Donor evaluation in the era of HIV-positive organ transplantation. The importance of the Infectious Diseases specialist.

Abstract

A 61- year old female with well controlled HIV and end-stage renal disease was on the kidney transplant waitlist awaiting an organ offer, including from HIV-positive donors through the HIV Organ Policy Equity (HOPE) Act. We present three different scenarios where HIV-positive donor offers were evaluated for this one recipient, discuss the donor evaluation process, explain where the Infectious Diseases provider fits in this scheme and describe the challenges encountered by Organ Procurement Organizations. This is the first case under the HOPE Act at our center where discovery of an HIV-specific issue led to a turndown of an organ offer.

Background

Organ transplantation has become standard of care for HIV-positive individuals experiencing end-organ failure, and outcomes are similar to HIV-negative recipients¹. In 2013, the HIV Organ Policy Equity (HOPE) Act was signed into law in the United States, allowing organs from HIV-positive donors to be transplanted into HIV-positive recipients under the National Institute of Health (NIH) -stipulated research umbrella². Consequently, there is now both the opportunity for people living with HIV (PLWH) to become organ donors, living and deceased, but also the need for the Infectious Diseases (ID) physician to become familiar with the donor evaluation process. Until recently, primary HIV providers were rarely involved in donor evaluation, yet now may be called upon to provide critical historical information if their patients suddenly become evaluated as HIV-positive deceased donors. Transplant ID involvement at the receiving center generally now happens after preliminary acceptance is granted by organ specific surgical teams, based on standard center-specific measures of organ quality. Specifically, Transplant ID will review the appropriateness for donation from an HIV standpoint in regards to donor disease, existence of other comorbidities or potential AIDS-defining illnesses, as well as to ensure potential resistances found during donor evaluation can be addressed with an appropriate regimen modification of the recipient that is being considered.

Here we present three different scenarios where organ offers from HIV-positive donors were evaluated for one recipient at a single institution. Each posed different challenges for the Organ Procurement Organization (OPO) and the Transplant ID team, ranging from additional microbiologic and pathologic testing to questions of viral resistance.

Main body text

Case

Recipient:

61- year old female, with well controlled HIV and end-stage renal disease secondary to polycystic kidney disease on hemodialysis, sequentially received several potential organ offers described herein. The patient was adherent to antiretroviral therapy (ART) consisting of dolutegravir, abacavir and lamivudine with an HIV viral load <20 copies/ml and a CD4 count of 405 cells/mcl (35.8%). She had no previous acquired immunodeficiency syndrome (AIDS) -defining events. Demographics, HIV lab tests and ART are noted in Table 1. She had been on the transplant wait list for 1.5 years prior to be consented for HOPE. Her first HOPE organ offer came shortly thereafter, and subsequent offers happened during the following 17 months.

Table 1.

Donor and Recipient Characteristics

	Age (years)	Sex	Race	PHS Increased Risk	HIV Ab/Ag test	HIV viral load (copies/ml) / NAT	Creatinine (mg/dl)		Antiretrovirals
							Admission	Terminal
Recipient	61	F	AA	N/A	+	<20	N/A	N/A	ABC, 3TC, RAL
Donor #1	46	M	AA	No	+	− *	1.2	2.97	TDF, FTC, ETR
Donor #2	43	F	Cauc	No	+	+ *	0.54	0.8	None
Donor #3	23	M	Cauc	Yes	+	183,326	1.7	0.9	TDF, FTC

F: female; M: male; AA: African-American; Cauc: Caucasian; PHS: Public Health Services; ABC: abacavir; 3TC: lamivudine; RAL: raltegravir; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; ETR: etravirine; NAT: nucleic acid testing; N/A: not applicable; +: positive; −: negative

^*Donor viral loads where qualitative, not quantitative.

Organ offer 1:

A male in his forties with a known history of HIV on ART and hypertension became a potential donor after he was found in cardiac arrest of unknown etiology with evidence of anoxic brain injury. The history was obtained from his girlfriend who was able to confirm regular attendance at a local HIV clinic and provide details as outlined in Table 1. After Transplant Infectious Diseases (ID) reviewed his ART regimen this offer was given a provisional “yes” pending organ biopsy. Reassuringly, local HIV providers confirmed the donor had not previously taken integrase strand inhibitors (INSTIs) and remained undetectable up until donation. Unfortunately, a kidney biopsy showed 65% glomerulosclerosis, above our standard center threshold, thus the offer was not accepted due to poor organ quality. The etiology of the glomerulosclerosis was not known.

Organ offer 2:

A potential liver and kidney donor in her forties was provisionally accepted for organ donation. Her terminal creatinine was 0.8mg/dL and her cause of death was initially listed as ‘stroke’. She was newly diagnosed as HIV-positive as a result of her OPO evaluation. State records, family history and medication review revealed no record of ART use or awareness of her HIV. On more detailed review of her history, she had bipolar depressive disorder and two weeks earlier had been admitted for possible seizures and confusion. These were self-limiting and attributed to behavioral issues and new psychiatric medications, with a normal computed tomography (CT) of the brain. She was readmitted less than two weeks later with tibia and fibula fractures secondary to a fall, requiring open reduction and internal fixation. During rehabilitation, she complained of severe headaches and was increasingly somnolent. A few days later she was again found seizing which prompted her terminal acute care admission. CT now showed cerebral edema and possible acute stroke. Notably, white blood count (WBC) was 6.1K/mcl (lymphocytes 10%), see Table 1. As part of her HOPE Act evaluation, and without a clear etiology of new onset seizures, the ID physician at the receiving center requested the OPO to perform a lumbar puncture (LP) and magnetic resonance imaging (MRI) of the brain. The MRI confirmed brain herniation and diffuse cerebral swelling. The LP showed moderate numbers of encapsulated yeast and a positive cryptococcal Ag (titer 1:640). The organ offer was declined by all centers due to cryptococcal meningitis, and risk of donor-derived transmission infection.

Organ offer 3:

A donor in his twenties was found down, underwent cardiopulmonary resuscitation twice but had evidence of cerebral edema upon arrival to the hospital. Limited history obtained from the parents suggested the donor was a Public Health Services Increased Risk donor due to intravenous drug use and same-sex sexual behavior. WBC were 15.7K/mcl (lymphocytes 36%); further workup is outlined in Table 1. The donor had reportedly been taking Pre-Exposure Prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), although next of kin were uncertain when he began and how compliant he was. Again, the diagnosis of HIV was made during donor evaluation. Organ quality was satisfactory and this kidney was used for the recipient, although the recipient ART was reinforced with the temporary addition of rilpivirine in case of PrEP failure resulting in M184V development. A donor genotype obtained in the peri-donation period eventually only noted a K103N mutation. Upon receiving this result, the rilpivirine was discontinued and she was continued on her original ART regimen with dolutegravir, abacavir and lamivudine. At 1-year post-transplant, the recipient remains well, with creatinine of 1.1mg/dL, and no evidence of breakthrough donor viremia.

Discussion

When evaluating HIV-positive donors, expertise in the management of HIV-positive transplantation is strongly encouraged³ but general ID providers should be familiar also so as to assist in the decision-making process^4,5. Complete evaluation of potential HIV-positive donors necessarily goes beyond the standard donor evaluation^6,7. Yet organ quality non-withstanding, there appears likely only a few scenarios that would exclude PLWH from being organ donors. One of them is presented here with organ offer 2: an active opportunistic infection that had not been diagnosed pre-mortem. Donor viral resistance should still be considered as a possible contraindication to transplant, or at least warrants recipient ART modification. Fortunately, the NIH Safeguards defer ART management in these cases to the study team, i.e. as long as the proposed regimen is safe, tolerable and effective. CD4 counts at time of death alone should not be used as a metric to determine the presence of AIDS. CD4 and CD8 counts are commonly reduced at time of death or during acute illness⁸.

Organ offer 1 also highlights the importance of why a biopsy prior to an HIV-positive donor transplant consideration should continue to be required. This is not standard in HIV-negative kidney offers but is included in the NIH Safeguards and Research Criteria for Transplantation of Organs Infected with HIV² in order to exclude underlying renal diseases such as glomerulosclerosis, frequently found in PLWH. Biopsy timing, influence on organ acceptance and recipient outcomes still need to be investigated. This donors’ terminal creatinine was robust, and his HIV was well controlled on a regimen that we otherwise felt very comfortable with.

As shown with organ offer 2 and 3, new uncontrolled HIV infection is not a contraindication for deceased organ donation, even when non-compliance or uncontrolled viremia is present. In the United States, about 15% or 1 in 7 PLWH don’t know that they’re infected⁹, and some still present with AIDS-defining infections or malignancy, thus we anticipate that these donors will continue to be identified by OPOs during donor evaluation. If potential donor and recipient ART resistance profiles align and an adequate post-transplant ART regimen can be described, this might still be a suitable multiorgan donor.

Donor 3 had intermittently been on PrEP. Our recipients’ ART regimen was reinforced with rilpivirine in addition to her pre-transplant regimen given the potential for PrEP failure, but was simplified as outlined above once the donors’ genotype became available, noting only a K103N. This is a good reminder that having an understanding of local community resistance patterns can help ensure safe post-transplant ART regimens^10,11. Notably, M184V and K103N are mutations occasionally seen in naïve patients, whereas INSTI mutations remain rare in the treatment naïve population^12,13. In addition to fewer drug interactions post-transplant and an excellent safety and efficacy profile¹⁴, this is another reason why changing potential recipients to INSTI-containing regimens, if possible, is now standard of care in transplantation.

Having an OPO partner willing to help with extended evaluation, can be crucial for the HOPE Act to be successful. As highlighted here, additional testing can be necessary, creating additional cost and delay for an OPO¹⁵, yet can also be lifesaving, as in our discovery of donor cryptococcal meningitis. Transplant ID physicians should be willing to ask additional questions or request additional diagnostic procedures of OPO partners if concerns during the donor evaluations arise. Donor 2 is a tragedy for many reasons, yet is an illustrative warning for caution moving forward. Donor 2 is the only case at our institution, where the discovery of an AIDS-defining illness during evaluation led to a turndown of an organ offer that otherwise might have been approved if not for ID intervention.

The HOPE Act continues to grow in the United States providing a valuable pathway to an expanded donor pool^16,17. Risk and benefits for transplantation under the HOPE Act protocol need to be judiciously weighted and explained to the patient. Mortality on the waitlist is considerable and should be taken into consideration^18,19. Careful evaluation by Infectious Disease and OPO partners remains key to the success of the program.

Abbreviations:

AIDS

Acquired Immunodeficiency Syndrome

ART

Antiretroviral therapy

CT

Computed tomography

FTC

Emtricitabine

HIV

Human Immunodeficiency Virus

HOPE Act

HIV Organ Policy Equity Act

ID

Infectious Diseases

LP

Lumbar puncture

INSTI

Integrase strand inhibitor

MRI

Magnetic resonance imaging

NIH

National Institute of Health

OPO

Organ Procurement Organization

PLWH

People living with HIV

PrEP

Pre-Exposure Prophylaxis

TDF

Tenofovir disoproxil fumarate

WBC

White blood count