1. SAMANTHA ALLEN PHARMACY STUDENT PHARMD CANDIDATE 2012 SEPTEMBER 27, 2011 Hepatitis B Vaccination in Cirrhotic Liver Transplant Candidates

2. Objectives List risk factors for acquiring Hepatitis B Identify current Hepatitis B vaccination recommendations for adults List current evidence available for accelerated Hepatitis B vaccination in liver transplant candidates Apply evidence to determine the appropriate Hepatitis B vaccination timeline and dosage based on patient characteristics

3. Overview of Hepatitis B Vaccination Images Courtesy of Merck & Co Inc. and GSK

4. Risk Factors for Hepatitis B 1 Behavioral:  Sexual activity multiple  Persons with STDs  Current or recent IVDU  Men who have sex with men Occupational:  Health-care personnel  Public-safety workers Medical:  Persons with ESRD  Persons with HIV infection  Persons with chronic liver disease Other:  Household contacts and sex partners of persons with chronic HBV infection  Clients and staff of institutions for persons with developmental disabilities  International travelers to countries with high or intermediate prevalence of chronic HBV infection

5. Only if an additional risk factor is present (medical, lifestyle, occupational, other) : For all persons who are >18 years of age and who lack evidence of immunity: HIV Infection Chronic Liver Disease Chronic Kidney Disease Hemodialysis Patients Healthcare Personnel Pregnant Women Immunocompromised Patients (except HIV) Diabetes Heart Disease Chronic Lung Disease Chronic Alcoholism Asplenia General Hepatitis B Vaccination Recommendations by CDC-ADULTS 2

6. Who Should NOT Receive Hepatitis B Vaccine 1 Contraindication: Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component Hypersensitivity to yeast Precaution: Moderate or severe acute illness with or without fever

7. Recommended Dosing Schedule 1,4,5 TraditionalAlternative 1Alternative 2Dialysis4 Dose 0 months 1 month 2 month1 month 6 months4 months 6 months2 months 6 months Recombivax HB ® (10mcg/mL) Recombivax HB ® (40mcg/mL) Energix-B ® (20 mcg/mL) Hepatitis B Vaccine ADULTS: *Note: CDC does NOT recommend restarting interrupted vaccine series but rather picking up where series was left off as soon as possible for healthy adults.

8. Determining Immunity Status 1

9. Hepatitis B Vaccine Response Rate 1 Healthy Adults ≤40 y/o:  30-55% after 1 st dose  75% after 2 nd dose  >90% after 3 rd dose Adults >40 y/o:  <90% after 3 doses Adults >60 y/o:  75% after 3 doses Response may also be affected by:  Smoking  Obesity and Genetics  Immune suppression

10. The Liver Transplant Candidate

11. Criteria for Consideration for Transplant 3 Advanced liver disease with no alternative treatment options ≥ 6 months abstinence alcohol or illicit drugs with low risk of relapse Full understanding of the transplant process No active infections No active cancers (except some liver cancers) Ability to demonstrate compliance to medical care No other medical issues (heart, lung, weight) that will interfere with the surgery, recovery, or long-term health Support System

12. Currently, the CDC recommends that ALL patients > 18 y/o with Chronic Liver Disease who lack evidence of immunity receive the Hepatitis B vaccine. 2

13. INCREASING THE NUMBER OF ORGANS A PATIENT IS ELIGIBLE TO RECEIVE FOR TRANSPLANT Evidence for Accelerated Dosing of Hepatitis B Vaccine

14. One Option for Accelerated Dosing 6,7 Double-dose recombinant vaccine Energix-B ® -40mcg 4 dose series Administration: 0, 2 weeks, 4 weeks, and 6 months Goal: Prevent HBV infection following transplant & ↑ number of organs that can be accepted for transplant in an individual patient MUST confirm antibody titers prior to utilizing a HepB core antibody-positive donor organ

15. CDC Recommendations-Accelerated Dosing 1,7,8 Accelerated dosing at 0, 2 weeks, 4 weeks, and 6 months is NOT FDA approved and is NOT recommended by CDC CDC and IDSA both recommend 4 dose series (double-dose=40 mcg) at 0,1,2 and 6 months as soon as possible in advanced liver disease patients due to ↓ response seen in ESLD patients  Not currently FDA approved in ESLD Assess antibodies 1-3 months after completion series

16. DOUBLE DOSE ACCELERATED HEPATITIS B VACCINE IN PATIENTS WITH ESLD 6 Arslan M, Weisner RH, Sievers et al Liver Transplantation Vol 7 April 2001.

17. DOUBLE DOSE ACCELERATED HEPATITIS B VACCINE IN PATIENTS WITH ESLD 6 Objective: Assess efficacy of HBV vaccination using an accelerated schedule and double dose of recombinant vaccine in OLT candidates Subjects: 356 OLT candidates without serological evidence for immunity to HBV or without evidence active HBV infection Exclusion Criteria:  Serological evidence previous HBV infection  Previous vaccination against HBV  Fulminant liver failure  Declined to be vaccinated

18. Treatment:  4 injections Energix-B ® 40 mcg (20mcg into deltoid muscle each arm)  0, 2 weeks, 4 weeks, and 6 months Follow-Up Anti-HBs Detection & Quantification:  24 hours prior OLT  1 year after OLT  2 years after OLT Primary Endpoint:  Efficacy HBV vaccination with accelerated double-dose schedule Secondary Endpoint:  Identify factors associated with seroconversion and persistence of antibody to Hepatitis B DOUBLE DOSE ACCELERATED HEPATITIS B VACCINE IN PATIENTS WITH ESLD 6

19. RESULTS-Primary Endpoint 6 36% patients anti-HBs prior to OLT 11.6% patients anti-HBs at 1 year post OLT 8% patients anti-HBs at 2 years post OLT 44% (series completed) vs. 32% (series not completed) of patients seroconverted prior to OLT Detectable titers not maintained at 1 and 2 years post transplant Some patients do maintain immunity without detectable titers (<10 mIU/mL)

20. RESULTS-Secondary Endpoints 6 Seroconversion pre-OLT  Completion series prior OLT  Younger age  HLA-A2, HLD-DR1, HLA-DQW5 Presence anti-HBs 1 year after OLT  Lower Child-Pugh Score before OLT  Absence ascites before OLT  HCV infection  HLA-A other than A1 or HLA-DR1 Presence anti-HBs 2 years after OLT  Lower Child-Pugh Score before OLT  Absence ascites before OLT  HCV infection  HLA-A other than A1 or HLA-A2

21. Conclusions 6 Response to Hepatitis B vaccine is poor among patients with ESLD and post OLT New vaccine needed with improved immunogenicity for ESLD patients Certain patient characteristics increase likelihood of seroconversion and maintenance anti-HBs Patients may have maintained immune memory cells to HBV even if anti-HBs are no longer detectable

22. CRITIQUE 6 Trial was not blinded or randomized Seroconversion assessed day prior to OLT regardless of day of vaccine initiation Power calculation was not performed Double-dose (20 mcg x 2 injections) Energix-B ® only assessed instead of 40 mcg x 1 injection dialysis formulation of Recombivax HB ®

23. GG 62 Y/O MALE ESLD LIVER TRANSPLANT CANDIDATE NO EVIDENCE IMMUNITY TO HEPATITIS B NO EVIDENCE PREVIOUS OR CURRENT INFECTION TO HEPATITIS B OLT EXPECTED IN NEXT 30 DAYS Patient Case

24. Determining Immunity Status 1

25. GG’s Dosing Schedule 4 dose series Double-Dose (40 mcg) 0,1,2, and 6 months Rationale against accelerated dosing (0, 2 weeks, 4 weeks, 6 months):  Expected OLT in next 30 days  Older gentleman  Advanced disease  Unlikely to seroconvert prior to OLT

26. Summary of Recommendations 1,7 Current evidence suggests decreased response to Hepatitis B vaccine in ESLD Vaccination against HBV should ideally be initiated at diagnosis of advanced liver disease May revaccinate with an additional 3 or 4 dose series if seroconversion is not achieved with initial series Several factors may increase responsiveness including:  Younger age  Genetic predisposition  Lesser degree of underlying liver disease

27. Use of Accelerated Dosing 1,7 0, 2 weeks, 4 weeks, and 6 months OLT candidates expecting transplant prior to completion of traditional 4-double dose injection series ( 1 month) Increased likelihood of seroconversion if series completed prior to transplant Greater likelihood seroconversion is anticipated if patient is younger and has less advanced liver disease Increased likelihood of maintaining immunity if higher protective titers are observed before OLT

28. References 1. CDC. A comprehensive immunization strategy to eliminate transmission of Hepatitis B virus infection in the United States. MMWR. 2006;55(RR- 16). 2. CDC. Recommended adult immunization schedule-United States, 2011. MMWR. 2011;60(4). 3. United States Department of Veteran Affairs. Listing process-Liver transplant. http://www.hepatitis.va.gov/patient/complications/transplant-listing- process.asp. (accessed 20 September 2011). 4. Recombivax HB package insert. Whitehouse Station, NJ: Merck & Co. Inc.; 2011 Jul. 5. Energix-B package insert. Research Triangle Park, NC: GSK;2010 Jan. 6. Arslan M, Wiesner RH, Sievers C et al. Double-dose accelerated Hepatitis B vaccine in patients with end-stage liver disease. Liver Transpl. 2001;7(4):314-320. 7. Chow J, Golan Y. Vaccination of solid-organ transplant candidates. CID. 2009;49:1550-1556.