Advisory Committee on Organ Transplantation (ACOT) November 17, 2015 Human immunodeficiency virus (HIV) Organ Policy Equity (HOPE) Act Safeguards and Research Criteria for Transplantation of Organs infected with HIV HOPE Act – Update Jonah Odim, MD, PhD Chief, Clinical Transplantation Section Transplantation Branch, NIAID Advisory Committee on Organ Transplantation (ACOT) November 17, 2015

HOPE: Background HIV+ to HV+ organ TX only under IRB-approved research protocols While Muller (NEJM, 2015) has presented excellent results in 27 HIV+ to HIV+ kidney transplants [South Africa] there is no such evidence for safety, efficacy or effectiveness in North America In aligning with the HOPE Act, the Final Safeguards and Research Criteria are meant to support the acquisition of new clinical knowledge and mechanistic insights about HIV+ to HIV+ organ transplantation in the US Emily Levine from the Office of General Counsel previously reviewed the statutory details of the HOPE Act for us six months ago and I will not repeat this here. The only world experience in HIV+ to HIV+ organ transplantation is from South Africa.

HOPE Act: Safeguards and Research Criteria Research Protocol/Consent development and IRB approval Drafting the Criteria HOPE Act ENACTMENT Final Delegation of Authority from NIH to NIAID: Jan. 20, 2015 ACOT: April 13, 2015 ACOT: March 13, 2015 ATC: May 2, 2015 Grant applications from the transplant community are starting to come in addressing the mandate of the HOPE Act Public Law 113-51 Signed into law by President Obama, Nov. 21, 2013 2013 2014 2015 2016 2017 HHS-NIH working group 2 YEARS POST ACT ENACTMENT 4 YEARS POST ACT ENACTMENT (+ annually thereafter) WTC: Town Hall meeting July 28, 2014 ICAAC meeting Sept. 7, 2014 Delegation of Authority from Secretary HHS to NIH: Nov. 25, 2014 Draft Safeguards and Research Criteria [Federal Register]: June 18, 2015 End 60-day comment: Aug. 17, 2015 ACOT: Nov. 17, 2015 Final Safeguards and Research Criteria: Nov. 21, 2015 Secretary shall review the results of scientific research in conjunction with the OPTN Determine whether the results warrant revision of the standards of quality

Living Donors HIV-infected living donors may be at long-term risk for renal and/or liver disease and some centers would not use living HIV+ donors It is premature to embark on living HIV+ donors without prior experience with deceased HIV+ donors (recommended a staged approach) Desire to donate is strong and the evaluation of the risks and benefits of such a decision is personal and unique to a given D/R pair The HOPE Act (2013) does not include any language addressing use of living HIV+ donors

Living Donors (2) Evidence for the safety of organ donation by an HIV infected individual will only be generated by clinical research Participation in HIV+ to HIV+ clinical research is made freely, based on informed consent, without coercion Provision of a rigorous, transparent education, informed consent process describing alternatives, risks, potential benefits, unknowns and the need for long-term follow-up. Discussions must address how research injuries are managed and paid for in the long-run, available independent advocates not a part of research team

Independent Advocates Some strongly supported the requirement for independent advocates for both the HIV+ recipients and prospective HIV+ living donors. Others viewed this as unnecessary 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 info, answer questions, and provide assurance of equal access to health care regardless of the patient’s decision regarding research participation

Transplant Hospital Experience Several from academic institutions, professional societies, and OPTN indicated the requirements for physicians’ and surgeons’ prior experience in HIV-negative to HIV+ organ transplants 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 ASTS to use the collective team experience rather than individual experience [5 cases of HIV negative to HIV+ organ transplantation over 4 years]

Donor eligibility criteria (CD4+ T-cell counts & HIV viral load) Concerns about the usefulness and relevance of requiring a minimum CD4+ T-cell count in the donor arguing these counts will not predict allograft function and among HIV+ to HIV+ transplants in South Africa excellent outcomes were observed in recipients of kidneys from donors with CD4+ cell counts well below the 200 minimum In response to these comments the Criteria were revised to acknowledge although collection of CD4+ T-cell counts during donor evaluation is required, no minimum criterion is imposed for organ acceptance

Donor eligibility criteria (2) Some commenters preferred excluding any donors with detectable plasma viral load due to risk of transmitting 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 in many cases that potential donors will have adequate medical history available to inform the team’s assessment and maximally reduce the risk of transmitting resistance virus.

Biospecimens Several commenters emphasized the importance of a pre-transplant donor organ biopsy. The Final Criteria includes a requirement for performance of a pre-implant “back-table” biopsy. Although there are no further specimen collection requirements, we strongly encourage the inclusion of serial biospecimens in the individual research protocols. These specimens will be a valuable resource to the community in studies related 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. A purpose of the criteria presented in the Final Safeguards and Research Criteria is to ensure all investigators conducting research in HIV+ to HIV+ TX collect similar data elements. This standardization will facilitate the subsequent review mandated in the HOPE Act

Program Specific Reports (PSRs) Negative impact of adverse outcomes at transplant centers conducting research in HIV+ to HIV+ transplants on transplant PSRs. Commenter proposed: “…transplants performed with HIV+ donor to HIV+ 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 take on these patients leading to fewer patients receiving life-saving organ transplants.”

Donor and Recipient eligibility criteria for HIV+ sero-concordant transplant pairs (D/R) HIV+ variables DD New Dx Known Dx Living Donor Recipient CD4+ T-cells (require) None ≥ 500 for 6 m before harvest ( ≥ 200) ≥ 200 (kidney) and ≥100 (liver); Hx of OI ≥ 200 HIV-1 RNA Pre-TX Biopsy < 50 < 50* OI No (invasive) Pre-TX Biopsy Independent Advocate Independent Advocate * Patients unable to tolerate ART due to organ failure or recent ART start

HHS appreciates the time and effort taken by the 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 HOPE Act Safeguards and Research Criteria for Transplantation of Organs Infected with HIV Special thanks to ACOT, AOPO, AST, ASTS, CDC, CMS, DHHS, FDA, HIVMA, HRSA, NATCO, NIH and the HIV community