Public Health Reports
Webinar on
New PHS Organ Transplantation Guideline
June 25th, 2013
1:00 PM - 2:00 PM EDT
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
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
Prior PHS Transplant Safety Guidelines
1985
Testing Donors of Organs, Tissues, and Semen for
Antibody to Human T-lymphotropic Virus Type III/
Lymphadenopathy-associated Virus. MMWR;34(20):294
1991
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
1994
Guidelines for Preventing Transmission of Human
Immunodeficiency Virus through Transplantation of
Human Tissue and Organs. MMWR; 43(RR-8): 1-17
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
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
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
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 100 written 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
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/
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
Public Health Service Guideline
Need 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”
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
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
PHS Guideline Development Methodology:
Five Phases in a Five Year Process
Phase 1: Organize Technical Advisors for
Guideline Development
2008
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
Phase 5: Guideline Development
2013
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
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
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
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?
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?
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?
Study Selection Process to Identify Articles Meeting
Inclusion Criteria for the 10 Key Questions
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
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
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)
Reduction in Undetected HCV Viremia from Use of
Nucleic Acid Testing in Addition to Serology Alone
“Normal Risk”
Potential
Donor
“High Risk”
Potential
Donor
Ellingson K et al, AJT, 2011
p(Viremia in
WP) per
100,000 py
One in How
Many?
Anti-HCV
20
5,000
HCV-NAT
2
50,000
Anti-HCV
105
1,000
HCV-NAT
10
10,000
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
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
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
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
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
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
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
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.
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
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
Public Health Reports
Meet the Author! Live Webcast
Recommendations for Further Study
Jay A. Fishman, M.D.
Director, Transplant Infectious Disease and Compromised Host Program,
Massachusetts General Hospital
Professor of Medicine, Harvard Medical School
Boston, MA, USA
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.
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. nontransplantation?
– Need data on the potential recipients’ perception and
tolerance of risk
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.
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?
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”
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.
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?
Questions?
Closing
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