Final Human Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act Safeguards and Research Criteria for Transplantation of Organs Infected With HIV, 73785-73796 [2015-30172]

Download as PDF Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Final Human Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act Safeguards and Research Criteria for Transplantation of Organs Infected With HIV AGENCY: National Institutes of Health, HHS. ACTION: Notice. The U.S. Department of Health and Human Services (HHS), through the National Institutes of Health (NIH), announces the publication of Final Safeguards and Research Criteria for transplantation of HIV-positive donor organs in HIV-positive recipients. All such transplants must occur under an institutional review board (IRB)approved research protocol that is compliant with federal regulations governing human subjects’ research. The goal of this research is to increase knowledge about the safety, efficacy, and effectiveness of solid organ transplantation (SOT) utilizing HIVpositive donors in HIV-positive recipients. A summary of public comments on the previously published Draft Safeguards and Research Criteria and HHS’ responses follow, as well as the Final Safeguards and Research Criteria. FOR FURTHER INFORMATION CONTACT: Dr. Jonah Odim, phone 240–627–3540, Email: HOPEAct@mail.nih.gov, Fax: 301–451–5671, 5601 Fishers Lane, Room 6B21, MSC 9827, Bethesda, MD 20892–9827. SUPPLEMENTARY INFORMATION: HHS initially published the Draft Human Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act Safeguards and Research Criteria for Transplantation of Organs Infected with HIV, subsequently referred to as the ‘‘Draft Safeguards and Research Criteria,’’ in the Federal Register on June 18, 2015, for a 60-day public comment period ending August 17, 2015. In the months leading up to the draft publication, HHS presented the research criteria at national meetings of transplantation and HIV medicine professionals and received their input. Several teleconferences were hosted with transplantation community stakeholders from the private, nonprofit, and government sectors. HHS received comments from a total of 13 individuals/entities on the Draft Safeguards and Research Criteria. Comments were submitted by transplant centers, Organ Procurement tkelley on DSK3SPTVN1PROD with NOTICES SUMMARY: VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 Organizations (OPOs), the Organ Procurement and Transplantation Network (OPTN), United Network of Organ Sharing (UNOS), HIV and transplantation professional societies, and a municipal agency. Overall, these comments were supportive of the HOPE Act and the Draft Safeguards and Research Criteria. Many commenters made useful suggestions that provided clarity and were incorporated into the Final Safeguards and Research Criteria. While the comments will not be addressed individually in this response document, questions, comments, and suggestions about specific aspects of the Draft Safeguards and Research Criteria are addressed by topic below. HOPE Act: Scope The HOPE Act permits HIV-positive to HIV-positive organ transplantation under IRB-approved research protocols conforming to the Final Human Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act Safeguards and Research Criteria for Transplantation of Organs Infected with HIV, which were developed as directed in the HOPE Act. Patients receiving HIV-positive kidneys from deceased HIV-positive donors in South Africa (Muller, 2015) had survival rates of 84 percent and 74 percent at 1 and 5 years, respectively; however, there is presently no evidence for the safety, efficacy, and effectiveness of HIV-positive to HIVpositive transplantation in North America. The Final Safeguards and Research Criteria are meant to support the acquisition of new clinical knowledge and mechanistic insights about HIV-positive to HIV-positive organ transplantation in the United States. The results of this research will be evaluated by the Secretary of HHS and the OPTN to determine whether and how the OPTN standards for organ transplantation shall be revised to address HIV-positive organ donors. One commenter raised concerns about the negative impact of adverse outcomes at transplant centers conducting research in HIV-positive to HIV-positive transplants on transplant programspecific reports. This commenter proposed ‘‘that transplants performed with HIV-positive donor to HIV-positive recipients are not included in the center specific reports. The risk of transplanting these patients is unknown, and there is no risk adjustment for it on the center specific reports. There will potentially be a strong disincentive for centers to do these patients leading to fewer patients receiving life-saving organ transplants.’’ Clearly this is an important issue but one that is beyond the authorities PO 00000 Frm 00088 Fmt 4703 Sfmt 4703 73785 delegated to the NIH to enable implementation of the HOPE Act (i.e., to develop safeguards and research criteria). Living Donors Several commenters stated that HIVinfected living donors may be at longterm risk for renal and/or liver disease and therefore their centers would not use HIV-infected living donors. Another commenter felt it was premature to embark on living HIV-positive donors without prior experience with deceased HIV-positive donors and recommended a staged approach. The Hope Act (2013) does not include any language addressing the use of living HIVinfected donors. The long-term risks of living organ donation to the donor might be greater for those infected with HIV than for those who are not. At the same time, the desire to donate an organ, (e.g., to save or prolong a life) is strong, and evaluation of the risks and benefits of such a decision is personal and unique to a given donor/recipient pair. Evidence for the safety of organ donation by an HIV-infected individual will only be generated by clinical research. HHS has included living donors in these Safeguards and Research Criteria so that, if investigators choose to pursue this line of research, that research can be conducted with appropriate informed consent, safeguards, and rigor. The decision to participate in HIVpositive to HIV-positive clinical research is made freely, based on informed consent in the absence of coercion. The health care team must provide a rigorous, transparent education and informed consent process that describes alternatives, risks, potential benefits, unknowns, and the need for long-term follow-up. These discussions must address how researchrelated injuries are managed and paid for, and must specifically include the present uncertainties about the outcomes for both HIV-positive living donors and the recipients of HIVpositive organs. Participation of knowledgeable, independent advocates for both the HIV-positive recipient and the HIV-positive donor is required by these Safeguards and Research Criteria. Independent Advocates Some commenters strongly supported the requirement for independent advocates for both HIV-positive recipients and prospective HIV-positive living donors. Others viewed this as unnecessary given the expertise of the principal investigator and study team and current OPTN standards. With E:\FR\FM\25NON1.SGM 25NON1 73786 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices respect to informed consent, the role of the independent advocate complements that of the investigator and does not replace it. The investigator is assumed to have the expertise necessary to discuss risks, benefits, expectations, and alternatives. The advocate is an additional knowledgeable person who is neither a member of the research team nor the patient’s health care provider, whose role is to provide information, answer questions, and provide assurance of equal access to health care regardless of the patient’s decisions regarding research participation. For example, the advocate can assure that the transplant candidate is aware that he or she has the right to be offered and to accept an HIV-negative deceased donor organ should one become available, and can assure the prospective living donor of confidentiality and support should he or she determine that donation is not in his or her own best interest. Transplant Hospital Experience Several commenters from academic institutions, professional societies, and the OPTN indicated that the requirements for physicians’ and surgeons’ prior experience in HIVnegative to HIV-positive organ transplant were excessive and would result in few centers being able to participate in the research allowed under the HOPE Act. In response to the wide consensus on this issue, we have accepted the specific suggestion of the American Society of Transplant Surgeons (ASTS). Section 3 of the Final Safeguards and Research Criteria describe collective team experience, rather than individual experience. Immunologic Criteria (CD4+ T-Cell Counts, HIV Viral Load) Several commenters expressed concerns about the usefulness and relevance of requiring a minimum CD4+ T-cell count/percentage in the donor. They argued that the CD4+ T lymphocyte count will not predict allograft function, and that, among HIV- positive to HIV-positive transplants in South Africa, excellent outcomes were observed in recipients of kidneys from donors with CD4+ T-cell counts well below 200. These commenters urged flexibility and the elimination of this minimum immunologic criterion. In response to these comments, Section 1 of the Final Safeguards and Research Criteria was revised to indicate that, although collection of CD4+ T cell counts and percentages during the donor evaluation is required, no minimum criterion is imposed for organ acceptance. Some commenters preferred excluding any donors with detectable plasma viral load due to the risk of transmitted drug resistance. Unfortunately, it will not be possible in all cases to mitigate the risk of transmitting viral resistance by setting viral load limits and/or assessing antiretroviral resistance profiles in the time available for donor evaluation. It is expected that in many cases, potential donors will have adequate medical history available to inform the transplantation team’s assessment and maximally reduce the risk of transmitting resistant virus. For these reasons, the Final Safeguards and Research Criteria do not stipulate a limit on the allowable viral load in a donor. The transplant team should only transplant the organ if the team is confident they can define a posttransplant antiretroviral regimen that will be safe, tolerable, and effective. Concerns about transmitted drug resistance must be included in the recipient informed consent process for the research study. In addition, at the time of an organ offer, the recipient informed consent must address the transplant team’s assessment of risk specific to the characteristics of the offered organ. Biospecimens Several commenters emphasized the importance of a pre-transplant donor organ biopsy. The final updated research criteria include a requirement for performance of a pre-implantation ‘‘back-table’’ biopsy for posttransplantation patient management and future scientific and mechanistic studies. Although there are no further specimen requirements, we strongly encourage the inclusion of serial biospecimens (e.g., allograft tissue, urine, serum, and cells) in the individual research protocols. These specimens will be a valuable resource to the community in studies relating to superinfection risks, for example. Failure to collect such specimens, particularly in organ donors, would be a regrettable lost opportunity. Required Outcomes Several commenters expressed concerns about data collection, quality, and reporting. The HOPE Act requires the Secretary of HHS to review the results of research conducted under the Act. One purpose of the criteria presented in the Final Safeguards and Research Criteria is to ensure that all investigators conducting research in HIV-positive to HIV-positive transplantation collect similar data elements. This standardization will facilitate the subsequent review mandated in the HOPE Act. Conclusion Regarding Comments Received HHS appreciates the time and effort taken by commenters to respond to the Request for Comments. The comments represented the deliberative efforts of truly dedicated individuals and organizations in transplantation and HIV medicine. All the responses were helpful in revising the draft Human Immunodeficiency Virus (HIV) Organ Policy Equity (HOPE) Act Safeguards and Research Criteria for Transplantation of Organs Infected with HIV. The Final Safeguards and Research Criteria for transplantation of HIVpositive (HIV+) donor organs in HIVpositive (HIV+) recipients are as follows: tkelley on DSK3SPTVN1PROD with NOTICES ABBREVIATIONS AIDS ................................................ APOL1 ............................................. ART ................................................. CD4 ................................................. CMS ................................................ CNS ................................................. dL .................................................... FDA ................................................. FIPSE .............................................. GESIDA ........................................... HAART ............................................ HBV ................................................. HCT/Ps ............................................ HCV ................................................. VerDate Sep<11>2014 19:15 Nov 24, 2015 Acquired Immunodeficiency Syndrome. Apolipoprotein 1. Antiretroviral Therapy. Cluster of Differentiation 4. Centers for Medicare & Medicaid Services. Central Nervous System. Deciliter. U.S. Food and Drug Administration. Spanish Foundation for AIDS Research. Spanish AIDS Study Group. Highly Active Antiretroviral Therapy. Hepatitis B Virus. Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). Hepatitis C Virus. Jkt 238001 PO 00000 Frm 00089 Fmt 4703 Sfmt 4703 E:\FR\FM\25NON1.SGM 25NON1 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices 73787 ABBREVIATIONS—Continued HIV .................................................. HOPE Act ........................................ INR .................................................. IRB .................................................. mL ................................................... NIH .................................................. NNRTI ............................................. NRTI ................................................ OI .................................................... OPO ................................................ OPTN .............................................. PCR ................................................. PML ................................................. RNA ................................................. SOPs ............................................... SOT ................................................. SRTR .............................................. UNOS .............................................. μL .................................................... Human Immunodeficiency Virus. HIV Organ Policy Equity Act. International Normalized Ratio. Institutional Review Board. Milliliter. National Institutes of Health. Non-Nucleoside (or Non-Nucleotide) Reverse Transcriptase Inhibitor. Nucleoside (or Nucleotide) Reverse Transcriptase Inhibitor. Opportunistic Infection. Organ Procurement Organization. Organ Procurement and Transplantation Network. Polymerase Chain Reaction. Progressive Multifocal Leukoencephalopathy. Ribonucleic Acid. Standard Operating Procedures. Solid Organ Transplantation. Scientific Registry of Transplant Recipients. United Network for Organ Sharing. Microliter. DEFINITIONS ABO compatible .............................. Antiretroviral therapy (ART) resistance. Types/classes of HIV/AIDS antiretroviral drugs (current at publication). HIV strain ........................................ HIV-negative ................................... HIV-positive ..................................... HIV undetectable viral load ............. Opportunistic infection .................... Suppressed viral load ..................... Viral detection threshold ................. People who have one blood type (A, B, AB, or O) form proteins (antibodies) that cause their immune system to react against other blood types. This is important when a patient needs to receive blood (transfusion) or have an organ transplant. The blood types must be matched to avoid an ABO incompatibility reaction. ABO compatible is when the blood types are matched. When an HIV strain develops drug resistance and/or genetic mutations associated with drug resistance. (1) Entry inhibitors. (2) Fusion inhibitors. (3) Nucleoside reverse transcriptase inhibitors (NRTIs). (4) Non-nucleoside reverse transcriptase inhibitors (NNRTIs). (5) Integrase inhibitors. (6) Protease inhibitors. (7) Multi-class combination products. Distinct genetic variants of the HIV retrovirus, conferring characteristics such as susceptibility or resistance to ART medications. Not testing positive for HIV by serology and/or nucleic acid testing using FDA-licensed, approved or cleared test devices. HIV-infected by serology and/or nucleic acid testing using FDA-licensed, approved, or cleared test devices. (The conventional definition at the time of the publication of this research criteria document, based on current clinical technology/practice): HIV ribonucleic acid (RNA) below 50 copies with current technology. Infections that are more frequent or more severe because of immunosuppression in HIV-infected persons (Kaplan, 1995a, 1995b; Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents, 2015). HIV RNA below 50 copies with current technology at time of publication of this research criteria document. HIV RNA below 50 copies with current technology at time of publication of this research criteria document. Executive Summary The HOPE Act requires the HHS Secretary (the Secretary) to develop and publish criteria for research involving transplantation of human immunodeficiency virus-infected donor organs in HIV-positive recipients. A summary of the criteria for conducting clinical research in HIV-positive to HIVpositive organ transplantation is included in the chart below, and the criteria are set forth in six broad categories (Donor Eligibility, Recipient Eligibility, Transplant Hospital Criteria, Organ Procurement Organization (OPO) Responsibilities, Prevention of Inadvertent Transmission of HIV, and Study Design/Required Outcome Measures). These criteria are in addition to current policies and regulations governing organ transplantation and tkelley on DSK3SPTVN1PROD with NOTICES Category human subjects’ research. The goals of these criteria are, first, to ensure that research using organs from HIV-positive donors is conducted under conditions protecting the safety of research participants and the general public; and second, to ensure that the results of this research provide a basis for evaluating the safety of solid organ transplantation (SOT) from HIV-positive donors to HIVpositive recipients. Criteria Donor Eligibility: All HIV-positive deceased donors. No evidence of invasive opportunistic complications of HIV infection. Pre-implant donor organ biopsy. Viral load: no requirement. VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 PO 00000 Frm 00090 Fmt 4703 Sfmt 4703 E:\FR\FM\25NON1.SGM 25NON1 73788 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices Category Criteria Deceased donor with known history of HIV infection and prior antiretroviral therapy (ART). HIV-positive living donor .......... Recipient Eligibility .......................... Transplant Hospital Criteria ............ OPO Responsibilities ...................... Prevention of Inadvertent Transmission of HIV. Required Outcome Measures: Wait List Candidates ................ Donors (all) .............................. Living Donors ........................... tkelley on DSK3SPTVN1PROD with NOTICES Transplant Recipients .............. The study team must describe the anticipated post-transplant antiretroviral regimen(s) to be prescribed for the recipient and justify its conclusion that the regimen will be safe, tolerable, and effective. Well-controlled HIV infection defined as: • CD4+ T-cell count ≥500/μL for the 6-month period before donation. • HIV–1 RNA <50 copies/mL. • No evidence of invasive opportunistic complications of HIV infection. Pre-implant donor organ biopsy. CD4+ T-cell count ≥200/μL (kidney). CD4+ T-cell count ≥100 μL (liver) within 16 weeks prior to transplant and no history of opportunistic infection (OI); or ≥200 μL if history of OI is present. HIV–1 RNA <50 copies/mL and on a stable antiretroviral regimen. No evidence of active opportunistic complications of HIV infection. No history of primary central nervous system (CNS) lymphoma or progressive multifocal leukoencephalopathy (PML). Transplant hospital with established program for care of HIV-positive subjects. HIV program expertise on the transplant team. Experience with HIV-negative to HIV-positive organ transplantation. Standard operating procedures (SOPs) and training for the organ procurement, implanting/operative, and postoperative care teams for handling HIV-infected subjects, organs, and tissues. Institutional review board (IRB)-approved research protocol in HIV-positive to HIV-positive transplantation. Institutional biohazard plan outlining measures to prevent and manage inadvertent exposure to and/or transmission of HIV. Provide each living HIV-positive donor and HIV-positive recipient with an ‘‘independent advocate’’. Policies and SOPs governing the necessary knowledge, experience, skills, and training for independent advocates. SOPs and staff training procedures for working with deceased HIV-positive donors and their families in pertinent history taking; medical chart abstraction; the consent process; and handling blood, tissues, organs, and biospecimens. Biohazard plan to prevent and manage HIV exposure and/or transmission. Each participating Transplant Program and OPO shall develop an institutional biohazard plan for handling organs from HIV-positive donors that is designed to prevent and/or manage inadvertent transmission or exposure to HIV. Procedures must be in place to ensure that human cells, tissues, and cellular and tissue-based products (HCT/Ps) are not recovered from HIV-positive donors for implantation, transplantation, infusion, or transfer into a human recipient; however, HCT/Ps from a donor determined to be ineligible may be made available for nonclinical purposes. 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. Type (Living or deceased). HIV status (HIV-infected [HIV-positive] new diagnosis, HIV-positive known diagnosis). CD4+ T-cell count. Co-infection (HCV, HBV). HIV viral load. ART resistance. Progression to renal insufficiency in kidney donors. Progression to hepatic insufficiency in liver donors. Change in ART regimen as a result of organ dysfunction. Progression to acquired immunodeficiency syndrome (AIDS). Failure to suppress viral replication (persistent HIV viremia). Death. Rejection rate (annual up to 5 years). Progression to AIDS. New OI. Failure to suppress viral replication (persistent HIV viremia). HIV-associated organ failure. Malignancy. Graft failure. Mismatched ART resistance versus donor. Death. The HOPE Act research criteria focus on liver and kidney transplantation, where there is substantial experience VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 with HIV-negative to HIV-positive transplantation. The intent is not to exclude the possibility of HIV-positive PO 00000 Frm 00091 Fmt 4703 Sfmt 4703 to HIV-positive transplantation of other organs; however, transplant organspecific teams must gain experience E:\FR\FM\25NON1.SGM 25NON1 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices tkelley on DSK3SPTVN1PROD with NOTICES with HIV-negative to HIV-positive transplantation before embarking on the more complex and less well-defined issues with HIV-positive to HIV-positive transplantation. The minimum combined experience required of the transplant physician and HIV physician on the team is five organ-specific cases over 4 years. The HOPE Act requires the Secretary and the Organ Procurement and Transplantation Network (OPTN) to review the results of the scientific research conducted under these criteria to determine whether the results warrant further revisions to the OPTN’s standards of quality. Under the HOPE Act, the Secretary may in the future determine that participation in research under such criteria is no longer required for HIV-positive to HIV-positive transplants. Background Public Law 113–51, The HOPE Act, requires the HHS Secretary (the Secretary) to, among other things, ‘‘develop and publish criteria for conduct of research relating to transplantation of organs from donors infected with human immunodeficiency virus (HIV) into individuals who are infected with HIV before receiving such organs.’’ (See Public Health Service Act section 377E(a) [codified at 42 U.S.C. 274f–5]). In addition, pursuant to section 377E(c) of the HOPE Act, the Secretary is required, in conjunction with the OPTN, to review the results of that research to determine whether revisions should be made to the standards of quality adopted under section 372(b)(2)(E) of the Public Health Service Act (OPTN standards for the acquisition and transportation of donated organs) and the regulations governing the operation of the OPTN (42 CFR 121.6). The authority vested in the Secretary under section 377E(a) to develop and publish research criteria was delegated to the Director, National Institutes of Health (NIH), and these research criteria are the subject of this document. They are meant to ensure first, that research using organs from HIV-positive donors is conducted under conditions protecting the safety of research participants and the general public; and second, that the results of this research provide a basis for evaluating the safety of transplantation of organs from HIVpositive donors to HIV-positive recipients. Process This document was authored by representatives of the NIH and Centers for Disease Control and Prevention. VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 Additional input from representatives of other federal agencies, including the Health Resources and Services Administration, Centers for Medicare & Medicaid Services (CMS), and the Food and Drug Administration (FDA), was solicited. In addition, perspectives and input were solicited from community stakeholders. Introduction The advent of effective antiretroviral therapy (ART) in the mid-1990s for treatment of individuals infected with HIV transformed a rapidly fatal disease into a well-controlled chronic illness. Currently, the life expectancy of individuals infected with HIV and receiving ART early in the course of their disease approaches that of individuals without HIV infection (Wada, 2013, 2014). In this era of greater longevity, liver failure, end-stage renal disease, and cardiovascular disease have emerged as important causes of morbidity and mortality in patients with HIV infection (Neuhaus, 2010). Organ transplantation prolongs survival and improves quality of life for individuals with end-stage organ disease (Matas, 2014; Kim, 2014). Until recently, however, organ transplantation was unavailable to those infected with HIV due to concerns that pharmacologic immunosuppression to prevent organ rejection would hasten the progression from HIV infection to AIDS, concerns about disease transmission, and reluctance to allocate organs to a population whose outcome was unpredictable (Blumberg, 2009, 2013a, 2013b; Mgbako, 2013; Taege, 2013). Nevertheless, a few transplant programs accepted HIV-positive patients on their transplant waiting lists and accumulated data showing kidney or liver transplantation could be done safely in these patients (Roland, 2002, 2003a, 2003b, 2003c; Blumberg, 2009; Stock, 2010; Yoon, 2011; Terrault, 2012). Subsequently, a prospective, multicenter clinical trial of kidney and liver transplantation in 275 patients demonstrated that, among HIV-positive kidney and liver transplant recipients, patient and graft survival rates were acceptable and within the range of outcomes currently achieved among non-infected transplant recipients. However, the rate of kidney rejection was unexpectedly high, demonstrating that the immune dysregulation resulting from HIV infection, HCV co-infection, and antirejection drugs is complex and incompletely understood. Some of the challenges encountered in that study remain relevant for clinical sites offering organ transplantation to HIV-positive individuals today (e.g., management of PO 00000 Frm 00092 Fmt 4703 Sfmt 4703 73789 drug interactions and toxicities when combining complex medical regimens, management of combined morbidities of two or more active diseases, and the need for ongoing collaboration among medical professionals from different specialties) (Frassetto, 2007, 2014; Locke, 2014). Despite the complexities, this study and others (Ragni, 1999; Frassetto, 2009; Huprikar, 2009; Stock, 2010; Touzot, 2010; Cooper, 2011; Duclos-Vallee, 2011; Reeves-Daniel, 2011; Fox, 2012; Terrault, 2012; Grossi, 2012; Gomez, 2013; Harbell, 2013) demonstrate that kidney and liver transplantation are appropriate in HIVpositive individuals with liver or kidney failure, although gaps in knowledge and many research questions remain. There is much less experience with heart (Calabrese, 2003; Bisleri, 2003; Pelletier, 2004; Uriel, 2009, 2014; Castel, 2011a, 2011b; Durante-Mangoni, 2011 and 2014) and lung (Mehta, 2000; Humbert, 2006; Petrosillo, 2006; Bertani, 2009; Kern, 2014a, 2014b) transplantation in HIV-positive recipients, or mechanical circulatory assistance (Brucato, 2004; Fieno, 2009; Mehmood, 2009; Sims, 2011) as a bridge to transplantation, although case reports and small case series suggest acceptable short-term outcomes are possible. Prior to the passage of the HOPE Act, U.S. law required that all U.S. transplants for HIV-positive recipients utilize organs from HIV-uninfected donors. (See 42 U.S.C. 273(b)(3)(C), 274(b) and 18 U.S.C. 1122, all prior to amendment by the HOPE Act). The potential for increasing the pool of available organ donors for all recipients by allowing the use of organs from donors infected with HIV for transplantation into recipients infected with HIV (hereinafter referred to as ‘‘HIV-positive to HIV-positive transplantation’’) is recognized (Boyarsky, 2011, 2015; Mgbako, 2013; Mascolini, 2014; Kucirka, 2015; Richterman, 2015). It is estimated that an additional 500 organ donors per year might be available if HIV-positive individuals were accepted as organ donors for HIV-positive recipients (Boyarsky, 2011). The published experience with HIV-positive to HIVpositive SOT at this time comes from Muller et al from the University of Cape Town in South Africa. Initially, Muller et al (2010) reported 100 percent patient and graft survival in a four-patient pilot study. Subsequently, the same group reported an additional 10 HIV-positive to HIV-positive renal transplants (Muller, 2012). All patients were restarted on ART early postoperatively in the immunosuppressive setting of T- E:\FR\FM\25NON1.SGM 25NON1 tkelley on DSK3SPTVN1PROD with NOTICES 73790 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices cell-depleting induction therapy, tacrolimus, mycophenolate mofetil, and prednisone. One to 4 years after transplantation, outcomes remained excellent and all patients had undetectable viral loads (Muller, 2012). The cumulative University of Cape Town experience of 27 HIV-positive to HIV-positive transplant procedures was recently summarized in the New England Journal of Medicine (Muller, 2015). The 1- and 5-year death-censored graft survival was 93 and 84 percent, respectively, and 1- and 5-year patient survival was 83 and 74 percent, respectively. Of note, the South African HIV-positive deceased donors were ¨ ART-naıve, without history of opportunistic infection or proteinuria, and had normal pre-transplant renal biopsies. While renal function has remained normal in the recipients, three have had routine post-transplant renal biopsies demonstrating new changes typical of early HIV-associated nephropathy that were not present in baseline biopsy specimens. The longterm significance of these findings remains unknown and awaits longer follow-up. All patients had undetectable plasma HIV viral loads after transplantation. Graft rejection rates were 8 percent at 1 year and 22 percent at 3 years. This document presents criteria for conducting research in HIV-positive to HIV-positive organ transplantation in the United States. The criteria are grouped into six broad categories: Donor Eligibility, Recipient Eligibility, Transplant Hospital Criteria, OPO Responsibilities, Prevention of Inadvertent Transmission of HIV, and Study Design/Required Outcome Measures. These research criteria do not describe all of the necessary components of a research protocol for HIV-positive to HIV-positive transplantation, such as the specific medication regimens, pre-transplant induction (if any), maintenance immunosuppression after transplantation, or control of HIV infection. These protocol elements and others will be determined by an investigator’s specific research questions and the expertise of those conducting the research. Rather, the criteria address the minimum safety and data requirements of clinical research in HIV-positive to HIV-positive transplantation. As mandated by the HOPE Act, the Secretary, together with the OPTN, is charged with reviewing the results of scientific research conducted under these criteria to determine whether the OPTN’s standards of quality should be further VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 modified and whether some HIVpositive to HIV-positive transplants should proceed outside the auspices of research conducted under such criteria. This document focuses on liver and kidney transplantation, as it is only in liver and kidney transplantation that there is substantial experience with transplantation from HIV-negative donors to HIV-positive recipients (Sawinski, 2015; Locke, 2015a, 2015b; Miro, 2015). The intent is not to exclude the possibility of HIV-positive to HIVpositive transplantation of other organs such as the heart or lung in the future; however, transplant teams must gain experience with HIV-negative to HIVpositive transplantation of a specific organ before taking on the more complex and less well-defined issues of HIV-positive to HIV-positive transplantation of that organ. Centers developing research protocols for HIVpositive to HIV-positive transplantation of organs other than kidney or liver must have a study team with demonstrated experience in HIVnegative to HIV-positive transplants, as noted in Section 3.1(ii), for the organ transplant(s) proposed in the research protocol. Specific criteria for the transplantation of organs other than the liver and kidney have not been provided in this document because no evidence base exists to support such recommendations. The study team developing a research protocol for HIVpositive to HIV-positive non-renal, nonliver transplantation must develop and justify specific criteria for review and approval by their IRB, based on the relevant experiences of the study team and others. These criteria are in addition to, not in place of, current policies and regulations governing organ transplantation and human subjects’ research. Accordingly, to emphasize the specific requirements unique to the investigational transplantation of organs from HIV-positive donors into HIVpositive recipients, the research criteria set forth here do not address related requirements that exist in federal regulations or OPTN bylaws or policies including, but not limited to, obligations imposed on OPTN transplant hospitals and transplant programs concerning informed consent of transplant recipients and living donors, the equitable allocation of organs, and organ offers. The regulations governing the operation of OPTN are codified at 42 CFR part 121 and OPTN policies and bylaws can be found at https:// optn.transplant.hrsa.gov/ ContentDocuments/OPTN_Policies.pdf. Under these research criteria, all HIVpositive to HIV-positive transplantation PO 00000 Frm 00093 Fmt 4703 Sfmt 4703 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 HIVpositive to HIV-positive transplantation under these research criteria must provide each living donor and recipient with an independent advocate. Although the criteria set forth in this document outline the minimum safety requirements for research involving HIV-positive to HIV-positive transplantation, it is expected that investigators will develop more specific eligibility criteria based on their individual research questions and protocols. In addition, it is likely, that researchers will wish to collect research specimens (blood, urine, tissue) in addition to those specified in the Research Criteria. 1 Donor Eligibility HIV-positive living donors and HIVpositive deceased donors of organs for transplantation into an HIV-positive recipient must fulfill applicable clinical criteria in place for HIV-uninfected organ donors. There is substantial concern about the consequences of transplanting an organ from an HIV-positive donor to a recipient infected with a strain of HIV that differs from the donor’s in terms of its responsiveness to antiretroviral therapy (ART). The likelihood and impact of HIV superinfection in this context are unknown. Adverse consequences could range from transient loss of viral suppression, necessitating a change in antiretroviral regimen to a worst-case scenario in which the new infecting strain of HIV is unresponsive to available antiretroviral treatment and the recipient progresses to AIDS (Redd, 2013). Information relevant to understanding the known or potential extent of antiretroviral resistance in the strain of HIV infecting the organ donor may be incomplete for many reasons: • There may be inadequate virus in donor specimens for antiretroviral resistance testing; • If the specimen is adequate, there may not be enough time within the decision-making evaluation window to fully assess antiretroviral resistance before the clinical deterioration of the donor, organ procurement, and implantation; • The donor’s history of antiretroviral treatment may be unknown or incomplete; E:\FR\FM\25NON1.SGM 25NON1 tkelley on DSK3SPTVN1PROD with NOTICES Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices • Results from prior antiretroviral resistance testing may be unavailable. These issues might be especially challenging when considering organ donation from deceased donors whose HIV infection is first identified during donor evaluation. As of 2011, an estimated 1 in 6 U.S. adults living with HIV infection were undiagnosed (Prevention, 2013) and an estimated 16 percent of newly diagnosed, untreated individuals were infected with virus resistant to at least one class of antiretroviral drug (Kim, 2013; Megens, 2013). It is anticipated that the risk of transmission of resistant HIV strains may be lower from deceased donors with a well-documented history of antiretroviral treatment, undetectable virus at demise, and robust and persistent undetectable viral load for at least 1 year prior to death. However, to impose this as an eligibility criterion would limit the pool of suitable donors and severely limit the ability to study transplantation of HIV-positive organs under the HOPE Act. In addition, it will not be possible in all cases to obtain viral loads and/or antiretroviral resistance profiles in the time available for donor evaluation. Transplant teams evaluating a donor must review all available donor and recipient information and be able to propose an antiretroviral regimen that will be equally or more safe, tolerable, and effective for the recipient after transplantation as the regimen in place in the recipient before transplantation. For instance, a donor who only achieves viral suppression with a regimen known to be intolerable to the recipient must not be accepted. If there is doubt about the ability to suppress viral replication after transplantation, the transplant must not move forward. Donors co-infected with hepatitis are not excluded from HIV-positive to HIVpositive transplant; however, careful consideration must be given when evaluating a donor co-infected with HBV and/or HCV (Terrault, 2012; Miro, 2012; Moreno, 2012; Sherman, 2014; Chen, 2014). Although HCV therapeutic strategies are rapidly evolving (Liang, 2013), it is possible that mixed genotype HCV infections may influence posttransplant treatment of HCV in the recipient. Prior antiretroviral treatment of the donor and/or recipient with agents active against HBV (i.e., lamivudine, emtricitabine, adefovir, and tenofovir) has the potential for inducing or uncovering archived HBV drug resistance in the recipient (Dieterich, 2007; Soriano, 2009; Pais, 2010). In the case of a living HIV-positive organ donor, the risk of future end-stage VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 liver or kidney failure in the donor must be carefully assessed as it is in other atrisk populations currently eligible to donate an organ. For example, kidney disease in HIV-positive patients has been associated with the apolipoprotein 1 (APOL1) coding variants that confer a very high risk of susceptibility and are almost exclusively found in patients of African descent (Freedman, 2013; Genovese, 2010). Living donation of a kidney from a donor having such a variant may be associated with an unacceptable risk of subsequent kidney disease to both the donor and the recipient (Freedman, 2015; ReevesDaniel, 2011; Parsa, 2013; Riella, 2015). The consent process for an HIVpositive living organ donor must include and document provision to the donor of information regarding: (1) The possibility that the loss of organ function resulting from donation could preclude the use of certain antiretroviral drugs in the future; (2) the risk of kidney or liver failure in the future; (3) the possibility of transmission of occult opportunistic infections to the recipient; and (4) the absence of U.S. experience in HIV-positive to HIV-positive organ transplantation, and thus the unpredictable nature of donor and recipient outcomes (Mgbako, 2013). HIV-positive transplant candidates who are listed for a transplant in the context of a research study of HIVpositive to HIV-positive transplantation must have the same opportunity as other transplant candidates to receive an organ from an HIV-negative donor, should one become available for them. 1.1 HIV-Positive Donor Eligibility Criteria The HIV-specific donor eligibility criteria for deceased donors and for living donors are listed (also refer to Table 1). Co-infection with HBV and/or HCV is not an exclusion criterion, although research that includes coinfected donors must address any additional eligibility criteria within their research protocol. 1.1.1 HIV-Positive Deceased Donors When evaluating HIV-positive deceased donors, it is understood that limited medical history may be available and/or known at the time of the donor evaluation. The OPO must make reasonable efforts to obtain prior medical history so that a transplant center team may best determine the suitability of the potential donor based on the information available. A complete history of antiretroviral regimens and a history of viral load tests and resistance testing are especially valuable for evaluating the likelihood of PO 00000 Frm 00094 Fmt 4703 Sfmt 4703 73791 donor HIV resistance to antiretroviral regimens. A history of OIs or cancers is also of high importance, due to the increased risk for both attributable to HIV, and the additional difficulty of treating some infections and neoplasms in a post-transplant setting. It is possible that deceased donors with lower CD4+ T-cell counts may pose an increased risk of harboring transmissible diseases (e.g., opportunistic infections or neoplasms) that may be difficult to detect during organ harvest and transplantation; teams conducting transplants under the HOPE Act are urged to assess donors with low CD4+ T-cell counts (e.g., ≤200/mL) with special caution and to promptly inform IRBs and protocol sponsors of known or suspected disease transmission events. Minimum eligibility criteria for all HIV-positive deceased donors: i. Documented HIV infection using an FDA-licensed, approved, or cleared test device(s). ii. No evidence of invasive opportunistic complications of HIV infection. iii. Pre-implant donor organ biopsy to be stored, at a minimum, for the duration of the study (or at least 5 years); additional specimens may be obtained to support specific research goals. Additional eligibility criteria for HIVpositive deceased donors with a known history of HIV and prior treatment with ART: i. The study team must describe the anticipated post-transplant antiretroviral regimen(s) to be prescribed for the recipient and justify their conclusion that the proposed regimen will be safe, tolerable, and effective. 1.1.2 HIV-Positive Living Donors Minimum eligibility criteria for HIVpositive living donors: i. Documented HIV infection using an FDA-licensed, approved, or cleared test device. ii. Well-controlled HIV infection, as evidenced by: a. CD4+ T-cell count ≥500/mL for the 6-month period preceding donation. b. Fewer than 50 copies/mL of HIV– 1 RNA detectable by ultrasensitive or real-time polymerase chain reaction (PCR) assay. iii. A complete history of ART regimens and ART resistance. iv. The study team must be able to predict a safe, tolerable, and effective regimen to be prescribed for the recipient based on the donor’s current ART regimen as well as the donor’s history of ART resistance. E:\FR\FM\25NON1.SGM 25NON1 73792 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices v. No evidence of invasive opportunistic complications of HIV infection. vi. A liver biopsy (in liver donors) or a kidney biopsy (in kidney donors) showing no evidence of a disease process that would put the donor at increased risk of progressing to endstage organ failure after donation, or that would present a risk of poor graft function to the recipient. 2 Recipient Eligibility A key consideration when evaluating potential HIV-positive transplant candidates is the ability to suppress HIV viral load post-transplant. This includes a thorough assessment by the transplant team of the candidate recipient’s prescribed antiretroviral medications, HIV RNA levels while on medications, adherence to HIV treatment, and any available HIV resistance testing; a similar evaluation of the donor must also be carried out. A transplant should only take place if, after evaluating both recipient and donor, the team is confident they can define a posttransplant antiretroviral regimen that will be safe, tolerable, and effective. If there is any doubt on the part of the transplant team about the ability to suppress viral replication posttransplant, the transplant should not move forward. Concerns about transmitted drug resistance must be included in the recipient informed consent process for the research study. At the time of an organ offer, the recipient informed consent must address the transplant team’s assessment of risk specific to the organ they are being offered. 2.1 HIV-Positive Recipient Eligibility Criteria The following HIV-specific criteria must be met when screening for an HIVpositive to HIV-positive organ transplant (also refer to Table 1): i. CD4+ T-cell count ≥200/mL (kidney) and ≥100/mL (liver) within 16 weeks prior to transplant; any patient with history of OI must have a CD4 positive T-cell count ≥200/uL. ii. HIV RNA less than 50 copies/mL and on a stable antiretroviral regimen.* iii. No evidence of active opportunistic complications of HIV infection. iv. No history of primary CNS lymphoma or progressive PML. v. Concurrence by the study team that, based on medical history and ART, viral suppression can be achieved in the recipient post-transplant. *Patients who are unable to tolerate ART due to organ failure or who have only recently started ART may have detectable viral load and still be considered eligible if the study team is confident there will be a safe, tolerable, and effective antiretroviral regimen for the patient once organ function is restored after transplantation. TABLE 1—SUMMARY OF DONOR AND RECIPIENT ELIGIBILITY CRITERIA FOR HIV-POSITIVE SERO-CONCORDANT ORGAN TRANSPLANT PAIRS UNDER THE HOPE ACT HIV-Related variables Deceased donor Living donor HIV-Positive recipient Current CD4+ T-cell count (T lymphocytes/μL) ........... No requirement ................................. ≥500 for 6 months prior to organ donation. Plasma HIV RNA viral load (copies/mL). Opportunistic infection ...... No requirement** ............................... <50 .................................................... No invasive OI ................................... No invasive OI ................................... If no history of OI • ≥200 If history of OI • ≥200 (kidney) • ≥100 (liver) CD4+ T-cell count measured within 16 weeks of transplantation <50* Currently, • No active OI Historically, no • CNS lymphoma • PML * Organ recipients who are unable to tolerate ART due to organ failure or who have only recently started ART may have detectable viral load and still be considered eligible if the study team is confident there will be a safe, tolerable, and effective antiretroviral regimen to be used by the recipient once organ function is restored after transplantation. ** In deceased donors with a known history of HIV infection and prior treatment with ART, the study team must describe the anticipated posttransplant antiretroviral regimen(s) to be used by the organ recipient and justify their conclusion that the proposed regimen will be safe, tolerable, and effective. tkelley on DSK3SPTVN1PROD with NOTICES 3 Transplant Hospital Criteria Expertise in the management of individuals with HIV infection is essential for this research. A transplant hospital participating in HIV-positive to HIV-positive transplantation must include experts in the field of transplantation as well as experts in the management of HIV infection working collaboratively as a part of a study team. 3.1 Specific Transplant Hospital Criteria i. An established program for the care of individuals infected with HIV. VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 ii. In order for a transplant hospital to initiate HIV-positive to HIV-positive transplantation, there must be a study team consisting of (at a minimum) a transplant surgeon, a transplant physician, and an HIV physician. The transplant physician and HIV physician collectively must have experience with at least 5 HIV-negative to HIV-positive transplants with the designated organ(s) over the last 4 years. This constitutes the minimal experience necessary, and the IRB must evaluate key personnel (i.e., transplant surgeon, transplant physician, and HIV physician) in the context of total expertise and experience with respect to HIV and/or organ PO 00000 Frm 00095 Fmt 4703 Sfmt 4703 transplantation (confirm and document HIV-negative to HIV-positive transplant experience of the team). iii. Defined SOPs and training for the hospital personnel involved in procurement and/or implantation regarding the following issues: a. Donor evaluation b. Organ recovery c. Handling, processing, packaging, shipping, and transporting of blood, lymph nodes, tissues, and organs to and/or within the transplant hospital d. Transplant procedure iv. Transplant hospitals with an IRBapproved research protocol in HIVpositive to HIV-positive transplantation E:\FR\FM\25NON1.SGM 25NON1 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices must inform the OPTN of additional organ-specific acceptance criteria for organs from HIV-positive donors. v. Transplant hospitals with an IRBapproved research protocol in HIVpositive to HIV-positive transplantation with HIV-positive candidates on the wait list willing to accept an HIVpositive organ must specify any additional acceptance criteria to the OPO. vi. The transplant hospital must verify the HIV status of both the donor and the recipient. vii. Defined SOPs and training regarding an institutional biohazard plan, which outlines the measures taken to prevent and manage inadvertent exposure and/or transmission of HIV. viii. Defined policies and SOPs for governing the necessary knowledge, experience, skills, and training for independent advocates. 3.2 Independent Advocates A transplant program conducting research in HIV-positive to HIV-positive transplantation under these research criteria must provide each HIV-positive living donor and recipient with an independent advocate. In the setting of a living donor transplant, there must be two independent advocates, one for the donor and another for the recipient. Each advocate must be independent of the research team and must have knowledge and experience with both HIV infection and organ transplantation. At a minimum, transplant hospitals conducting research in HIV-positive to HIV-positive transplantation shall develop policies and procedures addressing the role, knowledge, and experience of independent advocates in the setting of HIV infection, transplantation, medical ethics, informed consent, and the potential impact of external pressure on the HIVpositive recipient’s decision, and HIVpositive living donor’s decision (if applicable) about whether to enter the HIV-positive to HIV-positive transplant research study. tkelley on DSK3SPTVN1PROD with NOTICES 3.2.1 Independent HIV-Positive Recipient Advocate Transplant programs performing HIVpositive to HIV-positive transplants must designate and provide each HIVpositive recipient and prospective HIVpositive recipient with an independent advocate who is responsible for protecting and promoting the rights and interests of the HIV-positive recipient (or prospective recipient). The independent advocate for the HIVpositive recipient must: VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 i. Promote and protect the interests of the HIV-positive recipient (including with respect to having access to a suitable HIV-negative organ if it becomes available) and take steps to ensure that the HIV-positive recipient’s decision is informed and free from coercion. ii. Review whether the potential HIVpositive recipient has received information regarding the results of SOT in general and transplantation in HIVpositive recipients in particular and the unknown risks associated with HIVpositive to HIV-positive transplant. iii. Demonstrate knowledge of HIV infection and transplantation. 3.2.2 Independent HIV-Positive Living Donor Advocate Transplant programs performing HIVpositive donor transplantations must designate and provide each living HIVpositive donor and living prospective HIV-positive donor with an independent advocate who is responsible for promoting and protecting the rights and interests of the HIV-positive donor (or prospective donor). More specifically, the independent advocate for the HIVpositive living donor must: i. Promote and protect the interests of the HIV-positive donor (including with respect to having ample opportunity to withdraw consent from donation) and take steps to ensure that the HIVpositive donor’s decision is informed and free from external pressure. ii. Review whether the potential HIVpositive donor has received information regarding (a) risks of organ donation in general, as well as the additional potential risks that are the specific to the HIV-positive donor, including accelerated organ failure, and limitations of future use of specific antiretroviral agents; and (b) the unknown outcome of HIV-positive to HIV-positive organ transplantation. iii. Demonstrate knowledge of HIV infection and transplantation. 4 OPO Responsibilities Clinical research in HIV-positive to HIV-positive organ transplantation requires a partnership between OPOs and transplant programs. OPOs participating in the evaluation and allocation of HIV-positive organs to centers conducting research in HIVpositive to HIV-positive transplantation must adhere to the following criteria: i. Develop SOPs and staff training procedures to effectively work with the family and other sources of medical history for HIV-positive donors in assessing medical and behavioral risks; HIV clinic and pharmacy medical PO 00000 Frm 00096 Fmt 4703 Sfmt 4703 73793 record abstraction; obtaining research consent from next of kin of HIV-positive donors; performing physical examination of HIV-positive donors; collecting blood, tissue, and other biospecimens (e.g., urine, bronchoalveolar lavage, spleen, lymph nodes, and biopsy material); and handling, processing, storing, labeling, and shipping of the biospecimens. ii. Conduct training in obtaining relevant and pertinent HIV-positive history, duration of HIV infection, opportunistic illnesses and their therapy, risk factors for HIV, CD4+ Tcell counts (lows and highs), HIV resistance, ART medication history use and response, history of ART resistance, present ART, HIV viral loads, and HIV genotype and tropism, when known. iii. Develop a biohazard plan to prevent and manage exposure to or transmission of HIV. These criteria are in addition to, not in place of, current Organ Procurement and Transplantation Network (OPTN) policies and bylaws, state or local laws, and federal regulations governing organ transplantation and research that pertains to OPOs. 5 Prevention of Inadvertent Transmission of HIV Although the use of HIV-positive organs may help alleviate transplant shortages and reduce patient waiting list times, there also are patient safety concerns to consider. Prevention or management of inadvertent transmission of HIV or exposure of an HIV-negative recipient to organs or tissues from an HIV-positive donor due to identification error is paramount (Ison, 2009, 2011a, 2011b). The transplant community, with regulatory oversight at multiple levels, has been able to achieve a high level of safety through routine procedures and clinical practice. The precautions taken with ABO compatible donor-recipient pairs and HCV-infected donor organs in HCVinfected recipients (Morales, 2010; Kucirka, 2010; Mandal, 2000; Tector, 2006) are existing models. However, vulnerabilities still exist, and mishaps still occur. For instance, the risks of error during manual transcription of information are well documented. Each transplant hospital shall have an institutional biohazard plan for handling of HIV-positive organs—to include, for example, organ quarantine measures, electronic information capture on infectious disease testing results, communication protocols between OPOs and transplant hospitals—that is designed to prevent and/or manage inadvertent transmission of or exposure to HIV. E:\FR\FM\25NON1.SGM 25NON1 73794 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices 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 tkelley on DSK3SPTVN1PROD with NOTICES 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 VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 Donors (all) • Type (living or deceased) • HIV status (HIV-positive new diagnosis, HIV-positive known diagnosis) • CD4+ T-cell count • Co-infection (HCV, HBV) • HIV viral load • ART resistance • Pre-transplant donor allograft biopsy 6.3 Living Donors (6, 12, and 24 Months Following Organ Donation) • Progression to renal insufficiency in kidney donors: Æ Proteinuria defined as urinary protein excretion >150 mg/day or urine protein/creatinine ratio >0.2 Æ eGFR <60 mL/minute/1.73m2 • 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 There is a wide range of clinical and immunologic questions that might be addressed in the context of research in HIV-positive to HIV-positive transplantation. These include, for example, questions related to HIV superinfection; incidence and severity of OIs (including transmission of occult OIs from donor to recipient); immunologic mechanisms contributing to the increased rate of kidney rejection observed in HIV-positive recipients; quality of life for recipients of HIVpositive to HIV-positive transplantation; outcomes of living HIV-positive donors; and a host of others. The questions will be determined by the investigators who design research protocols for studying HIV-positive to HIV-positive transplantation. However, to ensure that all studies of HIV-positive to HIVpositive 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 HIVpositive to HIV-positive transplantation. 6.1 6.2 • • • • • • • • • Transplant Recipients Rejection rate (annual up to 5 years) Progression to AIDS New OIs Failure to suppress viral replication (persistent viremia) HIV-associated organ failure Malignancy Graft failure Mismatched ART resistance versus donor Death References Bertani, A., Grossi, P., Vitulo, P., et al. (2009). Successful lung transplantation in an HIV- and HBV-positive patient with cystic fibrosis. American Journal of Transplantation, 9, 2190–2196. Bisleri, G., Morgan, J. A., Deng, M. C., et al. (2003). Should HIV-positive recipients undergo heart transplantation? Journal of Thoracic and Cardiovascular Surgery, 126, 1639–1640. Blumberg, E. A., & Stock, P. (2009). Solid organ transplantation in the HIV-infected patient. American Journal of Transplantation, 9 Suppl 4, S131–135. Blumberg, E. A., & Rogers, C. C. (2013a). Human immunodeficiency virus in solid organ transplantation. American Journal of Transplantation, 13 Suppl 4, 169–178. Blumberg, E. A., Ison, M. G., Pruett, T. L., & Segev, D. L. (2013b). Optimal testing of the live organ donor for blood-borne viral pathogens: the report of a consensus conference. American Journal of Transplantation, 13(6), 1405–1415. Boyarsky, B. J., Hall, E. C., Singer, A. L., Montgomery, R. A., Gebo, K. A., & Segev, D. L. (2011). Estimating the potential pool of HIV-infected deceased organ PO 00000 Frm 00097 Fmt 4703 Sfmt 4703 donors in the United States. American Journal of Transplantation, 11(6), 1209– 1217. Boyarsky, B. J., Durand C. M., Palella F. J., Segev D.L., (2015). Challenges and clinical decision-making in HIV-to-HIV transplantation: insights from the HIV literature. American Journal of Transplantation, 15:2023–2030. Brucato, A., Colombo, T., Bonacina, E., et al. (2004). Fulminant myocarditis during HIV seroconversion: recovery with temporary left ventricular mechanical assistance. Italian Heart Journal, 5, 228– 231. Calabrese, L. H., Albrecht, M., Young, J., et al. (2003). Successful cardiac transplantation in an HIV–1-infected patient with advanced disease. New England Journal of Medicine, 348, 2323– 2328. ´ ´ Castel, M. A., Perez-Villa, F., Roig, E., & Miro, J. M. (2011a). Heart transplantation in an HIV–1-infected patient with ischemic cardiomyopathy and severe pulmonary ˜ hypertension. Revista Espanola de ´ Cardiologıa, 64, 1066–1067. ´ ´ Castel, M. A., Perez-Villa, F., & Miro, J. M. (2011b). Heart transplantation in HIVinfected patients: more cases in Europe. The Journal of Heart and Lung Transplantation, 30, 1418. Chen, J. Y., Feeney, E. R., & Chung, R. T. (2014). HCV and HIV co-infection: mechanisms and management. Nature Reviews: Gastroenterology & Hepatology, 11(6), 362–371. Cooper, C., Kanters, S., Klein, M., Chaudhury, P., Marotta, P., Wong, P., et al. (2011). Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with synthetic cohort. AIDS, 25(6), 777–786. Dieterich, D.T. (2007). Special considerations and treatment of patients with HBV–HIV coinfection. Antiviral Therapy, 12, H43– H51. Duclos-Vallee, J. C., Falissard, B., & Samuel, D. (2011). Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with a synthetic cohort. AIDS, 25(13), 1675– 1676. Durante-Mangoni, E., Maiello, C., & Sbreglia, C. (2011). A European first: successful heart transplant in a human immunodeficiency virus-positive recipient. The Journal of Heart and Lung Transplantation, 30, 845. Durante-Mangoni, E., Maiello, C., Limongelli, G., et al. (2014). Management of immunosuppression and antiretroviral treatment before and after heart transplant for HIV-associated dilated cardiomyopathy. International Journal of Immunopathology and Pharmacology, 27(1), 113–120. Fieno, D. S., Czer, L. S., Schwarz, E. R., et al. (2009). Left ventricular assist device placement in a patient with end-stage heart failure and human immunodeficiency virus. Interactive Cardiovascular and Thoracic Surgery, 9, 919–920. Fox, A. N., Vagefi, P. A., & Stock, P. G. (2012). Liver transplantation in HIV E:\FR\FM\25NON1.SGM 25NON1 tkelley on DSK3SPTVN1PROD with NOTICES Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices patients. Seminars in Liver Disease, 32(2), 177–185. Frassetto, L. A., Browne, M., Cheng, A., et al. (2007). Immunosuppressant pharmacokinetics and dosing modifications in HIV–1 Infected liver and kidney transplant recipients. American Journal of Transplantation, 7(12), 2816–2820. Frassetto, L. A., Tan-Tam, C., & Stock, P. G. (2009). Renal transplantation in patients with HIV. Nature Review: Nephrology, 5(10), 582–589. Frassetto, L. A., Tan-Tam, C. C., Barin, B., Browne, M., Wolfe, A. R., Stock, P. G., et al. (2014). Best Single Time Point Correlations with AUC for Cyclosporine and Tacrolimus in HIV-Infected Kidney and Liver Transplant Recipients. Transplantation, 97(6), 701–707. Freedman, B.I. (2013). APOL1 and nephropathy progression in populations of African ancestry. Seminars in Nephrology, 33(5):425–432. Freedman, B.I., Julian, B. A., Pastan, S. O. et al. (2015). Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. American Journal of Transplantation, 15:1615–1622. Genovese, G., Friedman, D. J., Ross, M. D., Lecordier, L., Uzureau, P., Freedman, B. I., et al. (2010). Association of trypanolytic APOL1 variants with kidney disease in African Americans. Science, 329(5993), 841–845. Gomez, V., Fernandez, A., Galeano, C., Oliva, J., Diez, V., Bueno, C., et al. (2013). Renal transplantation in HIV-infected patients: experience at a tertiary hospital in Spain and review of the literature. Transplant Proceedings, 45(3), 1255–1259. Grossi, P. A. (2012). Update in HIV infection in organ transplantation. Current Opinion Organ Transplantation, 17(6), 586–593. Harbell, J., Terrault, N. A., & Stock, P. (2013). Solid organ transplants in HIV-infected patients. Current HIV/AIDS Reports, 10(3), 217–225. Humbert, M., Sitbon, O., Chaouat A., et al. (2006). Pulmonary arterial hypertension in France: results from a national registry. American Journal of Respiratory and Critical Care Medicine, 173, 1023. Huprikar, S. (2009). Solid organ transplantation in HIV-infected individuals: an update. Reviews in Medical Virology, 19(6), 317–323. Ison, M. G., Hager, J., Blumberg, E., Burdick, J., Carney, K., Cutler, J., et al. (2009). Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee. American Journal of Transplantation, 9(8), 1929–1935. Ison, M. G., Llata, E., Conover, C. S., Friedewald, J. J., Gerber, S. I., Grigoryan, A., et al. (2011a). Transmission of human immunodeficiency virus and hepatitis C virus from an organ donor to four transplant recipients. American Journal of Transplantation, 11(6), 1218–1225. Ison, M. G., & Nalesnik, M. A. (2011b). An update on donor-derived disease VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 transmission in organ transplantation. American Journal of Transplantation, 11(6), 1123–1130. Kaplan, J. E., Masur, H., Holmes, K.K., et al. (1995a). USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: introduction. USPHS/IDSA Prevention of Opportunistic Infections Working Group. Clinical Infectious Diseases, 21 Suppl 1:S1–11. Available at https:// www.ncbi.nlm.nih.gov/pubmed/ 8547495. Kaplan, J. E., Masur, H., Jaffe, H.W., Holmes, K.K. (1995b). Reducing the impact of opportunistic infections in patients with HIV infection. New guidelines. Journal of the American Medical Association, 274(4):347–348. Available at https:// www.ncbi.nlm.nih.gov/pubmed/ 7609267. Kern, R. M., Seethamraju, H., Blanc, P. D., et al. (2014a). The feasibility of lung transplantation in HIV seropositive patients. Annals of the American Thoracic Society (in press, online). Kern, R., Seethamraju, H., Blanc, P., Sinha, N., Loebe, M., Golden, J., et al. (2014b). Lung Transplantation in HIV Seropositive Patients. Chest, 145(3 Suppl), 642A. Kim, D., Ziebell, R., Sadulvala, N., Kline, R., Ocfemia, C., Prejean, J., et al. (2013). Trends in Transmitted Drug Resistance Associated Mutations: 10 HIV Surveillance Areas, US, 2001–2010. Paper presented at the 20th Conference on Retroviruses and Opportunistic Infections. Kim, W. R., Smith, J. M., Skeans, M. A., et al. (2014). OPTN/SRTR 2012 Annual Data Report: Liver. American Journal of Transplantation, 1, 69–96. Kucirka, L. M., Singer, A. L., Ross, R. L., et al. (2010). Underutilization of hepatitis C-positive kidneys for hepatitis Cpositive recipients. American Journal of Transplantation, 10(5), 1238–1246. Kucirka, L.M., Bowring, M. G., Massie, A. B., et al, (2015) Landscape of deceased donors labeled increased risk for disease transmission under new guidelines. American Journal of Transplantation, (in press). Liang, T. J., & Ghany, M. G. (2013). Current and future therapies for hepatitis C virus infection. New England Journal of Medicine, 368(20), 1907–1917. Locke, J. E., James, N. T., Mannon, R. B., Mehta, S. G., Pappas, P. G., Baddley, J. W., et al. (2014). Immunosuppression Regimen and the Risk of Acute Rejection in HIV-Infected Kidney Transplant Recipients. Transplantation, 97(4), 446– 450. Locke, J. E., Reed R. D., Mehta S. G., et al. (2015a). Center-level experience and kidney transplant outcomes in HIVinfected recipients. American Journal of Transplantation, 15:2096–2104. Locke, J. E., Mehta, S., Reed, R. D., et al. (2015b). A national study of outcomes among HIV-infected kidney transplant recipients. Journal of the American Society of Nephrology, 26:1–8. PO 00000 Frm 00098 Fmt 4703 Sfmt 4703 73795 Mandal, A. K., Kraus, E.S., Samaniego, M., et al. (2000). Shorter waiting times for hepatitis C virus seropositive recipients of cadaveric renal allografts from hepatitis C virus seropositive donors. Clinical Transplantation, 14, 391–396. Mascolini, M. (2014). Four to Five HIV+ Dying in Care Yearly in Philadelphia Are Potential Organ Donors. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy: Abstract H–1199a. Presented September 7, 2014. Matas, A. J., Smith, J. M., Skeans, M. A., et al. (2014) OPTN/SRTR 2012 Annual Data Report: Kidney. American Journal of Transplantation, 1, 11–44. Megens, S., & Laethem, K. V. (2013). HIV–1 genetic variation and drug resistance development. Expert Review of AntiInfective Therapy, 11(11), 1159–1178. Mehmood, S., Blais, D., Martin S., & SaiSudhakar, C. (2009). Heartmate XVE destination therapy for end-stage heart failure in a patient with human immunodeficiency virus. Interactive Cardiovascular and Thoracic Surgery, 9, 909–910. Mehta, N. J., Khan, I. A., Mehta, R. N., et al. (2000). HIV-related pulmonary hypertension: analytic review of 131 cases. Chest, 118, 1133. Mgbako, O., Glazier, A., Blumberg, E., & Reese, P. P. (2013). Allowing HIVpositive organ donation: ethical, legal and operational considerations. American Journal of Transplantation, 13(7), 1636–1642. Miro, J. M., Montejo, M., Castells, L., Rafecas, A., Moreno, S., Aguero, F., et al. (2012). Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study. American Journal of Transplantation, 12(7), 1866– 1876. Miro, J. M., Stock, P., Teicher, E., et al, (2015). Outcome and management of HCV/HIV coinfection pre- and post-liver transplantation. A 205 update. Journal of Hepatology, 62:701–711. Morales, J. M., Campistol, J. M., DominguezGil, B., Andres, A., Esforzado, N., Oppenheimer, F., et al. (2010). Long-term experience with kidney transplantation from hepatitis C-positive donors into hepatitis C-positive recipients. American Journal of Transplantation, 10(11), 2453–2462. Moreno, A., Cervera, C., Fortun, J., et al. (2012). Epidemiology and outcome of infections in human immunodeficiency virus/hepatitis C virus-coinfected liver transplant recipients: a FIPSE/GESIDA prospective cohort study. Liver Transplantation, 18, 70–81. Muller, E., Kahn, D., & Mendelson, M. (2010). Renal transplantation between HIVpositive donors and recipients. New England Journal of Medicine, 362(24), 2336–2337. Muller, E., Barday, Z., Mendelson, M., & Kahn, D. (2012). Renal transplantation between HIV-positive donors and recipients justified. South African Medical Journal, 102(6), 497–498. Muller, E., Barday, Z., Mendelson, M., Kahn, E:\FR\FM\25NON1.SGM 25NON1 tkelley on DSK3SPTVN1PROD with NOTICES 73796 Federal Register / Vol. 80, No. 227 / Wednesday, November 25, 2015 / Notices D., et al. (2015). HIV-positive-to-HIVpositive kidney transplantation—results at 3 to 5 years. New England Journal of Medicine, 372:613–20. Neuhaus, J., Angus, B., Kowalska, J. D., et al. (2010). Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV. AIDS, 24(5), 697–706. OPTN Policies and Bylaws. From https:// optn.transplant.hrsa.gov/ policiesandbylaws/policies.asp. Pais, R. & Benhamou, Y. (2010). Long-term therapy for chronic hepatitis B in HIV ´ co-infected patients. Gastroenterologie Clinique et Biologique, 34, 136–41. Parsa, A., Kao, W. H. L., Xie, D., et al, (2013). APOL1 risk variants, race, and progression of chronic kidney disease. New England Journal of Medicine, 369:2183–96. Panel on Opportunistic Infections in HIVInfected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents; recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at https://aidsinfo.nih.gov/ contentfiles/lvguidelines/adult_oi.pdf. (Accessed September 2015). Pelletier S. J., Norman S. P., Christensen L. L., et al. (2004). Review of transplantation in HIV patients during the HAART era. Clinical Transplantation, 63–82. Petrosillo, N., Chinello, P., & Cicalini, S. (2006). Pulmonary hypertension in individuals with HIV infection. AIDS, 20, 2128. Prevention, C. f. D. C. a. (2013). HIV Surveillance Supplemental Report. Ragni, M. V., Dodson, S. F., Hunt, S. C., et al. (1999). Liver transplantation in a hemophilia patient with acquired immunodeficiency syndrome. Blood, 93, 1113–1114. Redd A. D., Quinn T. C., Tobian A. A. (2013). Frequency and implications of HIV superinfection. The Lancet Infectious Diseases, 13(7), 622–628. Reeves-Daniel, A. M., DePalma, J. A., Bleyer, A. J., Rocco, M. V., Murea, M., Adams, P. L., et al. (2011). The APOL1 Gene and Allograft Survival after Transplantation. American Journal of Transplantation, 11(5), 1025–1030. Richterman, A., Blumberg, E., (2015). The challenges and promise of HIV-infected donors for solid organ transplantation. Current Infectious Disease Reports, 17:1– 8. Richterman, A., Sawinski, D., Reese, P.P., et al, (2015). An assessment of HIV-infected patients dying in care for deceased organ donation in a United States urban center. American Journal of Transplantation, 15:2105–2116. Riella, L.V., Sheridan, A.M., (2015). Testing for high-risk APOL1 alleles in potential living kidney donors. American Journal of Kidney Disease, (in press). Roland, M., Carlson, L., & Stock, P. (2002). VerDate Sep<11>2014 19:15 Nov 24, 2015 Jkt 238001 Solid organ transplantation in HIVinfected individuals. AIDS Clinical Care, 14(7), 59–63. Roland, M. E., Adey, D., Carlson, L. L., & Terrault, N. A. (2003a). Kidney and liver transplantation in HIV-infected patients: case presentations and review. AIDS Patient Care STDS, 17(10), 501–507. Roland, M. E., Lo, B., Braff, J., & Stock, P. G. (2003b). Key clinical, ethical, and policy issues in the evaluation of the safety and effectiveness of solid organ transplantation in HIV-infected patients. Archives of Internal Medicine, 163(15), 1773–1778. Roland, M. E., & Stock, P. G. (2003c). Review of solid-organ transplantation in HIVinfected patients. Transplantation, 75(4), 425–429. Sawinski, D., Goldberg, D. S., Blumberg, E., et al. (2015) Beyond the NIH multicenter HIV transplant trial experience: Outcomes of HIV+ liver transplant recipients compared to HCV+ or HIV+/ HCV+ coinfected recipients in the United States. Clinical Infectious Disease, (in Press). Sherman, K. E., Thomas, D., & Chung, R. T. (2014). Human immunodeficiency virus and liver disease forum 2012. Hepatology, 59(1), 307–317. ´ Sims, D. B., Uriel, N., Gonzalez-Costello, J., et al. (2011). Human immunodeficiency virus infection and left ventricular assist devices: a case series. Journal of Heart and Lung Transplantation, 30, 1060– 1064. Soriano, V., Tuma, P., Labarga, P., et al. (2009). Hepatitis B in HIV patients: what is the current treatment and what are the challenges? Journal of HIV Therapy, 14(1), 13–18. Stock, P. G., Barin, B., Murphy, B., Hanto, D., Diego, J. M., Light, J., et al. (2010). Outcomes of kidney transplantation in HIV-infected recipients. New England Journal of Medicine, 363(21), 2004–2014. Taege, A. (2013). Organ transplantation and HIV progress or success? A review of current status. Curr Infectious Disease Reports, 15, 67–76. Tector, A. J., Mangu, R. S., Chestovich, P., et al. (2006). Use of extended criteria livers decreases wait time for liver transplantation without adversity impacting posttransplant survival. Annals of Surgery, 244, 439–450. Terrault, N. A., Roland, M. E., Schiano, T., Dove, L., Wong, M. T., Poordad, F., et al. (2012). Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transplantation, 18(6), 716–726. Touzot, M., Pillebout, E., Matignon, M., Tricot, L., Viard, J. P., Rondeau, E., et al. (2010). Renal transplantation in HIVinfected patients: the Paris experience. American Journal of Transplantation, 10(10), 2263–2269. Uriel, N., Jorde, U. P., Cotarlan, V., et al. (2009). Heart transplantation in human immunodeficiency virus-positive patients. Journal of Heart and Lung Transplant, 28, 667–669. Uriel, N., Nahumi, N., Colombo, P. C., et al. (2014). Advance heart failure in patients PO 00000 Frm 00099 Fmt 4703 Sfmt 4703 infected with human immunodeficiency virus: is there equal access to care? Journal of Heart and Lung Transplantation (in press, online). Wada, N., Jacobson, L. P., Cohen, M., French, A., Phair, J., & Munoz, A. (2013). Causespecific life expectancies after 35 years of age for human immunodeficiency syndrome-infected and human immunodeficiency syndrome-negative individuals followed simultaneously in long-term cohort studies, 1984–2008. American Journal of Epidemiology, 177(2), 116–125. Wada, N., Jacobson, L. P., Cohen, M., French, A., Phair, J., & Munoz, A. (2014). Causespecific mortality among HIV-infected individuals, by CD4 (+) cell count at HAART initiation, compared with HIVuninfected individuals. AIDS, 28(2), 257–265. Yoon, S. C., Hurst, F. P., Jindal, R. M., George, S. A., Neff, R. T., Agodoa, L. Y., et al. (2011). Trends in renal transplantation in patients with human immunodeficiency virus infection: an analysis of the United States renal data system. Transplantation, 91(8), 864–868. Dated: November 20, 2015. Francis S. Collins, Director, National Institutes of Health. [FR Doc. 2015–30172 Filed 11–24–15; 8:45 am] BILLING CODE 4140–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Center for Scientific Review; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of the following meetings. The meetings will be closed to the public in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5 U.S.C., as amended. The grant applications and the discussions could disclose confidential trade secrets or commercial property such as patentable material, and personal information concerning individuals associated with the grant applications, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy. Name of Committee: Center for Scientific Review Special Emphasis Panel; Member Conflict: Reproductive Biology. Date: December 8, 2015. Time: 1:00 p.m. to 4:00 p.m. Agenda: To review and evaluate grant applications. Place: National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD 20892, (Virtual Meeting). Contact Person: Michael Knecht, Ph.D., Scientific Review Officer, Center for Scientific Review, National Institutes of E:\FR\FM\25NON1.SGM 25NON1

Agencies

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

[[Page 73785]]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

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

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

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

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

FOR FURTHER INFORMATION CONTACT: Dr. Jonah Odim, phone 240-627-3540,
Email: HOPEAct@mail.nih.gov, Fax: 301-451-5671, 5601 Fishers Lane, Room
6B21, MSC 9827, Bethesda, MD 20892-9827.

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

HOPE Act: Scope

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

Living Donors

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

Independent Advocates

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

[[Page 73786]]

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

Transplant Hospital Experience

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

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

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

Biospecimens

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

Required Outcomes

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

Conclusion Regarding Comments Received

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

Abbreviations
------------------------------------------------------------------------

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

[[Page 73787]]

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

Definitions
------------------------------------------------------------------------

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

Executive Summary

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

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

[[Page 73788]]

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

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

[[Page 73789]]

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

Background

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

Process

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

Introduction

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

[[Page 73790]]

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

1 Donor Eligibility

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

[[Page 73791]]

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

1.1 HIV-Positive Donor Eligibility Criteria

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

[[Page 73792]]

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

2 Recipient Eligibility

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

2.1 HIV-Positive Recipient Eligibility Criteria

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

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

3 Transplant Hospital Criteria

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

3.1 Specific Transplant Hospital Criteria

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

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

[[Page 73793]]

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

3.2 Independent Advocates

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

4 OPO Responsibilities

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

5 Prevention of Inadvertent Transmission of HIV

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

[[Page 73794]]

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

6 Study Design/Required Outcome Measures

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

6.1 Wait List Candidates

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

6.2 Donors (all)

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

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

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

6.4 Transplant Recipients

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

References

Bertani, A., Grossi, P., Vitulo, P., et al. (2009). Successful lung
transplantation in an HIV- and HBV-positive patient with cystic
fibrosis. American Journal of Transplantation, 9, 2190-2196.
Bisleri, G., Morgan, J. A., Deng, M. C., et al. (2003). Should HIV-
positive recipients undergo heart transplantation? Journal of
Thoracic and Cardiovascular Surgery, 126, 1639-1640.
Blumberg, E. A., & Stock, P. (2009). Solid organ transplantation in
the HIV-infected patient. American Journal of Transplantation, 9
Suppl 4, S131-135.
Blumberg, E. A., & Rogers, C. C. (2013a). Human immunodeficiency
virus in solid organ transplantation. American Journal of
Transplantation, 13 Suppl 4, 169-178.
Blumberg, E. A., Ison, M. G., Pruett, T. L., & Segev, D. L. (2013b).
Optimal testing of the live organ donor for blood-borne viral
pathogens: the report of a consensus conference. American Journal of
Transplantation, 13(6), 1405-1415.
Boyarsky, B. J., Hall, E. C., Singer, A. L., Montgomery, R. A.,
Gebo, K. A., & Segev, D. L. (2011). Estimating the potential pool of
HIV-infected deceased organ donors in the United States. American
Journal of Transplantation, 11(6), 1209-1217.
Boyarsky, B. J., Durand C. M., Palella F. J., Segev D.L., (2015).
Challenges and clinical decision-making in HIV-to-HIV
transplantation: insights from the HIV literature. American Journal
of Transplantation, 15:2023-2030.
Brucato, A., Colombo, T., Bonacina, E., et al. (2004). Fulminant
myocarditis during HIV seroconversion: recovery with temporary left
ventricular mechanical assistance. Italian Heart Journal, 5, 228-
231.
Calabrese, L. H., Albrecht, M., Young, J., et al. (2003). Successful
cardiac transplantation in an HIV-1-infected patient with advanced
disease. New England Journal of Medicine, 348, 2323-2328.
Castel, M. A., P[eacute]rez-Villa, F., Roig, E., & Mir[oacute], J.
M. (2011a). Heart transplantation in an HIV-1-infected patient with
ischemic cardiomyopathy and severe pulmonary hypertension. Revista
Espa[ntilde]ola de Cardiolog[iacute]a, 64, 1066-1067.
Castel, M. A., P[eacute]rez-Villa, F., & Mir[oacute], J. M. (2011b).
Heart transplantation in HIV-infected patients: more cases in
Europe. The Journal of Heart and Lung Transplantation, 30, 1418.
Chen, J. Y., Feeney, E. R., & Chung, R. T. (2014). HCV and HIV co-
infection: mechanisms and management. Nature Reviews:
Gastroenterology & Hepatology, 11(6), 362-371.
Cooper, C., Kanters, S., Klein, M., Chaudhury, P., Marotta, P.,
Wong, P., et al. (2011). Liver transplant outcomes in HIV-infected
patients: a systematic review and meta-analysis with synthetic
cohort. AIDS, 25(6), 777-786.
Dieterich, D.T. (2007). Special considerations and treatment of
patients with HBV-HIV coinfection. Antiviral Therapy, 12, H43-H51.
Duclos-Vallee, J. C., Falissard, B., & Samuel, D. (2011). Liver
transplant outcomes in HIV-infected patients: a systematic review
and meta-analysis with a synthetic cohort. AIDS, 25(13), 1675-1676.
Durante-Mangoni, E., Maiello, C., & Sbreglia, C. (2011). A European
first: successful heart transplant in a human immunodeficiency
virus-positive recipient. The Journal of Heart and Lung
Transplantation, 30, 845.
Durante-Mangoni, E., Maiello, C., Limongelli, G., et al. (2014).
Management of immunosuppression and antiretroviral treatment before
and after heart transplant for HIV-associated dilated
cardiomyopathy. International Journal of Immunopathology and
Pharmacology, 27(1), 113-120.
Fieno, D. S., Czer, L. S., Schwarz, E. R., et al. (2009). Left
ventricular assist device placement in a patient with end-stage
heart failure and human immunodeficiency virus. Interactive
Cardiovascular and Thoracic Surgery, 9, 919-920.
Fox, A. N., Vagefi, P. A., & Stock, P. G. (2012). Liver
transplantation in HIV

[[Page 73795]]

patients. Seminars in Liver Disease, 32(2), 177-185.
Frassetto, L. A., Browne, M., Cheng, A., et al. (2007).
Immunosuppressant pharmacokinetics and dosing modifications in HIV-1
Infected liver and kidney transplant recipients. American Journal of
Transplantation, 7(12), 2816-2820.
Frassetto, L. A., Tan-Tam, C., & Stock, P. G. (2009). Renal
transplantation in patients with HIV. Nature Review: Nephrology,
5(10), 582-589.
Frassetto, L. A., Tan-Tam, C. C., Barin, B., Browne, M., Wolfe, A.
R., Stock, P. G., et al. (2014). Best Single Time Point Correlations
with AUC for Cyclosporine and Tacrolimus in HIV-Infected Kidney and
Liver Transplant Recipients. Transplantation, 97(6), 701-707.
Freedman, B.I. (2013). APOL1 and nephropathy progression in
populations of African ancestry. Seminars in Nephrology, 33(5):425-
432.
Freedman, B.I., Julian, B. A., Pastan, S. O. et al. (2015).
Apolipoprotein L1 gene variants in deceased organ donors are
associated with renal allograft failure. American Journal of
Transplantation, 15:1615-1622.
Genovese, G., Friedman, D. J., Ross, M. D., Lecordier, L., Uzureau,
P., Freedman, B. I., et al. (2010). Association of trypanolytic
APOL1 variants with kidney disease in African Americans. Science,
329(5993), 841-845.
Gomez, V., Fernandez, A., Galeano, C., Oliva, J., Diez, V., Bueno,
C., et al. (2013). Renal transplantation in HIV-infected patients:
experience at a tertiary hospital in Spain and review of the
literature. Transplant Proceedings, 45(3), 1255-1259.
Grossi, P. A. (2012). Update in HIV infection in organ
transplantation. Current Opinion Organ Transplantation, 17(6), 586-
593.
Harbell, J., Terrault, N. A., & Stock, P. (2013). Solid organ
transplants in HIV-infected patients. Current HIV/AIDS Reports,
10(3), 217-225.
Humbert, M., Sitbon, O., Chaouat A., et al. (2006). Pulmonary
arterial hypertension in France: results from a national registry.
American Journal of Respiratory and Critical Care Medicine, 173,
1023.
Huprikar, S. (2009). Solid organ transplantation in HIV-infected
individuals: an update. Reviews in Medical Virology, 19(6), 317-323.
Ison, M. G., Hager, J., Blumberg, E., Burdick, J., Carney, K.,
Cutler, J., et al. (2009). Donor-derived disease transmission events
in the United States: data reviewed by the OPTN/UNOS Disease
Transmission Advisory Committee. American Journal of
Transplantation, 9(8), 1929-1935.
Ison, M. G., Llata, E., Conover, C. S., Friedewald, J. J., Gerber,
S. I., Grigoryan, A., et al. (2011a). Transmission of human
immunodeficiency virus and hepatitis C virus from an organ donor to
four transplant recipients. American Journal of Transplantation,
11(6), 1218-1225.
Ison, M. G., & Nalesnik, M. A. (2011b). An update on donor-derived
disease transmission in organ transplantation. American Journal of
Transplantation, 11(6), 1123-1130.
Kaplan, J. E., Masur, H., Holmes, K.K., et al. (1995a). USPHS/IDSA
guidelines for the prevention of opportunistic infections in persons
infected with human immunodeficiency virus: introduction. USPHS/IDSA
Prevention of Opportunistic Infections Working Group. Clinical
Infectious Diseases, 21 Suppl 1:S1-11. Available at https://www.ncbi.nlm.nih.gov/pubmed/8547495.
Kaplan, J. E., Masur, H., Jaffe, H.W., Holmes, K.K. (1995b).
Reducing the impact of opportunistic infections in patients with HIV
infection. New guidelines. Journal of the American Medical
Association, 274(4):347-348. Available at https://www.ncbi.nlm.nih.gov/pubmed/7609267.
Kern, R. M., Seethamraju, H., Blanc, P. D., et al. (2014a). The
feasibility of lung transplantation in HIV seropositive patients.
Annals of the American Thoracic Society (in press, online).
Kern, R., Seethamraju, H., Blanc, P., Sinha, N., Loebe, M., Golden,
J., et al. (2014b). Lung Transplantation in HIV Seropositive
Patients. Chest, 145(3 Suppl), 642A.
Kim, D., Ziebell, R., Sadulvala, N., Kline, R., Ocfemia, C.,
Prejean, J., et al. (2013). Trends in Transmitted Drug Resistance
Associated Mutations: 10 HIV Surveillance Areas, US, 2001-2010.
Paper presented at the 20th Conference on Retroviruses and
Opportunistic Infections.
Kim, W. R., Smith, J. M., Skeans, M. A., et al. (2014). OPTN/SRTR
2012 Annual Data Report: Liver. American Journal of Transplantation,
1, 69-96.
Kucirka, L. M., Singer, A. L., Ross, R. L., et al. (2010).
Underutilization of hepatitis C-positive kidneys for hepatitis C-
positive recipients. American Journal of Transplantation, 10(5),
1238-1246.
Kucirka, L.M., Bowring, M. G., Massie, A. B., et al, (2015)
Landscape of deceased donors labeled increased risk for disease
transmission under new guidelines. American Journal of
Transplantation, (in press).
Liang, T. J., & Ghany, M. G. (2013). Current and future therapies
for hepatitis C virus infection. New England Journal of Medicine,
368(20), 1907-1917.
Locke, J. E., James, N. T., Mannon, R. B., Mehta, S. G., Pappas, P.
G., Baddley, J. W., et al. (2014). Immunosuppression Regimen and the
Risk of Acute Rejection in HIV-Infected Kidney Transplant
Recipients. Transplantation, 97(4), 446-450.
Locke, J. E., Reed R. D., Mehta S. G., et al. (2015a). Center-level
experience and kidney transplant outcomes in HIV-infected
recipients. American Journal of Transplantation, 15:2096-2104.
Locke, J. E., Mehta, S., Reed, R. D., et al. (2015b). A national
study of outcomes among HIV-infected kidney transplant recipients.
Journal of the American Society of Nephrology, 26:1-8.
Mandal, A. K., Kraus, E.S., Samaniego, M., et al. (2000). Shorter
waiting times for hepatitis C virus seropositive recipients of
cadaveric renal allografts from hepatitis C virus seropositive
donors. Clinical Transplantation, 14, 391-396.
Mascolini, M. (2014). Four to Five HIV+ Dying in Care Yearly in
Philadelphia Are Potential Organ Donors. 54th Interscience
Conference on Antimicrobial Agents and Chemotherapy: Abstract H-
1199a. Presented September 7, 2014.
Matas, A. J., Smith, J. M., Skeans, M. A., et al. (2014) OPTN/SRTR
2012 Annual Data Report: Kidney. American Journal of
Transplantation, 1, 11-44.
Megens, S., & Laethem, K. V. (2013). HIV-1 genetic variation and
drug resistance development. Expert Review of Anti-Infective
Therapy, 11(11), 1159-1178.
Mehmood, S., Blais, D., Martin S., & Sai-Sudhakar, C. (2009).
Heartmate XVE destination therapy for end-stage heart failure in a
patient with human immunodeficiency virus. Interactive
Cardiovascular and Thoracic Surgery, 9, 909-910.
Mehta, N. J., Khan, I. A., Mehta, R. N., et al. (2000). HIV-related
pulmonary hypertension: analytic review of 131 cases. Chest, 118,
1133.
Mgbako, O., Glazier, A., Blumberg, E., & Reese, P. P. (2013).
Allowing HIV-positive organ donation: ethical, legal and operational
considerations. American Journal of Transplantation, 13(7), 1636-
1642.
Miro, J. M., Montejo, M., Castells, L., Rafecas, A., Moreno, S.,
Aguero, F., et al. (2012). Outcome of HCV/HIV-coinfected liver
transplant recipients: a prospective and multicenter cohort study.
American Journal of Transplantation, 12(7), 1866-1876.
Miro, J. M., Stock, P., Teicher, E., et al, (2015). Outcome and
management of HCV/HIV coinfection pre- and post-liver
transplantation. A 205 update. Journal of Hepatology, 62:701-711.
Morales, J. M., Campistol, J. M., Dominguez-Gil, B., Andres, A.,
Esforzado, N., Oppenheimer, F., et al. (2010). Long-term experience
with kidney transplantation from hepatitis C-positive donors into
hepatitis C-positive recipients. American Journal of
Transplantation, 10(11), 2453-2462.
Moreno, A., Cervera, C., Fortun, J., et al. (2012). Epidemiology and
outcome of infections in human immunodeficiency virus/hepatitis C
virus-coinfected liver transplant recipients: a FIPSE/GESIDA
prospective cohort study. Liver Transplantation, 18, 70-81.
Muller, E., Kahn, D., & Mendelson, M. (2010). Renal transplantation
between HIV-positive donors and recipients. New England Journal of
Medicine, 362(24), 2336-2337.
Muller, E., Barday, Z., Mendelson, M., & Kahn, D. (2012). Renal
transplantation between HIV-positive donors and recipients
justified. South African Medical Journal, 102(6), 497-498.
Muller, E., Barday, Z., Mendelson, M., Kahn,

[[Page 73796]]

D., et al. (2015). HIV-positive-to-HIV-positive kidney
transplantation--results at 3 to 5 years. New England Journal of
Medicine, 372:613-20.
Neuhaus, J., Angus, B., Kowalska, J. D., et al. (2010). Risk of all-
cause mortality associated with nonfatal AIDS and serious non-AIDS
events among adults infected with HIV. AIDS, 24(5), 697-706.
OPTN Policies and Bylaws. From https://optn.transplant.hrsa.gov/policiesandbylaws/policies.asp.
Pais, R. & Benhamou, Y. (2010). Long-term therapy for chronic
hepatitis B in HIV co-infected patients. Gastroent[eacute]rologie
Clinique et Biologique, 34, 136-41.
Parsa, A., Kao, W. H. L., Xie, D., et al, (2013). APOL1 risk
variants, race, and progression of chronic kidney disease. New
England Journal of Medicine, 369:2183-96.
Panel on Opportunistic Infections in HIV-Infected Adults and
Adolescents. Guidelines for the prevention and treatment of
opportunistic infections in HIV-infected adults and adolescents;
recommendations from the Centers for Disease Control and Prevention,
the National Institutes of Health, and the HIV Medicine Association
of the Infectious Diseases Society of America. Available at https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. (Accessed
September 2015).
Pelletier S. J., Norman S. P., Christensen L. L., et al. (2004).
Review of transplantation in HIV patients during the HAART era.
Clinical Transplantation, 63-82.
Petrosillo, N., Chinello, P., & Cicalini, S. (2006). Pulmonary
hypertension in individuals with HIV infection. AIDS, 20, 2128.
Prevention, C. f. D. C. a. (2013). HIV Surveillance Supplemental
Report.
Ragni, M. V., Dodson, S. F., Hunt, S. C., et al. (1999). Liver
transplantation in a hemophilia patient with acquired
immunodeficiency syndrome. Blood, 93, 1113-1114.
Redd A. D., Quinn T. C., Tobian A. A. (2013). Frequency and
implications of HIV superinfection. The Lancet Infectious Diseases,
13(7), 622-628.
Reeves-Daniel, A. M., DePalma, J. A., Bleyer, A. J., Rocco, M. V.,
Murea, M., Adams, P. L., et al. (2011). The APOL1 Gene and Allograft
Survival after Transplantation. American Journal of Transplantation,
11(5), 1025-1030.
Richterman, A., Blumberg, E., (2015). The challenges and promise of
HIV-infected donors for solid organ transplantation. Current
Infectious Disease Reports, 17:1-8.
Richterman, A., Sawinski, D., Reese, P.P., et al, (2015). An
assessment of HIV-infected patients dying in care for deceased organ
donation in a United States urban center. American Journal of
Transplantation, 15:2105-2116.
Riella, L.V., Sheridan, A.M., (2015). Testing for high-risk APOL1
alleles in potential living kidney donors. American Journal of
Kidney Disease, (in press).
Roland, M., Carlson, L., & Stock, P. (2002). Solid organ
transplantation in HIV-infected individuals. AIDS Clinical Care,
14(7), 59-63.
Roland, M. E., Adey, D., Carlson, L. L., & Terrault, N. A. (2003a).
Kidney and liver transplantation in HIV-infected patients: case
presentations and review. AIDS Patient Care STDS, 17(10), 501-507.
Roland, M. E., Lo, B., Braff, J., & Stock, P. G. (2003b). Key
clinical, ethical, and policy issues in the evaluation of the safety
and effectiveness of solid organ transplantation in HIV-infected
patients. Archives of Internal Medicine, 163(15), 1773-1778.
Roland, M. E., & Stock, P. G. (2003c). Review of solid-organ
transplantation in HIV-infected patients. Transplantation, 75(4),
425-429.
Sawinski, D., Goldberg, D. S., Blumberg, E., et al. (2015) Beyond
the NIH multicenter HIV transplant trial experience: Outcomes of
HIV+ liver transplant recipients compared to HCV+ or HIV+/HCV+
coinfected recipients in the United States. Clinical Infectious
Disease, (in Press).
Sherman, K. E., Thomas, D., & Chung, R. T. (2014). Human
immunodeficiency virus and liver disease forum 2012. Hepatology,
59(1), 307-317.
Sims, D. B., Uriel, N., Gonz[aacute]lez-Costello, J., et al. (2011).
Human immunodeficiency virus infection and left ventricular assist
devices: a case series. Journal of Heart and Lung Transplantation,
30, 1060-1064.
Soriano, V., Tuma, P., Labarga, P., et al. (2009). Hepatitis B in
HIV patients: what is the current treatment and what are the
challenges? Journal of HIV Therapy, 14(1), 13-18.
Stock, P. G., Barin, B., Murphy, B., Hanto, D., Diego, J. M., Light,
J., et al. (2010). Outcomes of kidney transplantation in HIV-
infected recipients. New England Journal of Medicine, 363(21), 2004-
2014.
Taege, A. (2013). Organ transplantation and HIV progress or success?
A review of current status. Curr Infectious Disease Reports, 15, 67-
76.
Tector, A. J., Mangu, R. S., Chestovich, P., et al. (2006). Use of
extended criteria livers decreases wait time for liver
transplantation without adversity impacting posttransplant survival.
Annals of Surgery, 244, 439-450.
Terrault, N. A., Roland, M. E., Schiano, T., Dove, L., Wong, M. T.,
Poordad, F., et al. (2012). Outcomes of liver transplant recipients
with hepatitis C and human immunodeficiency virus coinfection. Liver
Transplantation, 18(6), 716-726.
Touzot, M., Pillebout, E., Matignon, M., Tricot, L., Viard, J. P.,
Rondeau, E., et al. (2010). Renal transplantation in HIV-infected
patients: the Paris experience. American Journal of Transplantation,
10(10), 2263-2269.
Uriel, N., Jorde, U. P., Cotarlan, V., et al. (2009). Heart
transplantation in human immunodeficiency virus-positive patients.
Journal of Heart and Lung Transplant, 28, 667-669.
Uriel, N., Nahumi, N., Colombo, P. C., et al. (2014). Advance heart
failure in patients infected with human immunodeficiency virus: is
there equal access to care? Journal of Heart and Lung
Transplantation (in press, online).
Wada, N., Jacobson, L. P., Cohen, M., French, A., Phair, J., &
Munoz, A. (2013). Cause-specific life expectancies after 35 years of
age for human immunodeficiency syndrome-infected and human
immunodeficiency syndrome-negative individuals followed
simultaneously in long-term cohort studies, 1984-2008. American
Journal of Epidemiology, 177(2), 116-125.
Wada, N., Jacobson, L. P., Cohen, M., French, A., Phair, J., &
Munoz, A. (2014). Cause-specific mortality among HIV-infected
individuals, by CD4 (+) cell count at HAART initiation, compared
with HIV-uninfected individuals. AIDS, 28(2), 257-265.
Yoon, S. C., Hurst, F. P., Jindal, R. M., George, S. A., Neff, R.
T., Agodoa, L. Y., et al. (2011). Trends in renal transplantation in
patients with human immunodeficiency virus infection: an analysis of
the United States renal data system. Transplantation, 91(8), 864-
868.

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

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.