count 158,000/mL • Spleen size (height) by ultrasonography 10.9 cm • PV diameter 11 mm • Liver heterogeneous on US assessment • Ferritin 330 ng/mL (normal for lab <50 ng/mL) • Iron saturation: 47% • The rest of the CBC, Chem P, INR, lipid panel were normal • HBV genotype A • HBeAg positive, anti-HBe negative • AFP 7 ng/mL (normal for lab <6 ng/mL)

  19. Distribution of HBV Genotypes in Africa Kramvis A, Kew MC. Hepatol Res. 2007;37(suppl 1):S9-S19.

  20. HBeAg-positive Patients (Study 103) and HBeAg-negative Patients (Study 102) Distribution of Viral Genotypes at Baseline by Race Patients (%) (n = 122) (n = 12) (n = 240) (n = 10) (n = 15) Tenofovir Licensing Studies; Combined data include both HBeAg-positive and HBeAg-negative patients. Gane E et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Poster 2780.

  21. HBV Genotyping and Clinical Profile • 13 genotypes have been identified • Prevalence varies by geographic region • Type A: • Ae: North America, Northern Europe • Aa: India, Africa, Phillipines • Types B and C: Asia • Type D: Mediterranean, North Africa, sub-Saharan Africa • Type G: United States and Europe • Type H: Central America and California • Type I: Vietnam • Type J: Japan • HBeAg-negative core/precore mutant seen more frequently in genotypes Aa, B, C, and D Lok AS and McMahon BJ. Hepatology. 2009;50(3):661-662; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):1315-1341.

  22. Genotype Affects Response to Interferon Therapy HBeAg Seroconversion at End of Follow-up PegIFN alfa 2ba PegIFN alfa 2ab Patients (%) Patients (%) A (n = 47) B (n = 12) C (n = 21) D (n = 51) A (n = 23) B (n = 76) C (n = 162) D (n = 9) HBV Genotype HBV Genotype Almost all genotype A in these studies were Ae (European variant). PegIFN, pegylated interferon. aJanssen HL et al. Lancet. 2005;365(9454):123-129; b Lau GK et al. N Engl J Med. 2005;352(26):2682-2695.

  23. Histologic Evidence of Liver Injury with Normal or Minimally Elevated ALT Knodell Inflammation >5 and Ishak >1 on Biopsy P <0.001 P = 0.088 Patients (%) P = 0.073 Normal Minimally Elevated Normal Minimally Elevated <6.5 ≥6.5 HBV DNA (log10 copies/mL) ALT AST n = 63 treatment-naïve CHB patients with normal or minimally elevated ALT levels (≤1.2 x ULN (HBeAg+) or ≤1.5 x ULN (HBeAg-) and active HBV replication (HBV DNA ≥4 log copies/mL). ULN, upper limit of normal. Hu K-Q et al. J Hepatol. 2008;48(suppl 2):S242

  24. Upper Limit of Normal ALT Levels • Updated ULNs • Males: 30 IU/L (↓ 25% from prior ULN) • Females: 19 IU/L (↓ 37% from prior ULN) • Based on retrospective cohort study • 6,835 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(12):1315-1341; Prati D et al. Ann Intern Med. 2002;137(1):1-10.

  25. Candidates for HBV Treatment APASL, Asian Pacific Association for the Study of Liver; EASL, European Association for the Study of Liver. Lok AS and McMahon BJ. Hepatology. 2009;50(3):661-662; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):1315-1341; EASL. J Hepatol. 2009:50(2):227-242; Liaw Y-F et al. 2008 APASL Guidelines for HBV Management. http://www.apasl.info/ guidelinesHBV.html

  26. AASLD Guidelines: HBeAg-positive Patients 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. Lok AS et al. Hepatology. 2009;50(3):661-662.

  27. 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 • CHB (HBeAg positive or negative) without advanced fibrosis or cirrhosis NIH, National Institutes of Health. Sorrell MF et al. Ann Intern Med. 2009;150(2):104-110.

  28. 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, very 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(2):104-110.

  29. AASLD Guidelines: HBeAg-positiveor HBeAg-negative Patients with Cirrhosis 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. Lok AS and McMahon BJ. Hepatology. 2009;50(3):661-662.

  30. CHB: Goals of Therapy • Achieve sustained suppression of HBV replication and remission of hepatic disease • Prevent the development of cirrhosis, hepatic failure, liver transplantation and hepatocellular carcinoma • HBV is never cured but rather controlled by limiting viral replication • Markers of treatment response • Decreased serum HBV DNA to low or undetectable levels • Improved liver histology • Decreased or normalized serum ALT • HBeAg loss or seroconversion (in HBeAg-negative patients) • HBsAg loss or seroconversion Lok AS and McMahon BJ. Hepatology. 2009;50(3):661-662; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):1315-1341.

  31. Approved Treatments for HBV

  32. Treatment Guidelines: Recommendations for First-line Therapy in Patients Without Cirrhosis HBeAg-positive or HBeAg-negative CHB a HBV DNA must be undetectable at 24 weeks to continue (Keeffe). AASLD guidelines: lamivudine and telbivudine not preferred due to relatively high rate of resistance. Adefovir not preferred due to weak antiviral activity and relatively high rate of resistance. Lok AS and McMahon BJ. Hepatology. 2009;50(3):661-662; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):1315-1341.

  33. Duration of HBV Treatment • HBeAg-positive • An additional 12 months after HBeAg seroconversion to reduce relapse rate (noncirrhotics) • 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(12):1315-1341.

  34. PegIFN and/or Lamivudine in Patients with HBeAg-positive CHB Responses at End of Follow-up (Week 72) Patients (%) HBeAg Seroconversion HBV DNA <105 copies/mL HBV DNA <400 copies/mL Normalized ALT PegIFN wasstatistically significantly better than lamivudine monotherapy for all measures. Lau GK et al. N Engl J Med. 2005;352(26):2682-2695.

  35. Extending PegIFN Treatment Duration in HBeAg-positive Patients • HBeAg-positive patients with a partial response to pegIFN alfa 2a (180 µg/week) at Week 48 were randomized • Partial response: HBV DNA <105 copies/mL without HBeAg seroconversion after 48 weeks of therapy • Randomized groups • Extension group: received an additional 24 weeks of pegIFN therapy (n=16) • Follow-up: received no further treatment (n=15) • At randomization • Baseline HBeAg levels were higher in the extension group (1061 vs. 826 IU/mL) • Baseline HBsAg levels were >250 IU/mL in both arms Zhu Y-Y et al. J Hepatol. 2009;50(suppl 1):S331-S332. Abstract 913.

  36. Increased Response to Extending PegIFN Treatment Duration Responses in HBeAg-positive Patients (Week 72) Patients (%) HBeAg Seroconversion HBsAg Clearance HBV DNA <103 copies/mL HBeAg Clearance Zhu Y-Y et al. J Hepatol. 2009;50(suppl 1):S331-S332. Abstract 913.

  37. 5-Year Follow-up of PegIFN + Lamivudine in HBeAg-negative Disease Responses by Follow-up Year After Treatment Discontinuation (n = 230) 47.4 Patients (%) 22.2 16.5 13.5 12.2 7.0 4.8 3.5 HBV DNA <400 copies/mL Normalized ALT HBsAg Seroconversion HBsAg Clearance All patients achieving HBsAg clearance at year 5 had a HBV DNA <400 copies/mL; therefore, the rate of HBsAg clearance in patients with a sustained virologic response was 72%. Marcellin P et al. J Hepatol. 2009;50(suppl 1):S336. Abstract 924.

  38. PegIFN and/or Adefovir inPatients with HBeAg-positive CHB Responses at End of Follow-up (Week 96) a b Patients (%) b a HBV DNA <500 copies/mL HBeAg Clearance HBeAg Seroconversion Normalized ALT Patients received treatment for 48 weeks (PegIFN 135 µg/week; adefovir 10 mg/day). aP <0.01 and b P <0.05 vs adefovir. Ma W-M et al. Hepatology. 2009;50(suppl 4):494A. Abstract 400.

  39. Key Points • CHB is a common problem that leads to morbidity and mortality • 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 pegIFN are preferred first-line agents

  40. Case 2: Managing the Pregnant Patient Who Has Chronic Hepatitis B Tram T. Tran, MD Associate Professor of Medicine Geffen UCLA School of Medicine Medical Director Liver Transplant Program Cedars-Sinai Medical Center Los Angeles, CA

  41. Disclosures • Consulting Fees: Bristol-Myers Squibb; Gilead Sciences, Inc • Fees for Non-CME/CE Services: Bristol-Myers Squibb; Gilead Sciences, Inc

  42. Laboratory Test Results • Labs • AST 22 IU/L • ALT 25 IU/L • ALP 100 IU/L • TB 0.8 mg/dL • INR 1.0 • HBsAg positive, HBeAg positive, HBeAb negative • HBV DNA 1010 copies/mL tested at 9 weeks gestation ALP, alkaline phosphatase; HBeAb, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; TB, total bilirubin.

  43. Perinatal HBV Transmission Risk Mother: HBsAg positive, HBeAg positive Child: • 70%-90% risk of chronic HBV infection by age 6 months without immunoprophylaxis1-3 • 38% not infected perinatally are positive by age 4 years4 1 Beasley RP et al. Am J Epidemiol. 1977;105(2):94-98; 2 Okada K et al. N Engl J Med. 1976;294(14):746-749; 3 Wong VC et al. Lancet. 1984;1(8383):921-926; 4 Beasley RP and Hwang LY. J Infect Dis. 1983;147(2):185-190.

  44. Risk of Chronic HBV Infection Risk (%) Age at Infection Chang MH. J Gastroenterol Hepatol. 2000;15 (suppl):E16-E19; McMahon BJ et al. J Infect Dis. 1985;151(4):599-603; Tassopoulos NC et al. Gastroenterology. 1987;92(6):1844-1850.

  45. Maternal HBV Status and Outcomeof HBV Infection in Infants HBIG, hepatitis B immunoglobulin. Chang MH. Semin Fetal Neonatal Med. 2007;12(3):160-167; Stevens CE et al. N Engl J Med. 1975;292(15):771-774.

  46. Newborn HBV Infection Is Related to High Levels of Maternal Viremia A case-controlled study of 773 HBsAg-positive mothers found that the odds ratio for having a persistently infected infant is • 147 among HBeAg-positive mothers with serum HBV DNA level ≥1.4 ng/ml (3.9 x 108 copies/mL, 8 x 107 IU/mL) • 19.2 among mothers who have high serum HBV DNA levels but are HBeAg negative Burk RD et al. J Infect Dis. 1994;170(6):1418-1423.

  47. Perinatal Transmission of HBV:An Australian Experience • Prospective, observational, cohort study (N = 313) • Asymptomatic, HBsAg-positive pregnant women • Antenatal clinics • All infants are routinely offered HBIG and HBV vaccination • HBsAg-positive infants at 9-month follow-up underwent further virologic testing HBeAg (%) HBsAg-positive Pregnant Women (N = 313) Positive (n = 91) Negative (n = 122) Low HBV DNA (n = 115) 9 106 Mothers With Detectable HBV DNA (n = 213) High HBV DNA (n = 29) 13 16 Very High HBV DNA (n = 69) 69 0 Infants Tested (N = 138) HBsAg-positive Infants (n = 4) HBV DNA (copies/mL) Low: <105 High: 105 to 108 Very High: >108 Wiseman E et al. Med J Aust. 2009;190(9):489-492.

  48. HBV DNA Level and Perinatal Transmission of HBV • No case of transmission from mothers with HBV DNA <108 copies/mL • One case of vaccine/HBIG escape mutation identified; however, the infant was not given HBIG Transmission Rate (%) All Infants of HBV DNA-positive Mothers HBeAg-positive Mothers <105 105-108 >108 Maternal HBV DNA (copies/mL) Wiseman E et al. Med J Aust. 2009;190(9):489-492.

  49. HBV Treatment During Pregnancy Study Design • 8 HBeAg-positive pregnant women with HBV DNA ≥1.2x109 copies/mL • 150 mg lamivudine after 34 weeks of gestation • 25 historical controls, born to untreated women with HBsAg and HBV DNA ≥1.2x109 copies/mL • All newborns received standard immunoprophylaxis and were followed up for 12 months Outcomes • High maternal viremia associated with vaccination failure • 5 of 8 mothers had decline in HBV DNA to <1.2x108 copies/mL • 4 of 8 infants were HBsAg positive at birth; 1 remained HBsAg positive at 12 months (12.5%) • 7 of 25 controls were HBsAg positive at 12 months (28%) • No adverse events were noted with lamivudine Van Zonneveld M et al. J Viral Hepat. 2003;10(4):294-297.

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