[Federal Register Volume 80, Number 117 (Thursday, June 18, 2015)]
[Notices]
[Pages 34912-34921]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-15034]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


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, Department of Health and Human 
Services.

ACTION: Notice of availability and request for comments.

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

SUMMARY: The HOPE Act requires the Secretary of Health and Human 
Services (the Secretary) to develop and publish criteria for research 
involving transplantation of HIV-infected (HIV+) donor organs in HIV+ 
recipients. The goals of these criteria are, first, to ensure that 
research using organs from HIV+ 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 solid organ transplantation (SOT) from HIV+ 
donors to HIV+ recipients. The National Institutes of Health (NIH), 
U.S. Department of Health and Human Services, invites the public to 
submit comments regarding the proposed HOPE Act criteria.

DATES: To ensure that comments will be considered, comments must be 
received no later than 5:00 p.m. on August 17, 2015.

ADDRESSES: Comments may be submitted by any of the following methods:
     Email: [email protected].
     Fax: 301-451-5671.
     Regular Mail: Dr. Jonah Odim, 5601 Fishers Lane, Room 
6B21, MSC 9827, Bethesda, MD 20892-9827.
     Hand Delivery, Overnight Mail, FedEx, and UPS: Dr. Jonah 
Odim, 5601 Fishers Lane, Room 6B21, MSC 9827, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Dr. Jonah Odim, 240-627-3540.

SUPPLEMENTARY INFORMATION: There is little evidence base for HIV+ to 
HIV+ organ transplantation, and it is only in liver and kidney 
transplantation that there is substantial experience with 
transplantation of organs from HIV-uninfected (HIV-) donors to HIV+ 
recipients. The criteria for conducting clinical research in HIV+ to 
HIV+ organ transplantation 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) and are summarized in the table below. 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+ 
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 SOT from 
HIV+ donors to HIV+ recipients.

------------------------------------------------------------------------
           Category                             Criteria
------------------------------------------------------------------------
Donor Eligibility:
    Deceased donor with known  Cluster of differentiation 4 (CD4)+ T-
     history of HIV infection.  cell count >=200/microliter ([mu]L) or
                                >=14%.
                               HIV-1 ribonucleic acid (RNA) <50 copies/
                                milliliter (mL); No history of viral
                                load >1000 copies/mL in the prior 12
                                months.
                               No active opportunistic infection (OI).
    Deceased donor with newly  CD4+ T-cell count >=200/[mu]L or >=14%.
     diagnosed HIV infection.  Viral load: no requirement.
                               No active OI.
    Living HIV+ donor........  Well-controlled HIV infection.
                               CD4+ T-cell count (lifetime nadir) >=200/
                                [mu]L.
                               CD4+ T-cell count >=500/[mu]L for the 6-
                                month period before donation.
                               HIV-1 RNA <50 copies/mL.
                               No OI.
                               Pre-transplant donor allograft biopsy
                                showing no evidence of disease that
                                would increase the risk of post-
                                transplant organ failure or poor graft
                                function.
    Recipient (HIV+)           CD4+ T-cell count >=200/[mu]L (kidney).
     Eligibility.              CD4+ T-cell count >=100[mu]L (liver)
                                within 16 weeks prior to transplant; or
                                >=200[mu]L with history of OI
                               HIV-1 RNA <50 copies/mL and on a stable
                                antiretroviral regimen.
                               No active OI or neoplasm.
                               No history of chronic cryptosporidiosis,
                                primary central nervous system (CNS)
                                lymphoma, or progressive multifocal
                                leukoencephalopathy (PML).

[[Page 34913]]

 
    Transplant Hospital        Transplant hospital with established
     Criteria.                  program for care of HIV+ subjects.
                               HIV program expertise on the transplant
                                team.
                               Experience with HIV- to HIV+ 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+ to HIV+
                                transplantation.
                               Institutional biohazard plan outlining
                                measures to prevent and manage
                                inadvertent exposure and/or transmission
                                of HIV.
                               Provide each living HIV+ donor and HIV+
                                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+ donors and
                                their family 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 Program and
     HIV Transmission.          OPO shall develop an institutional
                                biohazard plan for handling of HIV+
                                organs 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+ 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+ new diagnosis, HIV+
                                known diagnosis).
                               CD4+ T-cell count.
                               Co-infection (HCV, HBV).
                               HIV viral load.
                               ART resistance.
    Living Donors............  Progression to renal insufficiency in
                                kidney donors (serum creatinine >2 mg/
                                deciliter (dL), serum creatinine level
                                twice the pre-donation creatinine level,
                                or proteinuria).
                               Progression to hepatic insufficiency in
                                living donors (international normalized
                                ratio (INR) >1.5 and/or total bilirubin
                                >2.0).
                               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 (Years 1 and 2).
                               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.
------------------------------------------------------------------------

    Instructions for Submitting Comments: Comments are invited on but 
not limited to: (1) Donor and recipient eligibility criteria; (2) the 
inclusion of living HIV+ donors; (3) other viral co-infections in the 
donor and/or recipient (e.g., HBV and/or HCV) (4) transplant hospital 
criteria; (5) OPO responsibilities; (6) minimal required outcome 
measures under the HOPE Act; and (7) whether the proposed collection of 
these minimal outcome measures is sufficient to assess the safety of 
HIV+ to HIV+ transplant as outlined in the HOPE Act. Do not include 
personal information that you do not want publicly disclosed.

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.......................................  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.
HIV.......................................  Human Immunodeficiency
                                             Virus.
HIV-......................................  HIV-uninfected.
HIV+......................................  HIV-infected.
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 Reverse
                                             Transcriptase Inhibitor.

[[Page 34914]]

 
NRTI......................................  Nucleoside 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.
[mu]L.....................................  Microliter.
------------------------------------------------------------------------

Background

    Public Law 113-51, The HOPE Act, requires the Secretary of Health 
and Human Services (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 organ.'' (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+ 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 SOT from HIV+ donors to HIV+ 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 subjects 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 rejection would hasten progression from 
HIV infection to AIDS, concerns about disease transmission, and 
reluctance to allocate organs to a population whose outcome was 
unpredictable (Blumberg, 2009, 2013; Mgbako, 2013; Taege, 2013). 
Nevertheless, a few transplant programs accepted HIV+ 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; Blumberg, 2009; Stock, 2010; Yoon, 2011; Terrault, 2012). 
Subsequently, a prospective, multi-center clinical trial of kidney and 
liver transplantation in 275 patients demonstrated that among HIV+ 
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 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+ 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; 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+ individuals with 
liver or kidney failure, though 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, 2014) transplantation in 
HIV+ 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+ recipients utilize organs from HIV-uninfected 
(HIV-) donors. See 42 U.S.C. 273(b)(3)(C), 274(b); 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+ to HIV+ 
transplantation'') is recognized (Boyarsky, 2011; Mgbako, 2013; 
Mascolini, 2014). It is estimated that an additional 500 organ donors 
per year might be available if HIV+ individuals were accepted as organ 
donors for HIV+ recipients (Boyarsky, 2011). The only published 
experience with HIV+ to HIV+ SOT at this time is an early pilot report 
from South Africa (Muller, 2010) with 100 percent patient and graft 
survival in 4 patients. In a follow-up report from the same group, an 
additional 10 HIV+ to HIV+ renal transplants were performed (Muller, 
2012). All patients were restarted on ART early postoperatively in the 
immunosuppressive setting of T-cell-depleting induction therapy, 
tacrolimus, mycophenolate mofetil, and prednisone. One to four years 
post-transplantation, outcomes remained excellent and all patients had 
undetectable viral loads (Muller, 2012).
    This document presents criteria for conducting research in HIV+ to 
HIV+ SOT. 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

[[Page 34915]]

Outcome Measures. These research criteria do not describe all of the 
necessary components of a research protocol for HIV+ to HIV+ 
transplantation, such as the specific medication regimens, pre-
transplant induction (if any), maintenance immunosuppression after 
transplantation, or control of HIV infection. These considerations, 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+ to HIV+ 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+ to HIV+ 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- donors to HIV+ recipients. 
The intent is not to exclude the possibility of HIV+ to HIV+ 
transplantation of other organs such as heart or lung in the future; 
however, transplant teams should gain experience with HIV- to HIV+ 
transplantation of a specific organ before taking on the more complex 
and less well-defined issues of HIV+ to HIV+ transplantation of that 
organ. Centers developing research protocols for HIV+ to HIV+ non-
renal, non-liver transplantation must have a study team with 
demonstrated experience in HIV- to HIV+ 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 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+ to HIV+ non-renal, non-liver 
transplantation will need to 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 research. 
Accordingly, to emphasize the specific requirements unique to the 
transplantation of organs from HIV+ donors into HIV+ recipients in 
research, the research criteria set forth here do not address related 
requirements that may 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 can 
be found at http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf.
    Under these research criteria, all HIV+ to HIV+ 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+ to HIV+ transplantation under these 
research criteria must provide each living donor and recipient with an 
``Independent Advocate'' (as defined in CMS regulations at 42 CFR 
482.98(d)).

1 Donor Eligibility

    HIV+ living donors and HIV+ deceased donors of organs for 
transplantation into an HIV+ recipient must fulfill applicable clinical 
criteria in place for uninfected organ donors.
    There is substantial concern about the consequences of 
transplanting an organ from an HIV+ donor to a recipient infected with 
a strain of HIV that differs from the donor's in terms of its 
responsiveness to 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; there may be inadequate virus in donor 
specimens for antiretroviral resistance testing; if the specimen is 
adequate there may be a limited time, or decision-making window, to 
assess antiretroviral resistance before the organ must be implanted; 
the donor's history of antiretroviral treatment may be unknown; and 
results of any 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 matching donors and recipients infected with 
strains of HIV that have the same antiretroviral resistance pattern and 
whose infections are effectively controlled with comparable 
antiretroviral regimens will pose the lowest risk of harm to the 
recipient. However, such a stringent transplant eligibility criterion 
would limit the pool of suitable donors and constrain capacity to study 
transplantation of HIV+ organs under the HOPE Act. Transplant teams 
evaluating a donor should review all available donor and recipient 
information and be able to propose an antiretroviral regimen that will 
be equally or more effective, safe, and tolerable for the recipient 
after transplantation as the regimen in place before transplantation. 
If there is substantial doubt about the ability to suppress viral 
replication after transplantation, a different donor should be sought.
    Donors co-infected with hepatitis are not excluded from HIV+ to 
HIV+ 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 (Fofana, 2014; 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 and tenofovir) has the potential for 
revealing HBV drug resistance in the recipient (Dieterich, 2007; 
Soriano, 2009; Pais, 2010).
    In the case of a living HIV+ 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+ patients has been associated 
with variants in the apolipoprotein 1 (APOL1) coding variants that 
confer a very high risk of susceptibility, and are almost exclusively 
found in patients of African

[[Page 34916]]

descent (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 (Reeves-
Daniel, 2011).
    These criteria require that the consent process for an HIV+ 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 ART 
drugs in the future; (2) the risk of kidney or liver failure in the 
setting of HIV infection in the future; (3) the possibility of 
transmission of occult OIs to the recipient; and (4) the absence of 
U.S. experience in HIV+ to HIV+ organ transplantation, and thus the 
unpredictable nature of donor and recipient outcomes (Mgbako, 2013).
    HIV+ transplant candidates who are listed for a transplant in the 
context of a research study of HIV+ to HIV+ 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 Donor (HIV+) Eligibility Criteria
    The HIV-specific donor eligibility criteria specified below apply 
when screening HIV+ deceased and HIV+ living donors (also refer to 
Table 1). Co-infection with HBV and/or HCV is not an exclusion 
criterion, although researchers that include the co-infected donor must 
address any additional eligibility criterion within their research 
protocol.
1.1.1 Deceased Donors
    When evaluating HIV+ deceased donors, it is understood that limited 
medical history may be available and/or known at the time of the donor 
evaluation. The transplant team must make all reasonable efforts 
possible to obtain prior medical history to determine the suitability 
of the potential donor. 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 ART 
regimens. In addition, 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.
    Minimum eligibility criteria for all HIV+ deceased donors:
    i. Documented HIV infection using licensed test devices and with 
established confirmatory criteria.
    ii. No known history of a CD4+ T-cell count <200/[micro]L.
    Minimum eligibility criteria for deceased donors with a known 
history of HIV infection:
    i. Documented HIV infection using licensed test devices and with 
established confirmatory criteria.
    ii. Well-controlled HIV infection, as evidenced by:
    a. CD4+ T-cell count >=200/[micro]L or >=14 percent.
    b. Fewer than 50 copies/mL of HIV-1 RNA detectable by 
ultrasensitive or real-time polymerase chain reaction (PCR) assay.
    c. No known history of a viral load > 1000 copies/mL in the prior 
12 months.
    iii. The study team must be able to predict a tolerable regimen in 
the recipient based on the current regimen suppressing virus in the 
donor as well as the donor's history of ART resistance.
    iv. No evidence of active opportunistic complications of HIV 
infection.
    Minimum eligibility criteria for deceased donors newly diagnosed 
with HIV infection at the time of evaluation for organ donation:
    i. Documented HIV infection using licensed test devices and with 
established confirmatory criteria.
    ii. CD4+ T-cell count >=200/[micro]L or >=14 percent.
    iii. No evidence of active opportunistic complications of HIV 
infection.
1.1.2 Living Donors Infected With HIV
    Minimum eligibility criteria for living donors infected with HIV:
    i. Documented HIV infection using licensed test devices and with 
established confirmatory criteria.
    ii. Well-controlled HIV infection, as evidenced by:
    a. Lifetime nadir of >=200 CD4+ T cells/[micro]L.
    b. CD4+ T-cell count >=500/[micro]L for the 6-month period 
preceding donation.
    c. Fewer than 50 copies/mL of HIV-1 RNA detectable by 
ultrasensitive or real-time PCR assay.
    iii. A complete history of ART regimens and ART resistance.
    iv. The study team must be able to predict a tolerable regimen in 
the recipient based on the current regimen suppressing virus in the 
donor as well as the donor's history of ART resistance.
    v. No evidence of active 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+ transplant 
candidates is the ability to suppress HIV viral load post-transplant. 
This includes a thorough assessment by the transplant team of the 
patient's prescribed antiretroviral medications, HIV RNA levels while 
on medications, adherence to HIV treatment, and any available HIV 
resistance testing. The transplant team must be able to devise a post-
transplant medication regimen that is both tolerable and effective in 
suppressing HIV. If there is any significant doubt on the part of the 
transplant team about the ability to suppress viral replication post-
transplant, the patient should not be enrolled in a study of HIV+ to 
HIV+ organ transplantation.
2.1 Recipient Eligibility Criteria
    The following HIV-specific criteria must be met when screening for 
a HIV+ to HIV+ 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+ T-cell count >=200/[micro]L.
    ii. HIV RNA less than 50 copies/mL and on a stable antiretroviral 
regimen.*
    iii. No active OI or neoplasm.
    iv. No history of chronic cryptosporidiosis, 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 an 
effective antiretroviral regimen for the patient once organ function is 
restored after transplantation.

[[Page 34917]]



 Table 1--Summary of Donor (D) and Recipient (R) Eligibility Criteria for HIV+ Sero-Concordant Organ Transplant
                                         Pairs (D/R) Under the HOPE Act
----------------------------------------------------------------------------------------------------------------
                                              Deceased donor
                                 ----------------------------------------
      HIV-related variables        New HIV infection    History of HIV       Living donor       HIV+ recipient
                                       diagnosis           infection
----------------------------------------------------------------------------------------------------------------
Current CD4+ T-cell count (T      >=200 or >=14%....  >=200 or >=14%....  >=500 for six       If history of OI,
 lymphocytes/[micro]L).                                                    months prior to     >=200.
                                                                           organ harvest.     If no history of
                                                                                               OI,
                                                                                               >=200
                                                                                               (kidney).
                                                                                               >=100
                                                                                               (liver).
                                                                                              CD4+ T-cell count
                                                                                               measured within
                                                                                               16 weeks of
                                                                                               transplantation.
Plasma HIV RNA viral load         No requirement....  <50 AND No          <50...............  <50 *
 (copies/mL).                                          measurement >1000
                                                       over preceding 12
                                                       months.
Opportunistic infection.........  No active OI......  No active OI......  Currently,........
                                                                           No active
                                                                           OI..
                                                                          Historically, no,.
                                                                           Chronic
                                                                           cryptosporidiosis
                                                                           ..
                                                                           CNS
                                                                           lymphoma..
                                                                           PML......
----------------------------------------------------------------------------------------------------------------
* 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 an
  effective antiretroviral regimen for the patient once organ function is restored after transplantation.

3 Transplant Hospital Criteria

    Expertise in the management of individuals with HIV infection is 
essential for this research. A transplant hospital participating in 
HIV+ to HIV+ 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+ to HIV+ 
transplantation, there must be a study team consisting of (at a 
minimum) a transplant surgeon, a transplant physician, and an HIV 
physician, each of whom have experience with at least 5 HIV- to HIV+ 
transplants with the designated organ(s) over the last four years. This 
constitutes the minimal experience necessary, and the IRB should 
evaluate key personnel (transplant surgeon, transplant physician, and 
HIV physician) in the context of total expertise and experience with 
respect to HIV and/or organ transplantation.
    iii. Defined SOPs and training for the procurement team and 
implanting team 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+ to HIV+ transplantation must report to the OPTN organ-specific 
acceptance criteria for organs from HIV+ donors.
    v. Transplant hospitals with an IRB-approved research protocol in 
HIV+ to HIV+ transplantation with HIV+ candidates on the wait list 
willing to accept an HIV+ organ should specify any additional 
acceptance criteria to the OPO.
    vi. The transplant hospital must verify the accuracy of the donor 
and recipient HIV status.
    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+ to HIV+ 
transplantation under these research criteria must provide each living 
donor and recipient with an ``Independent Advocate'' (as defined in CMS 
regulations at 42 CFR 482.98(d).
    In the setting of living donor transplantation, the recipient and 
the living donor must each have his or her own advocate. Each advocate 
must be independent of the research team and must have knowledge and 
experience with both HIV infection and organ transplantation. In 
addition, in the setting of a living donor transplant, there must be 
two independent advocates, one for the donor and another for the 
recipient.
    At a minimum, transplant hospitals conducting research in HIV+ to 
HIV+ 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+ 
recipient's decision, and HIV+ living donor's decision (if applicable) 
about whether to enter the HIV+ to HIV+ transplant research study.
3.2.1 Independent HIV+ Recipient Advocate
    Transplant programs performing HIV+ recipient transplantations must 
designate and provide each HIV+ recipient and prospective HIV+ 
recipient with an independent advocate who is responsible for 
protecting and promoting the rights and interests of the HIV+ recipient 
(or prospective recipient). The independent advocate for the HIV+ 
recipient must:
    i. Promote and protect the interests of the HIV+ recipient 
(including with respect to having access to a suitable HIV- organ if it 
becomes available); and take steps to ensure that the HIV+ recipient's 
decision is informed and free from external pressure.

[[Page 34918]]

    ii. Review whether the potential HIV+ recipient has received 
information regarding the results of SOT in general and transplantation 
in HIV-infected recipients in particular; and the unquantifiable risks 
of transmission of HIV, OIs, ART resistance, and accelerated kidney, 
liver, and cardiovascular disease in HIV+ recipients of HIV+ donor 
organs.
    iii. Demonstrate knowledge of HIV infection and transplantation.
3.2.2 Independent HIV+ Living Donor Advocate
    Transplant programs performing HIV+ donor transplantations must 
designate and provide each living HIV+ donor and living prospective 
HIV+ donor with an independent advocate who is responsible for 
promoting and protecting the rights and interests of the HIV+ donor (or 
prospective donor). More specifically, the independent advocate for the 
HIV+ living donor must:
    i. Promote and protect the interests of the HIV+ donor (including 
with respect to having ample opportunity to withdraw consent from 
donation); and take steps to ensure that the HIV+ donor's decision is 
informed and free from external pressure.
    ii. Review whether the potential HIV+ 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+ 
donor, including accelerated organ failure, and limitations of future 
use of specific antiretroviral agents; and (b) the unknown outcome of 
HIV+ to HIV+ organ transplantation.
    iii. Demonstrate knowledge of HIV infection and transplantation.

4 OPO Responsibilities

    Clinical research in HIV+ to HIV+ organ transplantation requires a 
partnership between OPOs and transplant programs. OPOs participating in 
research of HIV+ to HIV+ organ transplantation must adhere to the 
following criteria:
    i. Develop SOPs and staff training procedures to effectively work 
with the family and friends of HIV+ subjects in history taking, medical 
record abstraction, HIV clinic and pharmacy medical record telephone 
abstraction, obtaining research consent from next of kin to HIV+ 
subjects, performing physical examination of HIV+ subjects, collecting 
blood, tissue, and other biospecimens (e.g., urine, bronchoalveolar 
lavage, spleen, lymph nodes, and biopsy material), handling, 
processing, storing, and shipping.
    ii. Conduct training in obtaining relevant and pertinent HIV+ 
history, duration of HIV infection, opportunistic infections 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.
    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 
policies 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 or exposure of an HIV- recipient to organs or 
tissues from an HIV+ donor due to identification error is paramount 
(Ison, 2011). 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 develop an institutional biohazard 
plan for handling of HIV+ organs (e.g., 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.
    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+ to HIV+ 
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+ 
recipients; quality of life for recipients of HIV+ to HIV+ 
transplantation; outcomes of living HIV+ donors; and a host of others. 
The questions will be determined by the investigators who design 
research protocols for studying HIV+ to HIV+ transplantation. However, 
to ensure that all studies of HIV+ to HIV+ 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+ to HIV+ 
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+ new diagnosis, HIV+ known diagnosis)
     CD4+ T-cell count
     Co-infection (HCV, HBV)
     HIV viral load
     ART resistance
6.3 Living Donors (12 months following organ donation)
     Progression to renal insufficiency in kidney donors (serum 
creatinine > 2 mg/dL, serum creatinine level twice the pre-donation 
creatinine level, or proteinuria).

[[Page 34919]]

     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 (Years 1 and 2)
     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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    Dated: June 12, 2015
Francis S. Collins,
Director, National Institutes of Health.
[FR Doc. 2015-15034 Filed 6-17-15; 8:45 am]
BILLING CODE 4140-01-P