Donors with HIV and HCV for Solid Organ Transplantation: What’s New

Abstract

Purpose of the review

Passage of the HOPE Act and the advent of direct-acting antiviral (DAA) therapies have allowed for expansion of the donor organ pool to include donors with HIV and HCV, thus providing new opportunities for waitlist candidates. This article provides updates on recent studies in solid organ transplantation utilizing donors with HIV and HCV.

Recent findings

The first pilot studies of kidney and liver transplantation from donors-with-HIV to recipients-with-HIV (HIV D+/R+) show robust patient survival, comparable graft survival to transplantation from donors without HIV (HIV D−/R+) and no increased rates of HIV breakthrough. The number of HIV D+ organs utilized has been lower than initial estimates due to several potential factors. With high numbers of overdose deaths from the opioid epidemic, there have been more HCV D+ organs available, leading to transplantation in recipients without HCV (HCV D+/R−) in combination with DAAs. Outcomes in both abdominal and thoracic HCV D+/R transplantation are excellent.

Summary

With recent findings of good outcomes in both HIV D+/R+ and HCV D+/R− SOT, we feel the evidence supports both practices as standard clinical care options to mitigate organ shortage and reduce waitlist mortality.

INTRODUCTION

The benefits of solid organ transplantation (SOT) are numerous, including extension of life, improved quality of life, and decreased healthcare costs [1, 2]. With an ever-growing candidate list and a severe lack of organ donors, there have been efforts to expand the potential donor pool to include donors with curable or treatable infections [3–6]. In 2021, a record 41,354 SOT occurred in the United States, though 5,831 patients died while on the wait list and the condition of 5,371 patients deteriorated to the point of waitlist removal [7]. Through advances in medicine and antiviral drugs, organs from donors with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are eligible for transplant. The HIV Organ Policy Equity (HOPE) Act has allowed for the practice of SOT with organs from donors-with-HIV to recipients-with-HIV (HIV D+/R+) under research protocols [8]. Advances in HCV direct-acting antiviral (DAA) treatments have revolutionized the ability to transplant organs from donors-with-HCV into recipients-with-HCV as well as those who are recipients-without-HCV (HCV D+/R−). With these medical advancements, hundreds of high-quality deceased-donor organs can be used instead of discarded, thus alleviating the organ shortage, reducing long wait times, and decreasing the high mortality of wait list candidates [3, 9–11].

HISTORY OF HIV AND TRANSPLANTATION

Even with antiretroviral therapy (ART), persons living with HIV (PLWH) are at a higher risk for non-AIDS-related chronic complications [12, 13] such as end-stage liver disease (ESLD) [14, 15], end-stage renal disease (ESRD) [14, 16], and cardiovascular disease [17–20]. Additionally, PLWH with end-stage renal and liver disease have a higher mortality than their counterparts with HIV [21, 22]. Multiple studies have demonstrated the benefit of SOT for PLWH [23–26], which is now considered standard of care [27]; however, access to transplantation remains an issue for this population in particular [28, 29].

The HOPE Act was a bill passed in 2013 that reverses a prior ban on the use of HIV D+ organs and allows researchers to investigate HIV D+/R+ transplantation under IRB-approved research protocols [30, 31]. Proof of concept that HIV D+/R+ was feasible and safe came from South Africa. South Africa’s high prevalence of HIV-infection and lack of access to renal replacement therapy motivated transplant surgeon Dr. Elmi Muller to pioneer HIV D+/R+ KT [6, 32]. Encouraging results from Muller’s study in South Africa fueled support for the HOPE Act in the United States by showing HIV D+/R+ deceased donor KT survival rates of 84% and 74% at 1 and 5 years, respectively [6]. While the outcomes were promising, major differences in the population of PLWH in the United States and South Africa made it difficult to directly translate the results. The United States has a lower prevalence of HIV, but a higher prevalence of transmitted antiretroviral drug resistance, HCV coinfection, and heterogeneous immunosuppression practices [14]. Theoretical risks of HIV D+/R+ include superinfection with a second strain of HIV resulting in HIV breakthrough and progressive disease, increased organ rejection, HIV-associated organ disease in allograft, infection, and malignancy [14].

By investigating the safety of HIV D+/R+ SOT, the HOPE Act aims to provide the data necessary for physicians to determine if the procedure should be standard clinical practice [30]. An initial registry study estimating the impact of the HOPE Act predicted there would be more than 500 deceased donors with HIV infection each year [5]. The HOPE Act additionally allows the use of organs from deceased donors with a false-positive anti-HIV antibody (Ab) or HIV nucleic acid test (NAT), which were previously discarded due to the chance of the organ being truly positive [33]. Thus, if adopted widely into practice, HIV D+/R+ SOT could directly mitigate the organ shortage for PLWH and all patients on the waitlist indirectly.

OUTCOMES OF HOPE TRANSPLANTATION IN THE US

In the United States, the first prospective multicenter pilot study comparing HIV D+/R+ deceased donor KT to donors-without-HIV to recipients-with-HIV (HIV D−/R+) KT studied outcomes of 75 KT in PLWH at 14 transplant centers [34,*]. Of these, 25 transplants were HIV D+ and 50 were HIV D−; 22 of which were kidneys from donors with false positive HIV tests during donor screening [34,*]. Overall results were promising, with no deaths and no differences in 1-year graft survival (91% D+ vs 92% D−), 1-year mean estimated glomerular filtration rate (62 mL/min vs 57 mL/min), infectious hospitalizations (28% vs 26%), or opportunistic infections (16% vs 12%).

In this first US study, 60% of HIV D+ were ART experienced [34,*], which contrasts the South African study with the majority (92%) of HIV D+ being ART-naïve [35]. Even with an ART experienced donor pool, there were no episodes of HIV breakthrough [34,*]; moreover, a follow up in-depth virologic analysis study found no evidence of donor-derived superinfection [36,**].

The only suggestion of increased complication was the 1-year rejection rate, which was higher for HIV D+/R+ SOT (50% vs 29% D−, P = 0.13), trending towards statistical significance [34,*]. However, no difference in rejection was seen between groups when anti-thymocyte globulin was used for induction immunosuppression. Overall, the HOPE kidney pilot experience demonstrated excellent transplant and HIV outcomes for participants. Further research is needed to understand long-term outcomes and the mechanisms and implications of the increased rejection rates.

Additionally, the first prospective multicenter pilot study comparing HIV D+/R+ deceased donor liver transplantation (LT) to HIV D−/R+ LT was conducted from March 2016 to July 2019, including 45 LTs (including 8 simultaneous liver-kidney transplants) at 9 centers [37,*]. Of these, 24 were HIV D+/R+ LT and 21 were HIV D−/R+ LT, including 10 from HIV false-positive donors. There were no differences in one year graft survival (96% D+ vs. 100% D−), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%) or serious adverse effects (SAEs) (p > 0.5). In contrast to the KT pilot study, the participants who received HIV D+/R+ LT experienced more opportunistic infections, infectious hospitalizations, and cancer. One-year survival was good in both groups, and improved compared to historical cohorts [23, 38], but slightly lower in HIV D+/R+ vs HIV D−/R+ (83% vs 100%).

The opportunistic infections primarily consisted of cytomegalovirus (CMV) viremia, which is one of the most common post-transplant infections, not specific to PLWH. There were also three cancers related to human herpesvirus 8 (HHV8), one of which was a fatal case of an HHV8-associated lymphoma. HHV8 infection has a higher prevalence in PLWH and can be exacerbated in transplant recipients due to immunosuppression [39, 40]. HIV breakthrough occurred in 2 D+ and 2 D− recipients, but was linked to ART non-adherence, rather than donor-derived HIV superinfection [36,**, 37,*]. While these results are encouraging, further research is needed to understand recipient infections and analyze survival benefit. The first three HIV D+/R+ trials (South Africa and the two United States multicenter prospective trials) are detailed in Table 1.

Table 1:

SUMMARY OF RECENT STUDIES OF HIV D+/R+ TRANSPLANTATION

Author	Center	HIV D+ Recipients (n)	Recipient Median Baseline CD4 T-cell Count (cells/μL)	Recipient Plasma HIV RNA Viral Load Pre-Transplant (n, %)	ART Treated (n, %)		1-year (3-year, 5-year) Survival Rate	1-year (3-year, 5-year) Graft Survival Rate	1-year (3-year) Rejection Rate	HIV Breakthrough (n, %)
					Recipient	Donor
Muller et al. [6, 32]	University of Cape Town	Kidney (27)	≥200	Undetectable 27/27 (100%)	27/27 (100%)	1/23 (4%)	84% (84%, 74%)	93% (84%, 84%)	8% (22%)	0/27 (0%)
Durand et al. [34,*]	Multicenter	Kidney (25)	550	Undetectable 25/25 (100%)	25/25 (100%)	9/15 (60%)	100%	92%	50%	1/25 (4%)
Durand et al. [37,*]	Multicenter	Liver (24)	287	Undetectable 23/24 (96%)	24/24 (100%)	16/24 (89%)	83.3%	96%	10.8%	2/24 (8%)

With the devastation of the COVID-19 pandemic and PLWH already being a high-risk population, there has been concern about high mortality from SARS-CoV-2 infection in KT or LT recipients with HIV. Within HOPE in Action, there was an early report of the first 11 cases of COVID-19 among 291 recipients followed from March 2020 to September 2020 [41,**]. Of these, 10 patients were hospitalized and 4/11 died, suggesting high morbidity and mortality from the convergence of HIV and immunosuppression. However, this study was conducted early in the pandemic and many affected were in New York City, thus the high mortality may also have been due to the time, location and structural and systemic factors, since many affected were Black and Hispanic transplant recipients [41,**].

Beyond these pilot trials, to better understand outcomes and complications of HIV D+/R+ KT and LT, results of larger ongoing multicenter NIH-funded trials are anticipated (clinicaltrials.gov NCT03408106 and NCT03734393).

OPPORTUNITIES TO EXPAND HIV D+/R+ SOT

Before the HOPE Act was passed, a major prediction in support of the bill was the estimated 500–600 donors with HIV infection each year [5]. This first estimate was supported by another study by Richterman et al. who used local data from HIV clinics in Philadelphia, projecting 356 donors nationally, yielding 192 kidneys and 247 livers each year [42]. To date, the actual numbers of eligible deceased donors have been lower than anticipated [43] with 92 donors from March 2016 to March 2020, though the numbers continue to grow each year [44,*].

Several factors may explain the gap between donor potential and donors in practice. New scientific discoveries are often slow to be adopted. A prior survey of transplant centers indicated that 50 were planning protocols [45], however, as of November 2021, only 34 transplant centers were approved by UNOS to perform HIV D+/R+ SOT [46], representing only 16% (34/209) of US transplant centers [45]. There may also be legislative barriers to HOPE, as some state laws still include bans on HIV D+/R+ transplant or remain silent on the practice [47]. Studies have shown that approximately 80% of PLWH are willing to be deceased donors [48], and 84% PLWH are willing to accept organs from deceased donors with HIV [49], yet only 21% are registered as donors [48]. Therefore, increased outreach to PLWH to register as organ donors and to increase the knowledge about HOPE on a community front are warranted [45, 50].

Stigma both within and outside of the healthcare system continues to be a barrier, impacting potential HOPE donors, recipients, and transplant centers [51,*]. More specifically, there seems to be preference for donors without HIV over donors with HIV in Organ Procurement Organizations (OPOs) which may be due to the small pool of candidates with HIV that can accept these organs, potential concerns about acquisition costs given that only kidney and livers are being transplanted currently, and HIV stigma within the healthcare system [51,*]. Education about HIV organ donation, interventions to reduce HIV stigma, and partnerships with HIV organizations might help further break down the barriers that prevent the HOPE Act from reaching its full potential [50]. These potential strategies to expand the HOPE Act and realize the full potential of HOPE donors are summarized in Figure 1.

Figure 1:

STRATEGIES TO REALIZE FULL HOPE DONOR POTENTIALS

HISTORY OF HCV AND TRANSPLANTATION

The advent of DAA therapies for HCV infection in January 2014 provided another opportunity to expand the potential donor pool. DAA therapy has been shown to have HCV cure rates approaching 100%, and these medications are well tolerated even in combination with post-transplant immunosuppression [52]. As a result, we have seen a broader use of organs from donors with HCV. First for candidates with HCV, but now expanding to HCV-uninfected candidates [3]. This has occurred due to a decreasing number of HCV-viremic recipients on the waitlist, with the high cure rates of DAAs, resulting in more HCV infected organs for fewer recipients with HCV infection [53,**, 54]. There has additionally been a recent increase in young, deceased donors with HCV due to the ongoing opioid epidemic, with up to 30% of donors who died of an overdose having HCV [55]. Unfortunately, there is no clear end of the opioid epidemic in sight, and the United States has not met targets to eradication HCV infection [52], thus sustaining a population of viable deceased donors with HCV infection.

OUTCOMES OF HCV D+/R− TRANSPLANTATION

Multiple trials of HCV D+/R+ SOT have been conducted in kidney, liver, lung, and heart transplantations. These trials are detailed in Table 2.

Table 2:

SUMMARY OF RECENT STUDIES OF HIV D+/R− TRANSPLANTATION

Author	Study Name	Center	Transplant recipients (n)	HCV Donor NAT+ (n, %)	Genotype (n)	Prophylactic or preemptive DAA approach	DAA Therapy (n)	SVR12 or transmission prevention (n, %)
Goldberg et al. (2017) [56]	THINKER	University of Pennsylvania	Kidney (20)	13/13 (100%)	1 (13)	Preemptive	Elbasvir/grazoprevir x 12 weeks (20)	20/20 (100%)
Durand et al. (2018) [57]	EXPANDER	Johns Hopkins University	Kidney (10)	10/10 (100%)	1a (3) 1a/3 (1) 2 (1) 3 (1) Indeterminate (4)	Prophylactic	Elbasvir/grazoprevir x 12 weeks (7) Elbasvir/grazoprevir/ sofobuvir x 12 weeks (3)	10/10 (100%)
Durand et al. (2020) [58,*]	REHANNA	Johns Hopkins University	Kidney (10)	10/10 (100%)	1a (6) 1b (1) 3 (2) Indeterminate (1)	Prophylactic	Glecaprevir/pibrentasvir x 4 weeks (10)	10/10 (100%)
Gupta et al. (2019) [59,**]	DaPPER	Virginia Commonwealth University	Kidney (50)	27/27 (100%)	1a (19) 2 (2) 3 (6)	Prophylactic	Sofosbuvir/velpatasvir x 2 days (10) Sofosbuvir/velpatasvir x 4 days (40)	7/10 (70%) 37/40 (93%)
Feld et al. (2020) [61,**]	N/A	University of Toronto	Lung (13) Kidney (10) Heart (6) Kidney-pancreas (1)	18/18 (100%)	1 (9) 2 (2) 3 (5) Unknown (2)	Prophylactic	Ezetimibe and glecaprevir/pibrentasvir x 8 days (30)	30/30 (100%)
Terrault et al. (2020) [53**]	PRO-ACT	Multicenter	Liver (13) Kidney (11)	13/13 (100%)	Not reported	Preemptive	Sofosbuvir/velpatasvir x 12 weeks	13/13 (100%) 10/10 (100%)
Reese et al. (2018) [63]	USHER	University of Pennsylvania	Heart (10)	10/10 (100%)	1a (10)	Preemptive	Elbasvir/grazoprevir x 12 weeks (9)	9/10 (90%)
Wooley et al. (2018) [64]	DONATE-HCV	Brigham and Women’s Hospital	Lung (36) Heart (8)	41/41 (100%)	1a (24) 1b (1) 2 (7) 3 (7) Indeterminate (2)	Preemptive	Sofosbuvir/velpatasvir x 4 weeks (44)	35/35 (100%)

Kidney

The initial pilot trials of HCV D+/R− KT were THINKER (Transplanting Hepatitis C Kidneys into Negative Kidney Recipients) and EXPANDER (Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV Negative Recipients). The THINKER trial examined 20 transplant recipients treated with preemptive elbasvir/grazoprevir for 12 weeks after detection of the virus in recipients [56]. The primary outcomes were HCV cure and SAEs related to HCV-infection, yet all 20 participants had undetectable HCV RNA within four weeks of beginning elbasvir/grazoprevir. Five patients experienced elevations in aminotransferase levels, but no other SAEs were found to be related to HCV infection or treatment [56]. The EXPANDER trial investigated outcomes of 10 transplant patients using prophylactic elbasvir/grazoprevir which was started preoperatively. It also included HCV genotypes 2 and 3, in contrast to THINKER’s restriction to donors with HCV genotype 1, and in these cases added another DAA, sofobuvir [57]. In each trial, none of the recipients developed chronic HCV infection, hepatopathy, rejection, graft loss, or death, and the wait times for these organs were dramatically reduced to 1–2 months for excellent quality organs [56, 57].

Since the THINKER and EXPANDER trials, additional trials of HCV D+/R− KT have explored the optimal use of DAAs. In the REHANNA [Renal Transplants in Hepatitis C Negative Recipients With RNA Positive Donors] trial, 10 HCV D+/R− KTs were treated with 4-weeks of grazoprevir-elbasvir prophylaxis treatment [58,*]. In all 10 recipients, this treatment prevented HCV infection without treatment-related SAEs demonstrating that a full course of DAAs is not needed to prevent infection. However, there are limits to how much the prophylaxis course can be shortened. In the DaPPER trial, ultrashort courses of perioperative pangenotypic sofosbuvir/velpatasvir (SOF/VEL) DAA prophylaxis for HCV D+/R− KT were studied. In this trial, a 2-dose course utilized in 10 patients resulted in 30% transmission and a 4-dose course utilized in 40 patients resulted in 7.5% transmission, requiring retreatment with 83% ultimately achieving sustained virologic response [59,**]. In a subsequent trial by the same group, even with a one-week course of DAA therapy, there were transmissions of HCV in 9/102 (9%) participants [60,*]. Another novel approach was studied by Feld and colleagues who explored 8 days of prophylaxis with glecaprevir/pibrentasvir plus ezetimibe, a lipid-lowering medication which blocks the receptor HCV uses for entry. They found no HCV transmissions with this strategy in 13 lung, 10 kidney, 6 heart, and 1 kidney-pancreas HCV D+/R− transplant recipients [61,**].

In contrast to prophylaxis, other studies have utilized a transmit-and-treat approach as was used in THINKER, in which treatment begins after HCV viremia is detected in the recipient post-transplant with a full course of DAAs. This approach is practical from a real-world perspective as centers can rely on insurance to provide medication rather than conducting a costly trial; however, insurance approval for DAAs can take several weeks to obtain post-transplant and long delays may have unwanted consequences. For example, in one trial where treatment was started at a median of 76 days post-transplant, several complications were noted, such as fibrosing cholestatic hepatitis, and higher than expected rates of allograft rejection, CMV, and BK infection [62].

Liver

HCV D+/R− transplantation has also been explored in the liver, although importantly in this scenario, prophylaxis is not an option as HCV infection has been established in the donor liver. In addition, the viral kinetics differ greatly between kidney and liver since the liver brings with it a greater initial viral burden. The PRO-ACT (Prevention of De Novo HCV with Antiviral HCV Therapy Post-Liver and Post-Kidney Transplant Recipients) trial was a multicenter prospective study reviewing the efficacy and safety of preemptive SOF/VEL in KT and LT with HCV-uninfected recipients [53,**]. This trial focused on the kinetics of HCV infection post-KT and -LT with a preemptive DAA strategy. Among 13 LT and 11 KT recipients, the median time from the operation to the start of DAAs was 7 and 16.5 days in LT and KT, respectively. The results showed that preemptive SOF-VEL for 12 weeks led to statistically significant faster rates of viral eradication in LT than KT recipients, with the mean change in HCV RNA from Day 1 to week 1 as −4.03 in liver recipients and −3.07 in kidney recipients (p=0.008). Additionally, the viral kinetics of infection appear to differ based on organ type, with slower viral clearance in KT. This difference in kinetics is potentially due to differences in initiation of DAAs, use of more intense immunosuppression in KT, and differences in immunological control [53,**]. These data support earlier treatment of HCV-infection rather than a delayed approach to reduce the risk of severe HCV recurrence.

Thoracic

USHER (Using Hepatitis C positive Hearts for Negative Recipients) was a single-arm trial of HCV D+/R− heart transplantation [63]. The trial used the DAA elbasvir/grazoprevir to treat 10 patients after recipient HCV infection was first detected and was limited to donors with HCV genotype 1. Among participants, 9 achieved sustained virologic response at 12 weeks, with one patient death due to antibody-mediated rejection and multi-organ failure considered unrelated to HCV transmission or treatment. Two other recipients had grade 2R acute cellular rejection on allograft biopsy, but this resolved. While SAEs occurred, they were not linked to HCV infection or its therapy, and there were overall high cure rates and positive clinical outcomes [63].

DONATE-HCV (The Donors of Hepatitis C NAT [nucleic acid amplification test] Positive Thoracic Allografts for Transplantation Evaluation in Non-HCV Recipients) studied 44 transplants (36 lung and 8 heart) using organs from donors with variable genotype HCV infection [64]. The participants were treated with preemptive SOF/VEL started a few hours post-transplantation and continued for 4 weeks, analogous to a postexposure prophylaxis treatment. The outcome of this trial was 100% sustained virological response and 100% graft survival at 6-months post-transplant of the first 35 patients enrolled. While there was an increase in acute cellular rejection cases (15/28, 54%) in the HCV D+/R− lung transplant recipients, compared to 13 of 44 HCV D−/R (30%); the difference did not reach statistical significance when adjusted for potential confounders [64].

OPPORTUNITIES TO EXPAND HCV TRANSPLANTATION

While HCV+-to-HCV- SOT is on the path to becoming standard of care, several challenges remain. The national utilization of HCV-exposed donors for HCV-naïve recipients in both KT and LT has grown dramatically, but high-quality HCV Ab+ donor organs, both viremic and aviremic, have remained underutilized [65]. DAAs continue to be expensive and patients often experience challenges obtaining insurance approval for DAA treatment before HCV infection [66]. As organ donors with HCV infection become more widely accepted, the question remains as when to begin DAA treatment: prophylactically (before transplantation, prevents viremia), preemptively (post-transplantation after viremia, before clinical manifestations), or delayed (after the disease presents clinically). A study of 838 HCV D+/R− KT and 355 HCV D+/R− LT between April 2015 and December 2018 saw an increase in KT from <1 to 26/month and an increase in LT from <1 to 8/month [65]. These recipients spent cumulatively less time on the waitlist and had lower Model for End-Stage Liver Disease (MELD) scores for the LT recipients, but these organs still remain underutilized [65]. Earlier treatment has shown promising results in preventing life-threatening complications, but coverage from third party payers for DAA therapy presents numerous roadblocks [67]. When HCV-NAT+ SOT becomes standard of care, transplants centers need to establish ways to support the costs of therapies, potentially establishing a pretransplant approval system [66].

CONCLUSION

There have been excellent outcomes with both HIV- and HCV-positive donor transplant. With the organ shortage, we feel that available evidence supports both practices becoming standard clinical practice with future studies continuing to refine the practice.

KEY POINTS.

• Both HIV D+/R+ SOT and HCV D+/R− SOT can alleviate the organ shortage by providing more donor organ options

• The HOPE Act revolutionized the use of organs from donors with HIV, yet there are still barriers to realizing the full potential in practice

• DAAs have HCV cure rates approaching 100% which allow donors with HCV to provide organs for recipients without HCV

• Research continues to be conducted to determine the optimal timing of DAAs depending on the organ, whether prophylactic, preemptive, or delayed