[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.
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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.
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Category Criteria
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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.
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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
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------------------------------------------------------------------------
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