Public Health Reports Webinar on New PHS Organ Transplantation Guideline

1. Public Health Reports Webinar on New PHS Organ Transplantation Guideline June 25th, 2013 1:00 PM - 2:00 PM EDT

2. Public Health Reports Webinar on New PHS Organ Transplantation Guideline Mary Beth Bigley, Dr.P.H., M.S.N., A.N.P. Acting Editor, Public Health Reports Office of the Surgeon General Office - 202 205-5642 Cell - 703 969-3300

3. Public Health Reports PHS Guideline for Reducing HIV, HBV, and HCV Transmission through Organ Transplantation - Overview - Ronald O. Valdiserri, MD, MPH Deputy Assistant Secretary for Health, Infectious Diseases Office of HIV/AIDS and Infectious Disease Policy Office of the Assistant Secretary for Health

4. Prior PHS Transplant Safety Guidelines 1985 1991 1994 Testing Donors of Organs, Tissues, and Semen for Antibody to Human T-lymphotropicVirus Type III/ Lymphadenopathy-associated Virus. MMWR;34(20):294 Public Health Service Inter-Agency Guidelines for Screening Donors of Blood, Plasma, Organs, Tissues and Semen for Evidence of Hepatitis B and Hepatitis C. MMWR; 40(RR-4): 1-17 Guidelines for Preventing Transmission of Human Immunodeficiency Virus through Transplantation of Human Tissue and Organs. MMWR; 43(RR-8): 1-17

5. Balancing Organ Safety and Availability • The number of people waiting for a transplant exceeds the number of organs available • Approx. 118,000 transplant candidates on the U.S. wait list • Approx. 28,500 transplants each year (living and deceased donors) • Approx. 6,500 deaths on wait list each year • Transmission of HIV, HBV or HCV through transplanted organs • Can cause serious illness and death in recipients • Can occur despite risk assessment and laboratory testing • But early diagnosis and treatment can improve recipient outcomes

6. Objective of New PHS Guideline • Formulate recommendations based on a systematic review of the best available evidence • Improve organ transplant recipient outcomes by reducing the risk of unexpected HIV, HBV, and HCV transmission • Allow for informed decision-making process for transplant teams and their patients • Guideline is not regulatory, but contains recommendations from PHS

7. Developing the PHS Guideline (1) • Literature review to identify most relevant studies and reports on which to base PHS guideline recommendations • U.S. Public Health Service entities actively involved in guideline development • Centers for Disease Control and Prevention • Food and Drug Administration • Health Resources and Services Administration • National Institutes for Health • Office of the Assistant Secretary for Health

8. Developing the PHS Guideline (2) • Multidisciplinary group, representing organ recovery, transplantation, public health, patients, laboratory testing, and consent issues served as technical advisors for expert input • Approximately 100written comments were received in response to a draft guideline posted in September 2011 • U.S. PHS considered all written comments and input from the technical advisory group before reaching final decision about guideline content • HHS Secretary approved guideline on March 8, 2013

9. Accessing the Guideline and Evidence Report • PHS Guideline for Reducing HIV, HBV, and HCV Transmission through Organ Transplantation • Published in the July/August issue of Public Health Reports • Includes commentaries by Howard Koh, MD, MPH, HHS Assistant Secretary for Health and Kenneth Moritsugu, MD, MPH, former HHS Acting Surgeon General • Open-access copy now on-line by the Association of Schools of Public Health at http://publichealthreports.org/issuecontents.cfm?Volume=128&Issue=4 • Solid Organ Transplantation and the Probability of Transmitting HIV, HBV, or HCV: A Systematic Review to Support an Evidence-Based Guideline • Comprises the primary evidence underlying the recommendations in the PHS guideline • Open-access copy now on-line at http://stacks.cdc.gov/view/cdc/12164/

10. Public Health Reports PHS Guideline for Reducing HIV, HBV and HCV Transmission through Organ Transplantation Recommendations and Evidence-based Process Matthew J. Kuehnert, M.D. Director, Office of Blood, Organ and Other Tissue Safety Division of Healthcare Quality Promotion National Center for Zoonotic and Emerging Infectious Diseases Centers for Disease Control and Prevention

11. Public Health Service GuidelineNeed and Intent of Development • 1994 PHS Guidelines for Preventing Transmission of Human Immunodeficiency Virus Through Transplantation of Human Tissue and Organs has been a transplant policy reference • 1994 PHS guideline revision needed • Update risk factors in donor and recipient evaluation • Integrate technological advances for better laboratory screening • Optimize decisions for risk assessment, and not exclude organs • Intent of revised PHS guideline • Reduce risk of infectious transmission, while preserving availability of high quality organs • Provide best available information for transplant teams and their patients to make informed decisions • Change terminology, e.g., from “CDC high risk” to “PHS increased risk”

12. What are the Important Differences Between the1994 and 2013 PHS Guideline? • 1994: PHS Guidelines for Preventing Transmission of Human Immunodeficiency Virus through Transplantation of Human Tissue and Organs • Organs and tissues; banked breast milk and semen • Transmission of HIV only • Developed via ad hoc expert input • 2013: PHS Guideline for Reducing HIV, HBV and HCV Transmission through Organ Transplantation • Organs and blood vessel conduits used for transplantation • Transmission of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) • Developed via evidence-based process and expert input

13. Evidence-based Process for Revision • On behalf of PHS, CDC led development of draft • HHS agencies and external experts from transplant community provided input • Recommendations based on systematic review of the best available evidence • Evidence review conducted by: • Center for Evidence-based Practice at University of Pennsylvania • ECRI Institute/Evidence-based Practice Center

14. PHS Guideline Development Methodology:Five Phases in a Five Year Process 2008 Phase 1:Organize Technical Advisors for Guideline Development Phase 2: Preliminary Literature Search in Support of Questions for Systematic Review Phase 3:Development of Questions for Systematic Review and Analytic Framework Phase 4:Production of Evidence Report 2013 Phase 5:Guideline Development

15. Technical Advisors for Guideline Development • Expert Panel • Experts in informed consent, hepatitis and HIV content, and laboratory medicine; • Individuals with expertise in organ recovery, transplantation, and infectious disease issues • Review Committee • Representatives from organ recovery, transplantation, and public health professional organizations • Council of State and Territorial Epidemiologists • Association of Organ Procurement Organizations • American Society for Transplantation • American Society of Transplant Surgeons • United Network for Organ Sharing • NATCO (Organization for Transplant Professionals) • laboratory test manufacturers • patient advocate • ad hoc members • PHS representatives from CDC, FDA, HHS/OPHS, HRSA, and NIH

16. Preliminary Literature Search to Support Questions for Systematic Review • Review of 1994 PHS guideline as basis for revision • Literature search with the following assumptions • Focus on solid organ transplantation • Focus on HIV, HBV, and HCV transmission • Retain current guideline structure, focusing on behavior/medical history interview, clinical data, and laboratory testing for risk assessment • Recognize the potential risks of new recommendations, as well as potential benefits

17. 5 Key Topics for PHS Guideline Development Process Resulting in 10 Key Questions Risk of disease transmission through solid organ transplantation Potential risks and benefits of transplantation of solid organs from infected donors Methods to mitigate the potential risks of transplantation of solid organs from infected donors Potential risks and benefits of interventions to mitigate transmission of transmissible diseases Approaches as to how recipients can be informed about the risk of disease transmission and be evaluated for possible exposure post-transplantation

18. Analytical Framework Depicting the Relationship Between Donor Characteristics, Organ Availability, Patient Interventions, and Subsequent Outcomes Key Question 1: What are the prevalence and incidence rates of HIV, HBV, and HCV among potential organ donors?

19. Analytical Framework Depicting the Relationship Between Donor Characteristics, Organ Availability, Patient Interventions, and Subsequent Outcomes Key Question 2: What are the rates of transmission to recipients from donors infected with HIV, HBV, or HCV? Do the rates vary by the organ transplanted or when the donor was infected?

20. Analytical Framework Depicting the Relationship Between Donor Characteristics, Organ Availability, Patient Interventions, and Subsequent Outcomes Key Question 3: What behavioral risk factors are associated with an increased probability of infection with HIV, HBV, or HCV? What is the prevalence of these characteristics among potential organ donors?

21. Study Selection Process to Identify Articles Meeting Inclusion Criteria for the 10 Key Questions

23. Categories of PHS Guideline Recommendations • Summary of Recommendations • Risk Factors for Recent HIV, HBV or HCV Infection • Risk Assessment (Screening) of Living and Deceased Donors • Testing of Living and Deceased Donors • Informed Consent Discussion with Transplant Candidates • Testing of Recipients Pre- and Post-transplant • Collection and/or Storage of Donor and Recipient Specimens • Tracking and Reporting of HIV, HBV and HCV • Recommendations for Further Study

24. Process for Revision of PHS Guideline • HHS offices and agencies, including CDC, HHS/OPHS, HRSA, FDA, and NIH, reviewed and approved the draft PHS Guideline • Federal Register Notice • Draft guideline accessed at www.regulations.gov • 90-day public comment period - ended 12/23/11 • Approximately 100 comments were received and reviewed • PHS Guideline Revision Work Group convened to review and discuss changes to recommendations • Agreed on changes to the guideline • Expert Panel and Review Committee • Provided further input

25. What is the need for these recommendations? • High profile transmission of HIV and HCV from a donor to 4 recipients, 2007 • From 2008 through 2011, there were more than 200 investigations of suspected disease transmission • 104 recipients were confirmed (i.e., proven or probable) to have recognized and unexpected donor-derived infectious disease transmission, including HIV, HBV, and HCV • HCV in 10 recipients involving 6 donors • HBV in 4 recipients involved 2 donors • HIV in 1 recipient (transmission from a living donor)

28. Reduction in Undetected HCV Viremia from Use of Nucleic Acid Testing in Addition to Serology Alone Ellingson K et al, AJT, 2011

29. Other Issues Raised During Guideline Development • Revised risk factors identified for HIV, HBV or HCV infection may result in more donors defined as at increased risk, raising fears of reduced acceptance of organs • New recommendations for nucleic acid testing (NAT) may result in more false positive tests, raising fears of decreased organ availability • New recommendations for pre- and post-transplant testing of transplant recipients may increase costs • for all recipients with organs transplanted from donors with identified risk factors, risk factors unknown, or known to be infected with HCV or HBV • New recommendation to limit blood vessel conduits from HBV/HCV infected donors only for use at transplant, raising the argument that they may be needed later for recipients

30. Major Changes to the PHS Guideline in Response to Public Comment and External Input Number of recommendations decreased from 54 to 34 Sections on HBV- and HCV-infected Donors and Transplantation were deleted Donor testing for HIV changed from NAT for all donors to NAT or Ag/Ab for increased risk donors Donor testing for HBV changed from NAT for increased risk donors to no recommendation Living Donor testing changed from within 7 to within 28 days of organ recovery Recipient testing (based on increased donor risk) reduced and changed to broader timeframes after transplant

31. Overview of PHS Guideline Policy after Public Comment and External Input • 12 criteria for donor risk factor assessment • 11 criteria apply in aggregate for HIV, HBV, and HCV • One criterion specific for HCV • 34 recommendations* • 6 recommendations with 2 subparts each • 20 recommendations for further study • Systematic evidence review • Expert review • Public comment *Guideline contains recommendations, which are not regulatory or required by policy

32. Examples of PHS Guideline recommendations – Donor Risk Assessment • 12 criteria • 11 for aggregate risk for HIV/HBV/HCV, and one for HCV only • 6 for sexual history, 6 for nonsexual history • Sexual history in last 12 months • Men who have had sex with another man (MSM) • Women who have had sex with MSM • Anyone with history of sex in exchange for money or drugs • Anyone with history of sex with a person with history of sex in exchange for money or drugs • Anyone with history of sex with a person who injected drugs (i.e., IV, IM, SQ routes) for nonmedical reasons • Anyone with history of sex with a person known or suspected to have HIV/HBV/HCV

33. Examples of HS Guideline Recommendations – Donor Risk Assessment • Other history in last 12 months • Anyone who has injected drugs (i.e., IV, IM, SQ routes) for nonmedical reasons • Anyone who has been in lockup, jail, prison, or a juvenile correctional facility for more than 72 consecutive hours • Anyone newly diagnosed with, or treated for, syphilis, gonorrhea, Chlamydia, or genital ulcers • Any child who has been breastfed from mother known to be infected with, or is at risk for, HIV • Other history • Any child < 18 months of age and born to a mother known to be infected with, or is at risk for, HIV • To assess risk of HCV only, anyone who has been on hemodialysis in the preceding 12 months

34. Examples of HS Guideline Recommendations – Donor Screening • Donor should be considered increased risk if known to be infected, behavioral history risk factors present or unknown, or if specimen hemodiluted • Nucleic Acid Testing (NAT) for donor screening • HIV: If no risk factor identified, serology only If risk factor identified, serology + (NAT or antigen assay*) • HBV: anti-HBc, HBsAg, but no NAT regardless of risk factor • HCV: anti-HCV + NAT regardless of risk factor • Living donors should be tested as close as possible to the date of the donor operation, but at least within 28 days prior to surgery *Includes 4th generation HIV antigen/antibody assay

35. Examples of HS Guideline Recommendations – Recipient Testing • If donor is “increased risk”, transplant candidate testing should occur just before transplant (during hospital admission) • Nucleic acid testing (NAT) for recipient • HIV: NAT or Ag/Ab combo assay between 1 and 3 months • HBV: NAT and HBsAg between 1 and 3 months Anti-HBs, anti-HBc, and either NAT or HBsAg at 12 months • HCV: NAT between 1 and 3 months

36. Examples of PHS Guideline Recommendations for Further Study • Estimate the incidence and prevalence of HIV, HBV, and HCV among deceased potential organ donors. • Develop (and implement) a validated uniform donor infection risk assessment questionnaire, including the number of sexual partners and intranasal use of an illicit drug in the preceding 12 months. • Evaluate the risk-benefit of transplanting organs from HIV-infected donors into HIV-infected transplant candidates, given the need… • Study the effectiveness of systems for traceability, including bar coding, to ensure blood vessel conduits are transplanted into the intended recipients… • Evaluate outcomes for recipients of organs from HBV and HCV infected donors.

37. Release of PHS Guideline • Guideline published in Public Health Reports in July/August 2013 issue; posted online June 19 • http://www.publichealthreports.org/issuecontents.cfm?Volume=128&Issue=4 • www.publichealthreports.org • Evidence Report is published in CDC STACKS • http://stacks.cdc.gov/view/cdc/12164/ • Notices/summaries will be submitted for publication in peer reviewed journals and MMWR

38. Summary The 2013 PHS Guideline is now published in Public Health Reports, with new recommendations on donor screening, recipient testing, informed consent, and disease reporting for US organ procurement organizations and transplant centers The Guideline provides a set of evidence-based recommendations, but are not regulatory and not to be construed as policy Recommendations for further study summarize major gaps in the knowledge base that will be important in order to improve recommendations in the future

39. Public Health ReportsMeet the Author! Live Webcast Recommendations for Further StudyJay A. Fishman, M.D. Director, Transplant Infectious Disease and Compromised Host Program, Massachusetts General Hospital Professor of Medicine, Harvard Medical School Boston, MA, USA

40. Background: The Systematic Review There are few studies that directly address the issue of transmission of infection with solid organ transplantation Data were intentionally limited to HIV, HCV, and HBV, but there are many other issues surrounding disease transmission in solid organ transplantation Testing is limited by the specific assays (targets) performed and the performance characteristics of those assays in the specific laboratory under consideration. The risk of “donor infection” (screening) is not the same as the risk of “transmission to the recipient” (infection) or the development of disease in the recipient – these require separate, but related, studies. There can never be absolute certainty about the degree of risk.

41. Potential Gaps in New Guidelines There are few data that define the characteristics of donors who will provide increased risk of HIV, HBV or HCV transmission. Incidence and prevalence in donor population Few data on actual transmission of HIV, HBV and HCV from infected donors following organ donation. Need more detail/data to validate individual risk factors (microbiological and behavioral) that increase risk for transmission – e.g., viral load? viral strains? Sexual contacts? How useful are behavioral criteria for exclusion? vs. non-transplantation? Need data on the potential recipients’ perception and tolerance of risk

42. Addressing Knowledge Gaps Easier to design studies for biological questions than for psychosocial issues. Both are important. Potential study populations (organ donors and recipients) need to be engaged in multicenter studies Goal should be dissemination of data via peer reviewed publications. May require the development of new technologies (e.g., for assays or for communication of data). Can draw on experience of CTOT (NIH- Clinical trials in Organ Transplantation) for harmonization of assays in transplantation across multiple sites.

43. Potential Gaps in New Guidelines: Assays Assays for HIV, HBV and HCV: Availability of FDA-approved, licensed or cleared screening assays vs. “home brew” Availability at live donor transplant centers and/or regional laboratories Optimal timing of assays compared with donation event Use of screening vs. diagnostic assays, qualitative vs. quantitative assays Performance in living vs. deceased donors Assay-specific studies: Prospectively evaluate the performance characteristics (sensitivity and specificity) of various assays (platforms) NAT vs. serologic testing (discordant data) For screening (donors) and diagnosis (recipients) Impact of storage of specimens for specific assays (e.g., -70), extraction for NAT, shipping, archiving costs Impact of donor characteristics (brain death, transfusion, colloid resuscitation, timing) relative to procurement. Rate of False + assays (and false negative) and impact on organ supply Confirmatory testing: Standardized algorithms for real time discrimination of true and false-positive assays (re-testing). Optimal laboratory proficiency testing; Minimum number of assays performed?

44. Potential Gaps in PHS Guidelines: Live Donors, Consent Screening of Live vs. Deceased donors Yield of testing for live donors: True positive vs. false positive assays Costs of various screening paradigms Impact of false positive assays on potential donor (psychological) and on organ pool availability Optimal approach to informed consent for testing of live donors Optimal approach to providing screening data to living donors Consent process: Which data are useful to potential recipients and their physicians? How to best quantify risk and convey information regarding transmission risk to potential recipients? How is this best measured? How much information does the recipient want? How to factor in individual values of the patients? How much responsibility does the physician carry vs. the recipient? Does the patient want this responsibility? Does this affect the utilization of organs? Develop and validate uniform donor infection risk questionnaire and mechanism to translate such data in usable information for physicians and patients regarding “informed consent”

45. Potential Gaps in New Guidelines: Changing Epidemiology Epidemiology of transmission: Changing epidemiology of HIV, HCV, HBV Ability to detect infection if/when it occurs? Asymptomatic carriers HCV+ “Baby boomers” Efficacy of protection with HBV vaccination Changing patterns of disease and risk with antiviral agents Consideration (future) of use of HIV+ donors for HIV+ recipients – need for study in vivo Potential value of large, prospective study of transplant donors and recipients (with stored sera) to assess actual rate if transmission and impact of disease vs. failure to transplant. Efficacy and cost of prevention strategies (donor treatment, recipient treatments) for infected donors using anti-viral agents (HIV, HBV, HCV). Outcomes with use of infected donor organs vs. non-transplantation or delayed transplantation.

46. Potential Gaps in New Guidelines Validation of models to predict risk based on patient and donor characteristics Compare with risk of non-transplantation (waiting) Optimal systems for tracking and sharing of screening data and reporting of transmission events “Syndromes” in recipients Future Directions: Use of donors with “unknown meningoencephalitis” or “sepsis” (treated or untreated) Use of donors from “endemic regions” Impact of donor “cultures” Role of immunosuppression on transmission Studies of mitigation of risk Is disease preventable or treatable?

47. Questions?

48. Closing For more information about the PHR, visit at: www.publichealthreports.org