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Welcome and Program Introduction Program Chair Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Leonard Miller Professor of Medicine Director, Schiff Liver.

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Presentation on theme: "Welcome and Program Introduction Program Chair Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Leonard Miller Professor of Medicine Director, Schiff Liver."— Presentation transcript:

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2 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

3 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

4 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

5 Program Agenda Treat or No Treat: Welcome and Program Overview Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, Program Chair Case 1: Initiating Treatment in Patients with HBV Robert Gish, MD Case 2: Managing the Pregnant Patient Who Has Chronic Hepatitis B Tram T. Tran, MD Case 3: Treating Patients Who Have Hepatitis B and Lymphoma Mark Sulkowski, MD Questions and Answers

6 Faculty 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 Robert Gish, MD Professor of Clinical Medicine Co-director, CHAT Chief of Clinical Hepatology University of California, San Diego Medical Center San Diego, CA Mark Sulkowski, MD Associate Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, MD 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

7 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.

8 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

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

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

11 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

12 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

13 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.

14 Immigration Patterns to the United States: The Impact on HBV The United States Citizenship and Immigration Services. Accessed April 5, Approximately 315,000 emigrate from Asia a Approximately 60,000 emigrate from Central America a a Annual emigration to the United States. FB, foreign born. Approximately 69,000 emigrate from South America a Approximately 174,000 emigrate from Mexico a Approximately 82,000 emigrate from the Caribbean a Approximately 63,000 emigrate from Africa a Approximately 130,000 emigrate from Europe a (predominantly Eastern Europe) 33.5 Million FB Residents in the United States (11.7% of the US Population)

15 Foreign Born Population and CHB Prevalence in the United States by Place of Birth: SUMMARY Welch S et al., 59 th AASLD; San Francisco, CA; October 31-November 1, Poster 853. Data for 93 countries grouped by world region (US Census regions). Prevalence of CHB Place of Birth 2008 Population LowHigh FB from all regions41,329, ,1451,522,7982,243,757 Asia10,970, ,244862,7791,163,700 Central America16,068, ,902208,804398,598 Caribbean3,588, ,90282,000140,074 South America2,856, ,25846,61469,783 Africa1,669, ,722196,338280,196 Europe5,113, ,073114,174174,361 Oceania174, ,490 North America888, Mid CHB Prevalence Rate (%)CHB Prevalence in the US LowHighMid

16 CHB, chronic hepatitis B; IDUs, injection drug users. Welch S et al., 59 th AASLD; San Francisco, CA; October 31-November 1, Poster 853. Published CHB Rates in Different Subpopulations in Country/Region of Origin Prevalence of CHB: Risks of CHB in Different Sub-populations 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 GroupsGeneral PopulationHigher-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)

17 Welch S et al., 59 th AASLD; San Francisco, CA; October 31-November 1, Poster 853. Prevalence of CHB FB Population and CHB Prevalence in the United States by Place of Birth: Asia a Asia n.e.c. Bahrain, Cyprus, Oman, Qatar, United Arab Emirate. Asia10,970, ,244862,7791,163,700 Eastern Asia3,490, ,579368,783472,293 South Central Asia2,748, ,41195,556168,467 South Eastern Asia3,817, ,160366,083473,966 Western Asia863, ,58931,09347,456 Asia n.e.c. a 50, Place of Birth Population LowHighMid CHB Prevalence Rate (%)CHB Prevalence in the US LowHighMid

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

19 Patient X Laboratory Testing Reveals HBV DNA of 10 6 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)

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

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

22 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): ; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):

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

24 Histologic Evidence of Liver Injury with Normal or Minimally Elevated ALT Patients (%) Knodell Inflammation >5 and Ishak >1 on Biopsy P = ALT Hu K-Q et al. J Hepatol. 2008;48(suppl 2):S242 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. P <0.001 P = AST HBV DNA (log 10 copies/mL) NormalMinimally Elevated NormalMinimally Elevated <6.5≥6.5

25 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 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): ; Prati D et al. Ann Intern Med. 2002;137(1):1-10.

26 Candidates for HBV Treatment APASL (2008) EASL (2009) Keeffe et al (2008) AASLD (2009) HBV DNA Threshold (IU/mL) HBeAg positive HBeAg negative 20,000 2,000 20,000 2,000 20,000 2,000-20,000 ALT: Normal Range ---Use revised, lower range (M: 30 IU/L; F: 19 IU/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 and McMahon BJ. Hepatology. 2009;50(3): ; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12): ; EASL. J Hepatol. 2009:50(2): ; Liaw Y-F et al APASL Guidelines for HBV Management. guidelinesHBV.html APASL, Asian Pacific Association for the Study of Liver; EASL, European Association for the Study of Liver.

27 HBV DNA (IU/mL) ALT (x ULN) Management Recommendation Preferred Drugs >20,000≤2Observe Consider biopsy in persons older than 40 years, with ALT persistently high normal, or with family history of hepatocellular carcinoma Consider treatment if biopsy shows moderate or severe inflammation or significant fibrosis >2Observe 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 PegIFN AASLD Guidelines: HBeAg-positive Patients Lok AS et al. Hepatology. 2009;50(3): 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.

28 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):

29 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):

30 HBV DNA (IU/mL) ALT (x ULN) Management Recommendation Preferred Drugs DetectableCirrhosis Compensated Treat if HBV DNA >2,000 IU/mL Consider treatment if HBV DNA is ≤2,000 IU/mL and ALT is elevated Tenofovir DF Entecavir Decompensated Refer for transplantation Evaluation Tenofovir DF or Entecavir UndetectableCirrhosisCompensated Observe Decompensated Refer for transplantation Evaluation AASLD Guidelines: HBeAg-positive or HBeAg-negative Patients with Cirrhosis Lok AS and McMahon BJ. Hepatology. 2009;50(3): 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.

31 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): ; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):

32 Approved Treatments for HBV Generic NameManufacturerYear Approved for HBV Interferon alfa-2bSchering Corporation1991 LamivudineGlaxoSmithKline1998 Adefovir dipivoxilGilead Sciences2002 EntecavirBristol-Myers Squibb2005 PegIFN alfa 2aHoffmann La-Roche2005 TelbivudineIdenix2006 Tenofovir DFGilead Sciences2008

33 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. PreferredAlternativeNot Preferred Tenofovir DFAdefovirLamivudine EntecavirTelbivudine a PegIFN alfa 2a Lok AS and McMahon BJ. Hepatology. 2009;50(3): ; Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6(12):

34 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):

35 PegIFN and/or Lamivudine in Patients with HBeAg-positive CHB Patients (%) Responses at End of Follow-up (Week 72) HBV DNA <400 copies/mL HBeAg Seroconversion HBV DNA <10 5 copies/mL Normalized ALT PegIFN was statistically significantly better than lamivudine monotherapy for all measures. Lau GK et al. N Engl J Med. 2005;352(26):

36 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 <10 5 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.

37 Increased Response to Extending PegIFN Treatment Duration Patients (%) Responses in HBeAg-positive Patients (Week 72) Zhu Y-Y et al. J Hepatol. 2009;50(suppl 1):S331-S332. Abstract 913. HBV DNA <10 3 copies/mL HBeAg Seroconversion HBsAg Clearance HBeAg Clearance

38 5-Year Follow-up of PegIFN + Lamivudine in HBeAg-negative Disease Patients (%) 13.5 Responses by Follow-up Year After Treatment Discontinuation (n = 230) HBV DNA <400 copies/mL HBsAg Seroconversion HBsAg Clearance Normalized ALT Marcellin P et al. J Hepatol. 2009;50(suppl 1):S336. Abstract 924. 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%.

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

40 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

41 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

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

43 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 copies/mL tested at 9 weeks gestation ALP, alkaline phosphatase; HBeAb, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; TB, total bilirubin.

44 Perinatal HBV Transmission Risk Mother: HBsAg positive, HBeAg positive Child:  70%-90% risk of chronic HBV infection by age 6 months without immunoprophylaxis 1-3  38% not infected perinatally are positive by age 4 years 4 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): ; 3 Wong VC et al. Lancet. 1984;1(8383): ; 4 Beasley RP and Hwang LY. J Infect Dis. 1983;147(2):

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

46 Maternal HBV Status and Outcome of HBV Infection in Infants Chang MH. Semin Fetal Neonatal Med. 2007;12(3): ; Stevens CE et al. N Engl J Med. 1975;292(15): HBIG, hepatitis B immunoglobulin. MotherInfant HBeAgHBsAgNo VaccinationWith Immunoprophylaxis ++ >90% chronic HBV Vaccine + HBIG: 10%-15% chronic HBV -+ <10% chronic HBV, risk of fulminant hepatitis, risk of acute hepatitis <1% chronic HBV, risk of fulminant hepatitis, reduced risk of acute hepatitis -- Not infected

47 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 10 8 copies/mL, 8 x 10 7 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):

48 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 Wiseman E et al. Med J Aust. 2009;190(9): HBsAg-positive Pregnant Women (N = 313) Mothers With Detectable HBV DNA (n = 213) Infants Tested (N = 138) HBsAg-positive Infants (n = 4) Low HBV DNA (n = 115) High HBV DNA (n = 29) Very High HBV DNA (n = 69) Negative (n = 122) HBeAg (%) Positive (n = 91) HBV DNA (copies/mL) Low: <10 5 High: 10 5 to 10 8 Very High: >10 8

49 HBV DNA Level and Perinatal Transmission of HBV >10 8 Transmission Rate (%) All Infants of HBV DNA- positive Mothers HBeAg-positive Mothers < Maternal HBV DNA (copies/mL) No case of transmission from mothers with HBV DNA <10 8 copies/mL One case of vaccine/HBIG escape mutation identified; however, the infant was not given HBIG Wiseman E et al. Med J Aust. 2009;190(9):

50 HBV Treatment During Pregnancy Study Design 8 HBeAg-positive pregnant women with HBV DNA ≥1.2x10 9 copies/mL 150 mg lamivudine after 34 weeks of gestation 25 historical controls, born to untreated women with HBsAg and HBV DNA ≥1.2x10 9 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 <1.2x10 8 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):

51 Third-trimester Use of Lamivudine in Women With High HBV Viral Load Primary end point: HBsAg positive infant at 12 months Secondary end point: HBsAb positive, HBV DNA positive Xu WM et al. J Viral Hepat. 2009;16(2): µ All Infants Received HBV Vaccine (10 μg/0.5 mL) HBlG (200 IU, single dose) HBsAg-positive Pregnant Women HBV DNA >10 9 copies/mL (n = 115) Lamivudine (100 mg/day) from 32 ± 2 Weeks of Gestation to 4 Weeks Postpartum (n = 56) Placebo (n = 59)

52 Third-trimester Use of Lamivudine Reduces Risk of Perinatal Transmission a P = 0.014; b P = 0.003; c P = vs control. Patients (%) Infant Outcomes at Week 52 Xu WM et al. J Viral Hepat. 2009;16(2):

53 Treatment Options for Chronic HBV MedicationFDA Pregnancy Category Interferon alpha 2bC Pegylated interferon 2aC AdefovirC EntecavirC LamivudineC TelbivudineB TenofovirB FDA, Food and Drug Administration.

54 Use of Lamuvidine or Tenofovir During Pregnancy: The Antiretroviral Pregnancy Registry Study The Antiretroviral Pregnancy Registry. Interim Report. Accessed September 26, CI, confidence interval. First Trimester Second/Third Trimester Any Antiretroviral Drug Birth-defect rate % (95% CI) Exposures (n) 2.8 ( ) ( ) 6100 Lamivudine Birth-defect rate % (95% CI) Exposures (n) 2.9 ( ) ( ) 5017 Tenofovir DF Birth-defect rate % (95% CI) Exposures (n) 2.4 ( ) ( ) 461

55 Suggested Management of HBV Infection During Pregnancy First Trimester Check HBsAg, Anti-HBc, Anti-HBs HBsAg Negative, Anti-HBs Negative Initiate Maternal HBV Vaccination Series in High-Risk Individuals Infant Receives Vaccine at Birth HBsAg Positive Confirm HBsAg Positivity, Check Quantitative HBV DNA at Baseline and at Week 28 Tran TT. Cleve Clin J Med. 2009;76(suppl 3):S25-S29.

56 Suggested Management of HBV Infection During Pregnancy (continued) HBsAg Positive Yes Refer for Consideration for Treatment With Lamivudine, Tenofovir DF, or Telbivudine at Week 32 HBV DNA >10 8 copies/mL HBV DNA <10 8 copies/mL a Infant Receives HBIG + HBV Vaccine at Birth a May consider treatment if previous child HBV positive Tran TT. Cleve Clin J Med. 2009;76(suppl 3):S25-S29.

57 Case 3: Treating Patients Who Have Hepatitis B and Lymphoma Mark S. Sulkowski, MD Associate Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, MD

58 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

59 NIH Consensus Conference: 2008 Observational studies indicate that patients with HBV who receive immunosuppressive therapy or cancer chemotherapy are at high risk for developing exacerbation of hepatitis, including those who have chronic HBV and those who are in the inactive HBsAg carrier phase. HBsAg, hepatitis B surface antigen; NIH, National Institutes of Health. NIH Consensus Development Conference Statement on Management of Hepatitis B. Accessed September 22, 2010.

60 AASLD Practice Guidelines: 2009 Persons at risk of hepatitis B should be screened for HBsAg and anti-HBc prior to chemotherapy or immunosuppressive therapy. Anti-HBc, hepatitis B core antibody. Lok AS, McMahon BJ. Hepatology. 2009;50(3):

61 ASCO Provisional Clinical Opinion: 2010 Physicians may consider screening patients in high-risk groups for HBsAg, and some patients for anti-HBc Screening or treating HBV should not delay initiation of chemotherapy ASCO, American Society of Clinical Oncology. Artz AS et al. J Clin Oncol. 2010;28(19):

62 HBV Is Associated with an Increased Risk of NHL Korean Cancer Prevention Study  Enrolled , followed until 2006  53,045 (9%) of 603,585 with baseline HBsAg+ NHL  Incidence per 100,000 person-years: 19.4 for HBsAg+ vs 12.3 for HBsAg-  Hazard ratio: 1.74, 95% CI , adjusted for sex, age at baseline, and enrollment year  Risk highest for diffuse large B-cell lymphoma CI, confidence interval; NHL, non-Hodgkin lymphoma. Engels EA et al. Lancet Oncol. 2010;11(9):

63 HBV Is Associated with an Increased Risk of NHL (continued) Engels EA et al. Lancet Oncol. 2010;11(9): NHL HBV Infection No HBV Infection P < Proportion of Participants with Event, per T-cell NHL P = Years of Follow-up Years of Follow-up

64 NIH Consensus Conference: 2008 In patients with chronic HBV and those who are in the inactive HBsAg carrier phase, it is important to start antiviral therapy for hepatitis B before initiating immunosuppressive therapy or cancer chemotherapy Antiviral therapy should be maintained throughout the course of treatment NIH Consensus Development Conference Statement on Management of Hepatitis B. Accessed September 22, 2010.

65 AASLD Practice Guidelines: 2009 Prophylactic antiviral therapy is recommended for HBV carriers at the onset of chemotherapy  If baseline HBV DNA is not detected and treatment duration is 12 months or less, lamivudine or telbivudine can be used  If baseline HBV DNA is detected or treatment duration is longer than 12 months, tenofovir or entecavir is preferred Monitoring is recommended for patients who are anti-HBc+ but not HBsAg+ Lok AS, McMahon BJ. Hepatology. 2009;50(3):

66 ASCO Provisional Clinical Opinion: 2010 “When evidence for chronic HBV is found, antiviral therapy before and throughout the course of chemotherapy may be considered… although evidence from controlled trials of this approach is limited” Screening or treating HBV should not delay initiation of chemotherapy Artz AS et al. J Clin Oncol. 2010;28(19):

67 Prophylactic Lamivudine Reduces HBV Reactivation in HBV Carriers with NHL Prophylaxis a (n = 26) Treatment b (n = 25) P value HBV reactivation HBV reactivation and ALT >10 x ULN 09<0.001 HBV reactivation and bilirubin >1.5 x ULN ALT, alanine aminotransferase; ULN, upper limit of normal. a Patients started lamivudine at the onset of chemotherapy and continued until 2 months after completion. b Patients received chemotherapy alone and started lamivudine only if serum ALT levels >1.5-fold of the ULN. Hsu C et al. Hepatology. 2008;47(3):

68 Systematic Review of Randomized, Controlled Trials of Preventive vs Deferred or No Lamivudine; HBV Flare Study, Year (Reference)Lamivudine Group, n/n Control Group, n/n Relative Risk (95% CI) Randomized, controlled trial a Lau et al., 2003 (8)0/157/ ( ) Jang et al., 2006 (21)1/3611/ ( ) Prospective cohort study with controls a Jia and Lin., 2004 (20)1/87/ ( ) Idilman et al., 2004 (24)0/85/ ( ) Shibolet et al., 2005 (25)0/92/ ( ) Prospective cohort study with historical controls a Yeo et al., 2004 (15)3/6547/ ( ) Yeo et al., 2004 (26)2/3119/ ( ) Yeo et al., 2005 (13) Hsu et al., 2006 (23) 0/16 2/26 6/21 11/ ( ) 0.175( ) Retrospective cohort study b Lim et al., 2002 (17)0/167/ ( ) Leaw et al., 2004 (19)0/1117/ ( ) Nagamatsu et al., 2004 (16)0/83/ ( ) Retrospective cohort study a Lee et al., 2003 (18)1/1117/ ( ) a Preventive vs deferred lamivudine. b Preventive vs no lamivudine. Loomba R et al. Ann Intern Med. 2008;148(7): Favors Preventive Lamivudine Favors Control

69 Favors Preventive Lamivudine Favors Control 100 Systematic Review of Randomized, Controlled Trials of Preventive vs Deferred or No Lamivudine; HBV Death Study, Year (Reference)Lamivudine Group, n/n Control Group, n/n Relative Risk (95% CI) Randomized, controlled trial a Jang et al., 2006 (21)0/361/ ( ) Prospective cohort study with controls a Jia and Lin., 2004 (20)1/85/80.20 ( ) Prospective cohort study with historical controls a Dai et al., 2004 (22)0/111/90.00 ( ) Yeo et al., 2004 (15)0/655/ ( Yeo et al., 2005 (13) Hsu et al., 2006 (23) 0/16 3/26 1/121 0/ ( ) ∞ (0.68- ∞ ) Retrospective cohort study b Lim et al., 2002 (17)0/165/ ( ) Leaw et al., 2004 (19)0/115/ ( ) Nagamatsu et al., 2004 (16)0/83/90.00 ( ) Retrospective cohort study a Lee et al., 2003 (18)0/111/ ( ) a Preventive vs deferred lamivudine. b Preventive vs no lamivudine. Loomba R et al. Ann Intern Med. 2008;148(7): Favors Preventive Lamivudine Favors Control 100

70 Reactivation of HBV with Rituximab Rituximab, a chimeric mouse-human monoclonal antibody against CD20+ lymphocytes  CD20+ NHL; CLL; rheumatoid arthritis  Prolonged decrease in anti-HBs >7 months after last dose CLL, chronic lymphocytic leukemia. Tsutsumi Y et al. Expert Opin Drug Saf. 2005;4(3): Case 1 Case 2 Case 3 Case 4 Case 5 Number of Rituximab Administration Anti-HBs (mIU/mL)

71 HBV Screening Is Uncommon Prior to Starting Rituximab 1429 patients with NHL treated with rituximab at Massachusetts General Hospital from 1997 to 2009  Only 36.6% were screened  Prophylaxis was uncommon ALF, acute liver failure. Mendez-Navarro J et al. Liver Int. August 25, 2010; Epub ahead of print. Rituximab + Lymphoma 1429 Patients Patients Without HBV Serology: 905 Patients with HBV Serology: 524 (36.6%) HBsAg+: 20 (3.8%) 10 Known Prior to Rx 10 Unknown Prior to Rx HBV Reactivation: 10 (1.9%) Anti-HBc+ and HBsAg-: 25 (4.7%) HBV Reactivation: 0 (0%) 1 ALF

72 HBV Reactivation in HBsAg- NHL Patients Treated with Rituximab Anti-HBs, antibodies to hepatitis B surface antigen. Matsue K et al. Cancer. August 25, 2010; Epub ahead of print. Patients with CD20+ B-cell Neoplasma Received Rituximab Containing Treatment 261 Cases HBsAg- 252 Cases Anti-HBc Was Tested 230 Cases (100%) Anti-HBc Cases (75.6%) HBsAg Became + 0 Cases HBsAg Remained - 15 Cases (6.5%) HBsAg Became + 1 Case (0.4%) HBsAg Became + 0 Cases Anti-HBs+ 37 Cases (16.1%) Anti-HBs- 19 Cases (8.3%) HBsAg Became + 4 Cases (1.7%) Anti-HBc and Anti- HBs Were Not Checked 22 Cases Anti-HBc+ 56 Cases (24.3%) HBsAg+ 9 Cases Excluded

73 ALT and TB levels during and after the 6 courses of chemotherapy Fatal HBV Reactivation in a Patient Who Was HBsAg- and Anti-HBc+ MARS, molecular absorbent recirculating system; TB, total bilirubin. Wu JM et al. J Clin Gastroenterol. 43(5): Lamivudine 100 mg daily was initiated beginning on day 190. Entecavir 1 mg daily was added beginning on day 199. The patient expired on day ALT (U/L)TB (mg/dL) Expired MARS TB ALT Day: Cycle of Chemotherapy: HBsAg –Weak + Anti-HBs –Weak + Anti-HBc+ + HBV DNA (cp/mL)>1x x10 7 ETV 1 mg QD LAM 100 mg QD

74 Steven G. Follow-up Patient is admitted to the oncology service and made NPO awaiting an urgent evaluation by the on-call gastroenterologist Oxycodone/acetaminophen is stopped Ultrasound is negative After several days, his lab tests return  HBsAg+ and HBeAg+  HBV DNA detected at 2.65 million IU/mL  HCV EIA and RNA negative EIA, enzyme immunoassays; HBeAg; hepatitis B e antigen; NPO, nothing by mouth.

75 AASLD Guidelines Patients failing lamivudine after 6 months likely have the selection of resistant variants Entecavir has decreased activity against lamivudine-resistant variants with significantly more viral breakthrough than is observed in treatment-naïve patients Tenofovir has similar activity against wild-type and lamivudine-resistant viruses  Recommended as switch or add-on with lamivudine failure Lok AS, McMahon BJ. Hepatology. 2009;50(3):

76 Steven G. Follow-up: Managing Hepatitis B After Chemotherapy The patient now has chronic HBV infection independent of his prior course Rituximab depletes CD20+ lymphocytes after a prolonged period of time AASLD Guidelines recommend continuing tenofovir treatment until after HBeAg seroconversion and consolidation period

77 Risk-benefit Approach to HBV Management in Patients with Cancer Assessment for HBV risk may miss cases  HBsAg and anti-HBc testing is inexpensive Effectiveness of HBV prophylaxis has been consistently demonstrated  Morbidity, mortality, and disruption of chemotherapy In systematic review, no toxicity was observed with HBV prophylaxis For many patients, the benefits of screening prior to therapy and prophylaxis are greater than the risks

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