[Federal Register Volume 80, Number 227 (Wednesday, November 25, 2015)]
[Notices]
[Pages 73785-73796]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-30172]



[[Page 73785]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Final Human Immunodeficiency Virus (HIV) Organ Policy Equity 
(HOPE) Act Safeguards and Research Criteria for Transplantation of 
Organs Infected With HIV

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The U.S. Department of Health and Human Services (HHS), 
through the National Institutes of Health (NIH), announces the 
publication of Final Safeguards and Research Criteria for 
transplantation of HIV-positive donor organs in HIV-positive 
recipients. All such transplants must occur under an institutional 
review board (IRB)-approved research protocol that is compliant with 
federal regulations governing human subjects' research. The goal of 
this research is to increase knowledge about the safety, efficacy, and 
effectiveness of solid organ transplantation (SOT) utilizing HIV-
positive donors in HIV-positive recipients.
    A summary of public comments on the previously published Draft 
Safeguards and Research Criteria and HHS' responses follow, as well as 
the Final Safeguards and Research Criteria.

FOR FURTHER INFORMATION CONTACT: Dr. Jonah Odim, phone 240-627-3540, 
Email: [email protected], Fax: 301-451-5671, 5601 Fishers Lane, Room 
6B21, MSC 9827, Bethesda, MD 20892-9827.

SUPPLEMENTARY INFORMATION: HHS initially published the Draft Human 
Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act Safeguards 
and Research Criteria for Transplantation of Organs Infected with HIV, 
subsequently referred to as the ``Draft Safeguards and Research 
Criteria,'' in the Federal Register on June 18, 2015, for a 60-day 
public comment period ending August 17, 2015. In the months leading up 
to the draft publication, HHS presented the research criteria at 
national meetings of transplantation and HIV medicine professionals and 
received their input. Several teleconferences were hosted with 
transplantation community stakeholders from the private, nonprofit, and 
government sectors.
    HHS received comments from a total of 13 individuals/entities on 
the Draft Safeguards and Research Criteria. Comments were submitted by 
transplant centers, Organ Procurement Organizations (OPOs), the Organ 
Procurement and Transplantation Network (OPTN), United Network of Organ 
Sharing (UNOS), HIV and transplantation professional societies, and a 
municipal agency. Overall, these comments were supportive of the HOPE 
Act and the Draft Safeguards and Research Criteria. Many commenters 
made useful suggestions that provided clarity and were incorporated 
into the Final Safeguards and Research Criteria. While the comments 
will not be addressed individually in this response document, 
questions, comments, and suggestions about specific aspects of the 
Draft Safeguards and Research Criteria are addressed by topic below.

HOPE Act: Scope

    The HOPE Act permits HIV-positive to HIV-positive organ 
transplantation under IRB-approved research protocols conforming to the 
Final Human Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act 
Safeguards and Research Criteria for Transplantation of Organs Infected 
with HIV, which were developed as directed in the HOPE Act. Patients 
receiving HIV-positive kidneys from deceased HIV-positive donors in 
South Africa (Muller, 2015) had survival rates of 84 percent and 74 
percent at 1 and 5 years, respectively; however, there is presently no 
evidence for the safety, efficacy, and effectiveness of HIV-positive to 
HIV-positive transplantation in North America. The Final Safeguards and 
Research Criteria are meant to support the acquisition of new clinical 
knowledge and mechanistic insights about HIV-positive to HIV-positive 
organ transplantation in the United States. The results of this 
research will be evaluated by the Secretary of HHS and the OPTN to 
determine whether and how the OPTN standards for organ transplantation 
shall be revised to address HIV-positive organ donors.
    One commenter raised concerns about the negative impact of adverse 
outcomes at transplant centers conducting research in HIV-positive to 
HIV-positive transplants on transplant program-specific reports. This 
commenter proposed ``that transplants performed with HIV-positive donor 
to HIV-positive recipients are not included in the center specific 
reports. The risk of transplanting these patients is unknown, and there 
is no risk adjustment for it on the center specific reports. There will 
potentially be a strong disincentive for centers to do these patients 
leading to fewer patients receiving life-saving organ transplants.'' 
Clearly this is an important issue but one that is beyond the 
authorities delegated to the NIH to enable implementation of the HOPE 
Act (i.e., to develop safeguards and research criteria).

Living Donors

    Several commenters stated that HIV-infected living donors may be at 
long-term risk for renal and/or liver disease and therefore their 
centers would not use HIV-infected living donors. Another commenter 
felt it was premature to embark on living HIV-positive donors without 
prior experience with deceased HIV-positive donors and recommended a 
staged approach. The Hope Act (2013) does not include any language 
addressing the use of living HIV-infected donors.
    The long-term risks of living organ donation to the donor might be 
greater for those infected with HIV than for those who are not. At the 
same time, the desire to donate an organ, (e.g., to save or prolong a 
life) is strong, and evaluation of the risks and benefits of such a 
decision is personal and unique to a given donor/recipient pair. 
Evidence for the safety of organ donation by an HIV-infected individual 
will only be generated by clinical research. HHS has included living 
donors in these Safeguards and Research Criteria so that, if 
investigators choose to pursue this line of research, that research can 
be conducted with appropriate informed consent, safeguards, and rigor.
    The decision to participate in HIV-positive to HIV-positive 
clinical research is made freely, based on informed consent in the 
absence of coercion. The health care team must provide a rigorous, 
transparent education and informed consent process that describes 
alternatives, risks, potential benefits, unknowns, and the need for 
long-term follow-up. These discussions must address how research-
related injuries are managed and paid for, and must specifically 
include the present uncertainties about the outcomes for both HIV-
positive living donors and the recipients of HIV-positive organs. 
Participation of knowledgeable, independent advocates for both the HIV-
positive recipient and the HIV-positive donor is required by these 
Safeguards and Research Criteria.

Independent Advocates

    Some commenters strongly supported the requirement for independent 
advocates for both HIV-positive recipients and prospective HIV-positive 
living donors. Others viewed this as unnecessary given the expertise of 
the principal investigator and study team and current OPTN standards. 
With

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respect to informed consent, the role of the independent advocate 
complements that of the investigator and does not replace it. The 
investigator is assumed to have the expertise necessary to discuss 
risks, benefits, expectations, and alternatives. The advocate is an 
additional knowledgeable person who is neither a member of the research 
team nor the patient's health care provider, whose role is to provide 
information, answer questions, and provide assurance of equal access to 
health care regardless of the patient's decisions regarding research 
participation. For example, the advocate can assure that the transplant 
candidate is aware that he or she has the right to be offered and to 
accept an HIV-negative deceased donor organ should one become 
available, and can assure the prospective living donor of 
confidentiality and support should he or she determine that donation is 
not in his or her own best interest.

Transplant Hospital Experience

    Several commenters from academic institutions, professional 
societies, and the OPTN indicated that the requirements for physicians' 
and surgeons' prior experience in HIV-negative to HIV-positive organ 
transplant were excessive and would result in few centers being able to 
participate in the research allowed under the HOPE Act. In response to 
the wide consensus on this issue, we have accepted the specific 
suggestion of the American Society of Transplant Surgeons (ASTS). 
Section 3 of the Final Safeguards and Research Criteria describe 
collective team experience, rather than individual experience.

Immunologic Criteria (CD4+ T-Cell Counts, HIV Viral Load)

    Several commenters expressed concerns about the usefulness and 
relevance of requiring a minimum CD4+ T-cell count/percentage in the 
donor. They argued that the CD4+ T lymphocyte count will not predict 
allograft function, and that, among HIV-positive to HIV-positive 
transplants in South Africa, excellent outcomes were observed in 
recipients of kidneys from donors with CD4+ T-cell counts well below 
200. These commenters urged flexibility and the elimination of this 
minimum immunologic criterion. In response to these comments, Section 1 
of the Final Safeguards and Research Criteria was revised to indicate 
that, although collection of CD4+ T cell counts and percentages during 
the donor evaluation is required, no minimum criterion is imposed for 
organ acceptance. Some commenters preferred excluding any donors with 
detectable plasma viral load due to the risk of transmitted drug 
resistance. Unfortunately, it will not be possible in all cases to 
mitigate the risk of transmitting viral resistance by setting viral 
load limits and/or assessing antiretroviral resistance profiles in the 
time available for donor evaluation. It is expected that in many cases, 
potential donors will have adequate medical history available to inform 
the transplantation team's assessment and maximally reduce the risk of 
transmitting resistant virus. For these reasons, the Final Safeguards 
and Research Criteria do not stipulate a limit on the allowable viral 
load in a donor. The transplant team should only transplant the organ 
if the team is confident they can define a post-transplant 
antiretroviral regimen that will be safe, tolerable, and effective. 
Concerns about transmitted drug resistance must be included in the 
recipient informed consent process for the research study. In addition, 
at the time of an organ offer, the recipient informed consent must 
address the transplant team's assessment of risk specific to the 
characteristics of the offered organ.

Biospecimens

    Several commenters emphasized the importance of a pre-transplant 
donor organ biopsy. The final updated research criteria include a 
requirement for performance of a pre-implantation ``back-table'' biopsy 
for post-transplantation patient management and future scientific and 
mechanistic studies. Although there are no further specimen 
requirements, we strongly encourage the inclusion of serial 
biospecimens (e.g., allograft tissue, urine, serum, and cells) in the 
individual research protocols. These specimens will be a valuable 
resource to the community in studies relating to superinfection risks, 
for example. Failure to collect such specimens, particularly in organ 
donors, would be a regrettable lost opportunity.

Required Outcomes

    Several commenters expressed concerns about data collection, 
quality, and reporting. The HOPE Act requires the Secretary of HHS to 
review the results of research conducted under the Act. One purpose of 
the criteria presented in the Final Safeguards and Research Criteria is 
to ensure that all investigators conducting research in HIV-positive to 
HIV-positive transplantation collect similar data elements. This 
standardization will facilitate the subsequent review mandated in the 
HOPE Act.

Conclusion Regarding Comments Received

    HHS appreciates the time and effort taken by commenters to respond 
to the Request for Comments. The comments represented the deliberative 
efforts of truly dedicated individuals and organizations in 
transplantation and HIV medicine. All the responses were helpful in 
revising the draft Human Immunodeficiency Virus (HIV) Organ Policy 
Equity (HOPE) Act Safeguards and Research Criteria for Transplantation 
of Organs Infected with HIV.
    The Final Safeguards and Research Criteria for transplantation of 
HIV-positive (HIV+) donor organs in HIV-positive (HIV+) recipients are 
as follows:

                              Abbreviations
------------------------------------------------------------------------
 
------------------------------------------------------------------------
AIDS..............................  Acquired Immunodeficiency Syndrome.
APOL1.............................  Apolipoprotein 1.
ART...............................  Antiretroviral Therapy.
CD4...............................  Cluster of Differentiation 4.
CMS...............................  Centers for Medicare & Medicaid
                                     Services.
CNS...............................  Central Nervous System.
dL................................  Deciliter.
FDA...............................  U.S. Food and Drug Administration.
FIPSE.............................  Spanish Foundation for AIDS
                                     Research.
GESIDA............................  Spanish AIDS Study Group.
HAART.............................  Highly Active Antiretroviral
                                     Therapy.
HBV...............................  Hepatitis B Virus.
HCT/Ps............................  Human Cells, Tissues, and Cellular
                                     and Tissue-Based Products (HCT/Ps).
HCV...............................  Hepatitis C Virus.

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HIV...............................  Human Immunodeficiency Virus.
HOPE Act..........................  HIV Organ Policy Equity Act.
INR...............................  International Normalized Ratio.
IRB...............................  Institutional Review Board.
mL................................  Milliliter.
NIH...............................  National Institutes of Health.
NNRTI.............................  Non-Nucleoside (or Non-Nucleotide)
                                     Reverse Transcriptase Inhibitor.
NRTI..............................  Nucleoside (or Nucleotide) Reverse
                                     Transcriptase Inhibitor.
OI................................  Opportunistic Infection.
OPO...............................  Organ Procurement Organization.
OPTN..............................  Organ Procurement and
                                     Transplantation Network.
PCR...............................  Polymerase Chain Reaction.
PML...............................  Progressive Multifocal
                                     Leukoencephalopathy.
RNA...............................  Ribonucleic Acid.
SOPs..............................  Standard Operating Procedures.
SOT...............................  Solid Organ Transplantation.
SRTR..............................  Scientific Registry of Transplant
                                     Recipients.
UNOS..............................  United Network for Organ Sharing.
[micro]L..........................  Microliter.
------------------------------------------------------------------------


                               Definitions
------------------------------------------------------------------------
 
------------------------------------------------------------------------
ABO compatible....................  People who have one blood type (A,
                                     B, AB, or O) form proteins
                                     (antibodies) that cause their
                                     immune system to react against
                                     other blood types. This is
                                     important when a patient needs to
                                     receive blood (transfusion) or have
                                     an organ transplant. The blood
                                     types must be matched to avoid an
                                     ABO incompatibility reaction. ABO
                                     compatible is when the blood types
                                     are matched.
Antiretroviral therapy (ART)        When an HIV strain develops drug
 resistance.                         resistance and/or genetic mutations
                                     associated with drug resistance.
Types/classes of HIV/AIDS           (1) Entry inhibitors.
 antiretroviral drugs (current at   (2) Fusion inhibitors.
 publication).                      (3) Nucleoside reverse transcriptase
                                     inhibitors (NRTIs).
                                    (4) Non-nucleoside reverse
                                     transcriptase inhibitors (NNRTIs).
                                    (5) Integrase inhibitors.
                                    (6) Protease inhibitors.
                                    (7) Multi-class combination
                                     products.
HIV strain........................  Distinct genetic variants of the HIV
                                     retrovirus, conferring
                                     characteristics such as
                                     susceptibility or resistance to ART
                                     medications.
HIV-negative......................  Not testing positive for HIV by
                                     serology and/or nucleic acid
                                     testing using FDA-licensed,
                                     approved or cleared test devices.
HIV-positive......................  HIV-infected by serology and/or
                                     nucleic acid testing using FDA-
                                     licensed, approved, or cleared test
                                     devices.
HIV undetectable viral load.......  (The conventional definition at the
                                     time of the publication of this
                                     research criteria document, based
                                     on current clinical technology/
                                     practice): HIV ribonucleic acid
                                     (RNA) below 50 copies with current
                                     technology.
Opportunistic infection...........  Infections that are more frequent or
                                     more severe because of
                                     immunosuppression in HIV-infected
                                     persons (Kaplan, 1995a, 1995b;
                                     Panel on Opportunistic Infections
                                     in HIV-Infected Adults and
                                     Adolescents, 2015).
Suppressed viral load.............  HIV RNA below 50 copies with current
                                     technology at time of publication
                                     of this research criteria document.
Viral detection threshold.........  HIV RNA below 50 copies with current
                                     technology at time of publication
                                     of this research criteria document.
------------------------------------------------------------------------

Executive Summary

    The HOPE Act requires the HHS Secretary (the Secretary) to develop 
and publish criteria for research involving transplantation of human 
immunodeficiency virus-infected donor organs in HIV-positive 
recipients. A summary of the criteria for conducting clinical research 
in HIV-positive to HIV-positive organ transplantation is included in 
the chart below, and the criteria are set forth in six broad categories 
(Donor Eligibility, Recipient Eligibility, Transplant Hospital 
Criteria, Organ Procurement Organization (OPO) Responsibilities, 
Prevention of Inadvertent Transmission of HIV, and Study Design/
Required Outcome Measures). These criteria are in addition to current 
policies and regulations governing organ transplantation and human 
subjects' research. The goals of these criteria are, first, to ensure 
that research using organs from HIV-positive donors is conducted under 
conditions protecting the safety of research participants and the 
general public; and second, to ensure that the results of this research 
provide a basis for evaluating the safety of solid organ 
transplantation (SOT) from HIV-positive donors to HIV-positive 
recipients.

------------------------------------------------------------------------
             Category                             Criteria
------------------------------------------------------------------------
Donor Eligibility:                  ....................................
    All HIV-positive deceased       No evidence of invasive
     donors.                         opportunistic complications of HIV
                                     infection.
                                    Pre-implant donor organ biopsy.
                                    Viral load: no requirement.

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    Deceased donor with known       The study team must describe the
     history of HIV infection and    anticipated post-transplant
     prior antiretroviral therapy    antiretroviral regimen(s) to be
     (ART).                          prescribed for the recipient and
                                     justify its conclusion that the
                                     regimen will be safe, tolerable,
                                     and effective.
    HIV-positive living donor.....  Well-controlled HIV infection
                                     defined as:
                                     CD4+ T-cell count >=500/
                                     [micro]L for the 6-month period
                                     before donation.
                                     HIV-1 RNA <50 copies/mL.
                                     No evidence of invasive
                                     opportunistic complications of HIV
                                     infection.
                                    Pre-implant donor organ biopsy.
Recipient Eligibility.............  CD4+ T-cell count >=200/[micro]L
                                     (kidney).
                                    CD4+ T-cell count >=100 [micro]L
                                     (liver) within 16 weeks prior to
                                     transplant and no history of
                                     opportunistic infection (OI); or
                                     >=200 [micro]L if history of OI is
                                     present.
                                    HIV-1 RNA <50 copies/mL and on a
                                     stable antiretroviral regimen.
                                    No evidence of active opportunistic
                                     complications of HIV infection.
                                    No history of primary central
                                     nervous system (CNS) lymphoma or
                                     progressive multifocal
                                     leukoencephalopathy (PML).
Transplant Hospital Criteria......  Transplant hospital with established
                                     program for care of HIV-positive
                                     subjects.
                                    HIV program expertise on the
                                     transplant team.
                                    Experience with HIV-negative to HIV-
                                     positive organ transplantation.
                                    Standard operating procedures (SOPs)
                                     and training for the organ
                                     procurement, implanting/operative,
                                     and postoperative care teams for
                                     handling HIV-infected subjects,
                                     organs, and tissues.
                                    Institutional review board (IRB)-
                                     approved research protocol in HIV-
                                     positive to HIV-positive
                                     transplantation.
                                    Institutional biohazard plan
                                     outlining measures to prevent and
                                     manage inadvertent exposure to and/
                                     or transmission of HIV.
                                    Provide each living HIV-positive
                                     donor and HIV-positive recipient
                                     with an ``independent advocate''.
                                    Policies and SOPs governing the
                                     necessary knowledge, experience,
                                     skills, and training for
                                     independent advocates.
OPO Responsibilities..............  SOPs and staff training procedures
                                     for working with deceased HIV-
                                     positive donors and their families
                                     in pertinent history taking;
                                     medical chart abstraction; the
                                     consent process; and handling
                                     blood, tissues, organs, and
                                     biospecimens.
                                    Biohazard plan to prevent and manage
                                     HIV exposure and/or transmission.
Prevention of Inadvertent           Each participating Transplant
 Transmission of HIV.                Program and OPO shall develop an
                                     institutional biohazard plan for
                                     handling organs from HIV-positive
                                     donors that is designed to prevent
                                     and/or manage inadvertent
                                     transmission or exposure to HIV.
                                    Procedures must be in place to
                                     ensure that human cells, tissues,
                                     and cellular and tissue-based
                                     products (HCT/Ps) are not recovered
                                     from HIV-positive donors for
                                     implantation, transplantation,
                                     infusion, or transfer into a human
                                     recipient; however, HCT/Ps from a
                                     donor determined to be ineligible
                                     may be made available for
                                     nonclinical purposes.
Required Outcome Measures:          ....................................
    Wait List Candidates..........  HIV status.
                                    CD4+ T-cell counts.
                                    Co-infection (hepatitis C virus
                                     [HCV], hepatitis B virus [HBV]).
                                    HIV viral load.
                                    ART resistance.
                                    Removal from wait list (death or
                                     other reason).
                                    Time on wait list.
    Donors (all)..................  Type (Living or deceased).
                                    HIV status (HIV-infected [HIV-
                                     positive] new diagnosis, HIV-
                                     positive known diagnosis).
                                    CD4+ T-cell count.
                                    Co-infection (HCV, HBV).
                                    HIV viral load.
                                    ART resistance.
    Living Donors.................  Progression to renal insufficiency
                                     in kidney donors.
                                    Progression to hepatic insufficiency
                                     in liver donors.
                                    Change in ART regimen as a result of
                                     organ dysfunction.
                                    Progression to acquired
                                     immunodeficiency syndrome (AIDS).
                                    Failure to suppress viral
                                     replication (persistent HIV
                                     viremia).
                                    Death.
    Transplant Recipients.........  Rejection rate (annual up to 5
                                     years).
                                    Progression to AIDS.
                                    New OI.
                                    Failure to suppress viral
                                     replication (persistent HIV
                                     viremia).
                                    HIV-associated organ failure.
                                    Malignancy.
                                    Graft failure.
                                    Mismatched ART resistance versus
                                     donor.
                                    Death.
------------------------------------------------------------------------

    The HOPE Act research criteria focus on liver and kidney 
transplantation, where there is substantial experience with HIV-
negative to HIV-positive transplantation. The intent is not to exclude 
the possibility of HIV-positive to HIV-positive transplantation of 
other organs; however, transplant organ-specific teams must gain 
experience

[[Page 73789]]

with HIV-negative to HIV-positive transplantation before embarking on 
the more complex and less well-defined issues with HIV-positive to HIV-
positive transplantation. The minimum combined experience required of 
the transplant physician and HIV physician on the team is five organ-
specific cases over 4 years.
    The HOPE Act requires the Secretary and the Organ Procurement and 
Transplantation Network (OPTN) to review the results of the scientific 
research conducted under these criteria to determine whether the 
results warrant further revisions to the OPTN's standards of quality. 
Under the HOPE Act, the Secretary may in the future determine that 
participation in research under such criteria is no longer required for 
HIV-positive to HIV-positive transplants.

Background

    Public Law 113-51, The HOPE Act, requires the HHS Secretary (the 
Secretary) to, among other things, ``develop and publish criteria for 
conduct of research relating to transplantation of organs from donors 
infected with human immunodeficiency virus (HIV) into individuals who 
are infected with HIV before receiving such organs.'' (See Public 
Health Service Act section 377E(a) [codified at 42 U.S.C. 274f-5]). In 
addition, pursuant to section 377E(c) of the HOPE Act, the Secretary is 
required, in conjunction with the OPTN, to review the results of that 
research to determine whether revisions should be made to the standards 
of quality adopted under section 372(b)(2)(E) of the Public Health 
Service Act (OPTN standards for the acquisition and transportation of 
donated organs) and the regulations governing the operation of the OPTN 
(42 CFR 121.6).
    The authority vested in the Secretary under section 377E(a) to 
develop and publish research criteria was delegated to the Director, 
National Institutes of Health (NIH), and these research criteria are 
the subject of this document. They are meant to ensure first, that 
research using organs from HIV-positive donors is conducted under 
conditions protecting the safety of research participants and the 
general public; and second, that the results of this research provide a 
basis for evaluating the safety of transplantation of organs from HIV-
positive donors to HIV-positive recipients.

Process

    This document was authored by representatives of the NIH and 
Centers for Disease Control and Prevention. Additional input from 
representatives of other federal agencies, including the Health 
Resources and Services Administration, Centers for Medicare & Medicaid 
Services (CMS), and the Food and Drug Administration (FDA), was 
solicited. In addition, perspectives and input were solicited from 
community stakeholders.

Introduction

    The advent of effective antiretroviral therapy (ART) in the mid-
1990s for treatment of individuals infected with HIV transformed a 
rapidly fatal disease into a well-controlled chronic illness. 
Currently, the life expectancy of individuals infected with HIV and 
receiving ART early in the course of their disease approaches that of 
individuals without HIV infection (Wada, 2013, 2014). In this era of 
greater longevity, liver failure, end-stage renal disease, and 
cardiovascular disease have emerged as important causes of morbidity 
and mortality in patients with HIV infection (Neuhaus, 2010).
    Organ transplantation prolongs survival and improves quality of 
life for individuals with end-stage organ disease (Matas, 2014; Kim, 
2014). Until recently, however, organ transplantation was unavailable 
to those infected with HIV due to concerns that pharmacologic 
immunosuppression to prevent organ rejection would hasten the 
progression from HIV infection to AIDS, concerns about disease 
transmission, and reluctance to allocate organs to a population whose 
outcome was unpredictable (Blumberg, 2009, 2013a, 2013b; Mgbako, 2013; 
Taege, 2013). Nevertheless, a few transplant programs accepted HIV-
positive patients on their transplant waiting lists and accumulated 
data showing kidney or liver transplantation could be done safely in 
these patients (Roland, 2002, 2003a, 2003b, 2003c; Blumberg, 2009; 
Stock, 2010; Yoon, 2011; Terrault, 2012). Subsequently, a prospective, 
multicenter clinical trial of kidney and liver transplantation in 275 
patients demonstrated that, among HIV-positive kidney and liver 
transplant recipients, patient and graft survival rates were acceptable 
and within the range of outcomes currently achieved among non-infected 
transplant recipients. However, the rate of kidney rejection was 
unexpectedly high, demonstrating that the immune dysregulation 
resulting from HIV infection, HCV co-infection, and antirejection drugs 
is complex and incompletely understood. Some of the challenges 
encountered in that study remain relevant for clinical sites offering 
organ transplantation to HIV-positive individuals today (e.g., 
management of drug interactions and toxicities when combining complex 
medical regimens, management of combined morbidities of two or more 
active diseases, and the need for ongoing collaboration among medical 
professionals from different specialties) (Frassetto, 2007, 2014; 
Locke, 2014). Despite the complexities, this study and others (Ragni, 
1999; Frassetto, 2009; Huprikar, 2009; Stock, 2010; Touzot, 2010; 
Cooper, 2011; Duclos-Vallee, 2011; Reeves-Daniel, 2011; Fox, 2012; 
Terrault, 2012; Grossi, 2012; Gomez, 2013; Harbell, 2013) demonstrate 
that kidney and liver transplantation are appropriate in HIV-positive 
individuals with liver or kidney failure, although gaps in knowledge 
and many research questions remain. There is much less experience with 
heart (Calabrese, 2003; Bisleri, 2003; Pelletier, 2004; Uriel, 2009, 
2014; Castel, 2011a, 2011b; Durante-Mangoni, 2011 and 2014) and lung 
(Mehta, 2000; Humbert, 2006; Petrosillo, 2006; Bertani, 2009; Kern, 
2014a, 2014b) transplantation in HIV-positive recipients, or mechanical 
circulatory assistance (Brucato, 2004; Fieno, 2009; Mehmood, 2009; 
Sims, 2011) as a bridge to transplantation, although case reports and 
small case series suggest acceptable short-term outcomes are possible.
    Prior to the passage of the HOPE Act, U.S. law required that all 
U.S. transplants for HIV-positive recipients utilize organs from HIV-
uninfected donors. (See 42 U.S.C. 273(b)(3)(C), 274(b) and 18 U.S.C. 
1122, all prior to amendment by the HOPE Act). The potential for 
increasing the pool of available organ donors for all recipients by 
allowing the use of organs from donors infected with HIV for 
transplantation into recipients infected with HIV (hereinafter referred 
to as ``HIV-positive to HIV-positive transplantation'') is recognized 
(Boyarsky, 2011, 2015; Mgbako, 2013; Mascolini, 2014; Kucirka, 2015; 
Richterman, 2015). It is estimated that an additional 500 organ donors 
per year might be available if HIV-positive individuals were accepted 
as organ donors for HIV-positive recipients (Boyarsky, 2011). The 
published experience with HIV-positive to HIV-positive SOT at this time 
comes from Muller et al from the University of Cape Town in South 
Africa. Initially, Muller et al (2010) reported 100 percent patient and 
graft survival in a four-patient pilot study. Subsequently, the same 
group reported an additional 10 HIV-positive to HIV-positive renal 
transplants (Muller, 2012). All patients were restarted on ART early 
postoperatively in the immunosuppressive setting of T-

[[Page 73790]]

cell-depleting induction therapy, tacrolimus, mycophenolate mofetil, 
and prednisone. One to 4 years after transplantation, outcomes remained 
excellent and all patients had undetectable viral loads (Muller, 2012). 
The cumulative University of Cape Town experience of 27 HIV-positive to 
HIV-positive transplant procedures was recently summarized in the New 
England Journal of Medicine (Muller, 2015). The 1- and 5-year death-
censored graft survival was 93 and 84 percent, respectively, and 1- and 
5-year patient survival was 83 and 74 percent, respectively. Of note, 
the South African HIV-positive deceased donors were ART-na[iuml]ve, 
without history of opportunistic infection or proteinuria, and had 
normal pre-transplant renal biopsies. While renal function has remained 
normal in the recipients, three have had routine post-transplant renal 
biopsies demonstrating new changes typical of early HIV-associated 
nephropathy that were not present in baseline biopsy specimens. The 
long-term significance of these findings remains unknown and awaits 
longer follow-up. All patients had undetectable plasma HIV viral loads 
after transplantation. Graft rejection rates were 8 percent at 1 year 
and 22 percent at 3 years.
    This document presents criteria for conducting research in HIV-
positive to HIV-positive organ transplantation in the United States. 
The criteria are grouped into six broad categories: Donor Eligibility, 
Recipient Eligibility, Transplant Hospital Criteria, OPO 
Responsibilities, Prevention of Inadvertent Transmission of HIV, and 
Study Design/Required Outcome Measures. These research criteria do not 
describe all of the necessary components of a research protocol for 
HIV-positive to HIV-positive transplantation, such as the specific 
medication regimens, pre-transplant induction (if any), maintenance 
immunosuppression after transplantation, or control of HIV infection. 
These protocol elements and others will be determined by an 
investigator's specific research questions and the expertise of those 
conducting the research. Rather, the criteria address the minimum 
safety and data requirements of clinical research in HIV-positive to 
HIV-positive transplantation. As mandated by the HOPE Act, the 
Secretary, together with the OPTN, is charged with reviewing the 
results of scientific research conducted under these criteria to 
determine whether the OPTN's standards of quality should be further 
modified and whether some HIV-positive to HIV-positive transplants 
should proceed outside the auspices of research conducted under such 
criteria.
    This document focuses on liver and kidney transplantation, as it is 
only in liver and kidney transplantation that there is substantial 
experience with transplantation from HIV-negative donors to HIV-
positive recipients (Sawinski, 2015; Locke, 2015a, 2015b; Miro, 2015). 
The intent is not to exclude the possibility of HIV-positive to HIV-
positive transplantation of other organs such as the heart or lung in 
the future; however, transplant teams must gain experience with HIV-
negative to HIV-positive transplantation of a specific organ before 
taking on the more complex and less well-defined issues of HIV-positive 
to HIV-positive transplantation of that organ. Centers developing 
research protocols for HIV-positive to HIV-positive transplantation of 
organs other than kidney or liver must have a study team with 
demonstrated experience in HIV-negative to HIV-positive transplants, as 
noted in Section 3.1(ii), for the organ transplant(s) proposed in the 
research protocol. Specific criteria for the transplantation of organs 
other than the liver and kidney have not been provided in this document 
because no evidence base exists to support such recommendations. The 
study team developing a research protocol for HIV-positive to HIV-
positive non-renal, non-liver transplantation must develop and justify 
specific criteria for review and approval by their IRB, based on the 
relevant experiences of the study team and others.
    These criteria are in addition to, not in place of, current 
policies and regulations governing organ transplantation and human 
subjects' research. Accordingly, to emphasize the specific requirements 
unique to the investigational transplantation of organs from HIV-
positive donors into HIV-positive recipients, the research criteria set 
forth here do not address related requirements that exist in federal 
regulations or OPTN bylaws or policies including, but not limited to, 
obligations imposed on OPTN transplant hospitals and transplant 
programs concerning informed consent of transplant recipients and 
living donors, the equitable allocation of organs, and organ offers. 
The regulations governing the operation of OPTN are codified at 42 CFR 
part 121 and OPTN policies and bylaws can be found at http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf.
    Under these research criteria, all HIV-positive to HIV-positive 
transplantation must occur under an IRB-approved research protocol and 
shall comply with any other existing laws, policies, and regulations 
governing the conduct of human subjects' research (see Public Law 113-
51 and, e.g., 45 CFR part 46, as applicable). In addition, a transplant 
program conducting research in HIV-positive to HIV-positive 
transplantation under these research criteria must provide each living 
donor and recipient with an independent advocate.
    Although the criteria set forth in this document outline the 
minimum safety requirements for research involving HIV-positive to HIV-
positive transplantation, it is expected that investigators will 
develop more specific eligibility criteria based on their individual 
research questions and protocols. In addition, it is likely, that 
researchers will wish to collect research specimens (blood, urine, 
tissue) in addition to those specified in the Research Criteria.

1 Donor Eligibility

    HIV-positive living donors and HIV-positive deceased donors of 
organs for transplantation into an HIV-positive recipient must fulfill 
applicable clinical criteria in place for HIV-uninfected organ donors.
    There is substantial concern about the consequences of 
transplanting an organ from an HIV-positive donor to a recipient 
infected with a strain of HIV that differs from the donor's in terms of 
its responsiveness to antiretroviral therapy (ART). The likelihood and 
impact of HIV superinfection in this context are unknown. Adverse 
consequences could range from transient loss of viral suppression, 
necessitating a change in antiretroviral regimen to a worst-case 
scenario in which the new infecting strain of HIV is unresponsive to 
available antiretroviral treatment and the recipient progresses to AIDS 
(Redd, 2013). Information relevant to understanding the known or 
potential extent of antiretroviral resistance in the strain of HIV 
infecting the organ donor may be incomplete for many reasons:
     There may be inadequate virus in donor specimens for 
antiretroviral resistance testing;
     If the specimen is adequate, there may not be enough time 
within the decision-making evaluation window to fully assess 
antiretroviral resistance before the clinical deterioration of the 
donor, organ procurement, and implantation;
     The donor's history of antiretroviral treatment may be 
unknown or incomplete;

[[Page 73791]]

     Results from prior antiretroviral resistance testing may 
be unavailable.
    These issues might be especially challenging when considering organ 
donation from deceased donors whose HIV infection is first identified 
during donor evaluation. As of 2011, an estimated 1 in 6 U.S. adults 
living with HIV infection were undiagnosed (Prevention, 2013) and an 
estimated 16 percent of newly diagnosed, untreated individuals were 
infected with virus resistant to at least one class of antiretroviral 
drug (Kim, 2013; Megens, 2013).
    It is anticipated that the risk of transmission of resistant HIV 
strains may be lower from deceased donors with a well-documented 
history of antiretroviral treatment, undetectable virus at demise, and 
robust and persistent undetectable viral load for at least 1 year prior 
to death. However, to impose this as an eligibility criterion would 
limit the pool of suitable donors and severely limit the ability to 
study transplantation of HIV-positive organs under the HOPE Act. In 
addition, it will not be possible in all cases to obtain viral loads 
and/or antiretroviral resistance profiles in the time available for 
donor evaluation. Transplant teams evaluating a donor must review all 
available donor and recipient information and be able to propose an 
antiretroviral regimen that will be equally or more safe, tolerable, 
and effective for the recipient after transplantation as the regimen in 
place in the recipient before transplantation. For instance, a donor 
who only achieves viral suppression with a regimen known to be 
intolerable to the recipient must not be accepted. If there is doubt 
about the ability to suppress viral replication after transplantation, 
the transplant must not move forward.
    Donors co-infected with hepatitis are not excluded from HIV-
positive to HIV-positive transplant; however, careful consideration 
must be given when evaluating a donor co-infected with HBV and/or HCV 
(Terrault, 2012; Miro, 2012; Moreno, 2012; Sherman, 2014; Chen, 2014). 
Although HCV therapeutic strategies are rapidly evolving (Liang, 2013), 
it is possible that mixed genotype HCV infections may influence post-
transplant treatment of HCV in the recipient. Prior antiretroviral 
treatment of the donor and/or recipient with agents active against HBV 
(i.e., lamivudine, emtricitabine, adefovir, and tenofovir) has the 
potential for inducing or uncovering archived HBV drug resistance in 
the recipient (Dieterich, 2007; Soriano, 2009; Pais, 2010).
    In the case of a living HIV-positive organ donor, the risk of 
future end-stage liver or kidney failure in the donor must be carefully 
assessed as it is in other at-risk populations currently eligible to 
donate an organ. For example, kidney disease in HIV-positive patients 
has been associated with the apolipoprotein 1 (APOL1) coding variants 
that confer a very high risk of susceptibility and are almost 
exclusively found in patients of African descent (Freedman, 2013; 
Genovese, 2010). Living donation of a kidney from a donor having such a 
variant may be associated with an unacceptable risk of subsequent 
kidney disease to both the donor and the recipient (Freedman, 2015; 
Reeves-Daniel, 2011; Parsa, 2013; Riella, 2015).
    The consent process for an HIV-positive living organ donor must 
include and document provision to the donor of information regarding: 
(1) The possibility that the loss of organ function resulting from 
donation could preclude the use of certain antiretroviral drugs in the 
future; (2) the risk of kidney or liver failure in the future; (3) the 
possibility of transmission of occult opportunistic infections to the 
recipient; and (4) the absence of U.S. experience in HIV-positive to 
HIV-positive organ transplantation, and thus the unpredictable nature 
of donor and recipient outcomes (Mgbako, 2013).
    HIV-positive transplant candidates who are listed for a transplant 
in the context of a research study of HIV-positive to HIV-positive 
transplantation must have the same opportunity as other transplant 
candidates to receive an organ from an HIV-negative donor, should one 
become available for them.

1.1 HIV-Positive Donor Eligibility Criteria

    The HIV-specific donor eligibility criteria for deceased donors and 
for living donors are listed (also refer to Table 1). Co-infection with 
HBV and/or HCV is not an exclusion criterion, although research that 
includes co-infected donors must address any additional eligibility 
criteria within their research protocol.
1.1.1 HIV-Positive Deceased Donors
    When evaluating HIV-positive deceased donors, it is understood that 
limited medical history may be available and/or known at the time of 
the donor evaluation. The OPO must make reasonable efforts to obtain 
prior medical history so that a transplant center team may best 
determine the suitability of the potential donor based on the 
information available. A complete history of antiretroviral regimens 
and a history of viral load tests and resistance testing are especially 
valuable for evaluating the likelihood of donor HIV resistance to 
antiretroviral regimens. A history of OIs or cancers is also of high 
importance, due to the increased risk for both attributable to HIV, and 
the additional difficulty of treating some infections and neoplasms in 
a post-transplant setting. It is possible that deceased donors with 
lower CD4+ T-cell counts may pose an increased risk of harboring 
transmissible diseases (e.g., opportunistic infections or neoplasms) 
that may be difficult to detect during organ harvest and 
transplantation; teams conducting transplants under the HOPE Act are 
urged to assess donors with low CD4+ T-cell counts (e.g., <=200/
[micro]L) with special caution and to promptly inform IRBs and protocol 
sponsors of known or suspected disease transmission events.
    Minimum eligibility criteria for all HIV-positive deceased donors:
    i. Documented HIV infection using an FDA-licensed, approved, or 
cleared test device(s).
    ii. No evidence of invasive opportunistic complications of HIV 
infection.
    iii. Pre-implant donor organ biopsy to be stored, at a minimum, for 
the duration of the study (or at least 5 years); additional specimens 
may be obtained to support specific research goals.
    Additional eligibility criteria for HIV-positive deceased donors 
with a known history of HIV and prior treatment with ART:
    i. The study team must describe the anticipated post-transplant 
antiretroviral regimen(s) to be prescribed for the recipient and 
justify their conclusion that the proposed regimen will be safe, 
tolerable, and effective.
1.1.2 HIV-Positive Living Donors
    Minimum eligibility criteria for HIV-positive living donors:
    i. Documented HIV infection using an FDA-licensed, approved, or 
cleared test device.
    ii. Well-controlled HIV infection, as evidenced by:
    a. CD4+ T-cell count >=500/[micro]L for the 6-month period 
preceding donation.
    b. Fewer than 50 copies/mL of HIV-1 RNA detectable by 
ultrasensitive or real-time polymerase chain reaction (PCR) assay.
    iii. A complete history of ART regimens and ART resistance.
    iv. The study team must be able to predict a safe, tolerable, and 
effective regimen to be prescribed for the recipient based on the 
donor's current ART regimen as well as the donor's history of ART 
resistance.

[[Page 73792]]

    v. No evidence of invasive opportunistic complications of HIV 
infection.
    vi. A liver biopsy (in liver donors) or a kidney biopsy (in kidney 
donors) showing no evidence of a disease process that would put the 
donor at increased risk of progressing to end-stage organ failure after 
donation, or that would present a risk of poor graft function to the 
recipient.

2 Recipient Eligibility

    A key consideration when evaluating potential HIV-positive 
transplant candidates is the ability to suppress HIV viral load post-
transplant. This includes a thorough assessment by the transplant team 
of the candidate recipient's prescribed antiretroviral medications, HIV 
RNA levels while on medications, adherence to HIV treatment, and any 
available HIV resistance testing; a similar evaluation of the donor 
must also be carried out. A transplant should only take place if, after 
evaluating both recipient and donor, the team is confident they can 
define a post-transplant antiretroviral regimen that will be safe, 
tolerable, and effective. If there is any doubt on the part of the 
transplant team about the ability to suppress viral replication post-
transplant, the transplant should not move forward. Concerns about 
transmitted drug resistance must be included in the recipient informed 
consent process for the research study. At the time of an organ offer, 
the recipient informed consent must address the transplant team's 
assessment of risk specific to the organ they are being offered.

2.1 HIV-Positive Recipient Eligibility Criteria

    The following HIV-specific criteria must be met when screening for 
an HIV-positive to HIV-positive organ transplant (also refer to Table 
1):
    i. CD4+ T-cell count >=200/[micro]L (kidney) and >=100/[micro]L 
(liver) within 16 weeks prior to transplant; any patient with history 
of OI must have a CD4 positive T-cell count >=200/uL.
    ii. HIV RNA less than 50 copies/mL and on a stable antiretroviral 
regimen.*
    iii. No evidence of active opportunistic complications of HIV 
infection.
    iv. No history of primary CNS lymphoma or progressive PML.
    v. Concurrence by the study team that, based on medical history and 
ART, viral suppression can be achieved in the recipient post-
transplant.
    *Patients who are unable to tolerate ART due to organ failure or 
who have only recently started ART may have detectable viral load and 
still be considered eligible if the study team is confident there will 
be a safe, tolerable, and effective antiretroviral regimen for the 
patient once organ function is restored after transplantation.

 Table 1--Summary of Donor and Recipient Eligibility Criteria for HIV-Positive Sero-Concordant Organ Transplant
                                            Pairs under the HOPE Act
----------------------------------------------------------------------------------------------------------------
        HIV-Related variables               Deceased donor            Living donor        HIV-Positive recipient
----------------------------------------------------------------------------------------------------------------
                                                                                         If no history of OI
                                                                                          >=200
Current CD4+ T-cell count............  No requirement.........  >=500 for 6 months       If history of OI
(T lymphocytes/[micro]L).............                            prior to organ           >=200 (kidney)
                                                                 donation.
                                                                                          >=100 (liver)
                                                                                         CD4+ T-cell count
                                                                                          measured within 16
                                                                                          weeks of
                                                                                          transplantation
Plasma HIV RNA viral load (copies/mL)  No requirement**.......  <50....................  <50*
Opportunistic infection..............  No invasive OI.........  No invasive OI.........  Currently,
                                                                                          No active OI
                                                                                         Historically, no
                                                                                          CNS
                                                                                         lymphoma
                                                                                          PML
----------------------------------------------------------------------------------------------------------------
* Organ recipients who are unable to tolerate ART due to organ failure or who have only recently started ART may
  have detectable viral load and still be considered eligible if the study team is confident there will be a
  safe, tolerable, and effective antiretroviral regimen to be used by the recipient once organ function is
  restored after transplantation.
** In deceased donors with a known history of HIV infection and prior treatment with ART, the study team must
  describe the anticipated post-transplant antiretroviral regimen(s) to be used by the organ recipient and
  justify their conclusion that the proposed regimen will be safe, tolerable, and effective.

3 Transplant Hospital Criteria

    Expertise in the management of individuals with HIV infection is 
essential for this research. A transplant hospital participating in 
HIV-positive to HIV-positive transplantation must include experts in 
the field of transplantation as well as experts in the management of 
HIV infection working collaboratively as a part of a study team.

3.1 Specific Transplant Hospital Criteria

    i. An established program for the care of individuals infected with 
HIV.
    ii. In order for a transplant hospital to initiate HIV-positive to 
HIV-positive transplantation, there must be a study team consisting of 
(at a minimum) a transplant surgeon, a transplant physician, and an HIV 
physician. The transplant physician and HIV physician collectively must 
have experience with at least 5 HIV-negative to HIV-positive 
transplants with the designated organ(s) over the last 4 years. This 
constitutes the minimal experience necessary, and the IRB must evaluate 
key personnel (i.e., transplant surgeon, transplant physician, and HIV 
physician) in the context of total expertise and experience with 
respect to HIV and/or organ transplantation (confirm and document HIV-
negative to HIV-positive transplant experience of the team).
    iii. Defined SOPs and training for the hospital personnel involved 
in procurement and/or implantation regarding the following issues:
a. Donor evaluation
b. Organ recovery
c. Handling, processing, packaging, shipping, and transporting of 
blood, lymph nodes, tissues, and organs to and/or within the transplant 
hospital
d. Transplant procedure

    iv. Transplant hospitals with an IRB-approved research protocol in 
HIV-positive to HIV-positive transplantation

[[Page 73793]]

must inform the OPTN of additional organ-specific acceptance criteria 
for organs from HIV-positive donors.
    v. Transplant hospitals with an IRB-approved research protocol in 
HIV-positive to HIV-positive transplantation with HIV-positive 
candidates on the wait list willing to accept an HIV-positive organ 
must specify any additional acceptance criteria to the OPO.
    vi. The transplant hospital must verify the HIV status of both the 
donor and the recipient.
    vii. Defined SOPs and training regarding an institutional biohazard 
plan, which outlines the measures taken to prevent and manage 
inadvertent exposure and/or transmission of HIV.
    viii. Defined policies and SOPs for governing the necessary 
knowledge, experience, skills, and training for independent advocates.

3.2 Independent Advocates

    A transplant program conducting research in HIV-positive to HIV-
positive transplantation under these research criteria must provide 
each HIV-positive living donor and recipient with an independent 
advocate.
    In the setting of a living donor transplant, there must be two 
independent advocates, one for the donor and another for the recipient. 
Each advocate must be independent of the research team and must have 
knowledge and experience with both HIV infection and organ 
transplantation.
    At a minimum, transplant hospitals conducting research in HIV-
positive to HIV-positive transplantation shall develop policies and 
procedures addressing the role, knowledge, and experience of 
independent advocates in the setting of HIV infection, transplantation, 
medical ethics, informed consent, and the potential impact of external 
pressure on the HIV-positive recipient's decision, and HIV-positive 
living donor's decision (if applicable) about whether to enter the HIV-
positive to HIV-positive transplant research study.
3.2.1 Independent HIV-Positive Recipient Advocate
    Transplant programs performing HIV-positive to HIV-positive 
transplants must designate and provide each HIV-positive recipient and 
prospective HIV-positive recipient with an independent advocate who is 
responsible for protecting and promoting the rights and interests of 
the HIV-positive recipient (or prospective recipient). The independent 
advocate for the HIV-positive recipient must:
    i. Promote and protect the interests of the HIV-positive recipient 
(including with respect to having access to a suitable HIV-negative 
organ if it becomes available) and take steps to ensure that the HIV-
positive recipient's decision is informed and free from coercion.
    ii. Review whether the potential HIV-positive recipient has 
received information regarding the results of SOT in general and 
transplantation in HIV-positive recipients in particular and the 
unknown risks associated with HIV-positive to HIV-positive transplant.
    iii. Demonstrate knowledge of HIV infection and transplantation.
3.2.2 Independent HIV-Positive Living Donor Advocate
    Transplant programs performing HIV-positive donor transplantations 
must designate and provide each living HIV-positive donor and living 
prospective HIV-positive donor with an independent advocate who is 
responsible for promoting and protecting the rights and interests of 
the HIV-positive donor (or prospective donor). More specifically, the 
independent advocate for the HIV-positive living donor must:
    i. Promote and protect the interests of the HIV-positive donor 
(including with respect to having ample opportunity to withdraw consent 
from donation) and take steps to ensure that the HIV-positive donor's 
decision is informed and free from external pressure.
    ii. Review whether the potential HIV-positive donor has received 
information regarding (a) risks of organ donation in general, as well 
as the additional potential risks that are the specific to the HIV-
positive donor, including accelerated organ failure, and limitations of 
future use of specific antiretroviral agents; and (b) the unknown 
outcome of HIV-positive to HIV-positive organ transplantation.
    iii. Demonstrate knowledge of HIV infection and transplantation.

4 OPO Responsibilities

    Clinical research in HIV-positive to HIV-positive organ 
transplantation requires a partnership between OPOs and transplant 
programs. OPOs participating in the evaluation and allocation of HIV-
positive organs to centers conducting research in HIV-positive to HIV-
positive transplantation must adhere to the following criteria:
    i. Develop SOPs and staff training procedures to effectively work 
with the family and other sources of medical history for HIV-positive 
donors in assessing medical and behavioral risks; HIV clinic and 
pharmacy medical record abstraction; obtaining research consent from 
next of kin of HIV-positive donors; performing physical examination of 
HIV-positive donors; collecting blood, tissue, and other biospecimens 
(e.g., urine, bronchoalveolar lavage, spleen, lymph nodes, and biopsy 
material); and handling, processing, storing, labeling, and shipping of 
the biospecimens.
    ii. Conduct training in obtaining relevant and pertinent HIV-
positive history, duration of HIV infection, opportunistic illnesses 
and their therapy, risk factors for HIV, CD4+ T-cell counts (lows and 
highs), HIV resistance, ART medication history use and response, 
history of ART resistance, present ART, HIV viral loads, and HIV 
genotype and tropism, when known.
    iii. Develop a biohazard plan to prevent and manage exposure to or 
transmission of HIV.
    These criteria are in addition to, not in place of, current Organ 
Procurement and Transplantation Network (OPTN) policies and bylaws, 
state or local laws, and federal regulations governing organ 
transplantation and research that pertains to OPOs.

5 Prevention of Inadvertent Transmission of HIV

    Although the use of HIV-positive organs may help alleviate 
transplant shortages and reduce patient waiting list times, there also 
are patient safety concerns to consider. Prevention or management of 
inadvertent transmission of HIV or exposure of an HIV-negative 
recipient to organs or tissues from an HIV-positive donor due to 
identification error is paramount (Ison, 2009, 2011a, 2011b). The 
transplant community, with regulatory oversight at multiple levels, has 
been able to achieve a high level of safety through routine procedures 
and clinical practice. The precautions taken with ABO compatible donor-
recipient pairs and HCV-infected donor organs in HCV-infected 
recipients (Morales, 2010; Kucirka, 2010; Mandal, 2000; Tector, 2006) 
are existing models. However, vulnerabilities still exist, and mishaps 
still occur. For instance, the risks of error during manual 
transcription of information are well documented.
    Each transplant hospital shall have an institutional biohazard plan 
for handling of HIV-positive organs--to include, for example, organ 
quarantine measures, electronic information capture on infectious 
disease testing results, communication protocols between OPOs and 
transplant hospitals--that is designed to prevent and/or manage 
inadvertent transmission of or exposure to HIV.

[[Page 73794]]

    Tissues (e.g., cornea, blood vessels, or cartilage) not associated 
with the organ to be transplanted and organs are often recovered from 
organ donors. The FDA regulates human cells, tissues, and cellular and 
tissue-based products (HCT/Ps) that are intended for implantation, 
transplantation, infusion, or transfer into a human recipient under the 
authority of section 361 of the Public Health Service Act and the 
implementing regulations in 21 CFR part 1271. Under 21 CFR part 1271, 
persons with risk factors for, or clinical evidence of, relevant 
communicable diseases, or whose test results are positive or reactive 
for relevant communicable diseases (including HIV) are ineligible to 
donate HCT/Ps. Procedures must be in place to ensure that HCT/Ps are 
not recovered from HIV-positive donors for implantation, 
transplantation, infusion, or transfer into a human recipient; however, 
HCT/Ps from a donor who has been determined to be ineligible may be 
made available for nonclinical purposes.

6 Study Design/Required Outcome Measures

    There is a wide range of clinical and immunologic questions that 
might be addressed in the context of research in HIV-positive to HIV-
positive transplantation. These include, for example, questions related 
to HIV superinfection; incidence and severity of OIs (including 
transmission of occult OIs from donor to recipient); immunologic 
mechanisms contributing to the increased rate of kidney rejection 
observed in HIV-positive recipients; quality of life for recipients of 
HIV-positive to HIV-positive transplantation; outcomes of living HIV-
positive donors; and a host of others. The questions will be determined 
by the investigators who design research protocols for studying HIV-
positive to HIV-positive transplantation. However, to ensure that all 
studies of HIV-positive to HIV-positive transplantation can contribute 
to evaluation of the safety of the procedure, the following key donor 
and recipient characteristics and outcome measures must be incorporated 
into the design of all clinical trials of HIV-positive to HIV-positive 
transplantation.

6.1 Wait List Candidates

 HIV status
 CD4+ T-cell count
 Co-infection (HCV, HBV)
 HIV viral load
 ART resistance
 Removal from wait list (death or other reason)
 Time on wait list

6.2 Donors (all)

 Type (living or deceased)
 HIV status (HIV-positive new diagnosis, HIV-positive known 
diagnosis)
 CD4+ T-cell count
 Co-infection (HCV, HBV)
 HIV viral load
 ART resistance
 Pre-transplant donor allograft biopsy

6.3 Living Donors (6, 12, and 24 Months Following Organ Donation)

 Progression to renal insufficiency in kidney donors:
    [cir] Proteinuria defined as urinary protein excretion >150 mg/day 
or urine protein/creatinine ratio >0.2
    [cir] eGFR <60 mL/minute/1.73m\2\
 Progression to hepatic insufficiency in liver donors (INR >1.5 
and/or total bilirubin >2.0)
 Change in ART regimen as a result of decreased organ function
 Progression to AIDS
 Failure to suppress viral replication (persistent viremia)
 Death

6.4 Transplant Recipients

 Rejection rate (annual up to 5 years)
 Progression to AIDS
 New OIs
 Failure to suppress viral replication (persistent viremia)
 HIV-associated organ failure
 Malignancy
 Graft failure
 Mismatched ART resistance versus donor
 Death

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868.

    Dated: November 20, 2015.
Francis S. Collins,
Director, National Institutes of Health.
[FR Doc. 2015-30172 Filed 11-24-15; 8:45 am]
BILLING CODE 4140-01-P