The Times, They are a-Changing

HOPE for HIV-to-HIV Organ Transplantation

Abstract

HIV-infected persons who achieve undetectable viral loads on antiretroviral therapy currently have near-normal lifespans. Liver disease is a major cause of non–AIDS-related deaths, and as a result of longer survival, the prevalence of end-stage renal disease in HIV is increasing. HIV-infected persons undergoing organ transplantation generally achieve comparable patient and graft survival rates compared to their HIV-uninfected counterparts, despite a nearly threefold increased risk of acute rejection. However, the ongoing shortage of suitable organs can limit transplantation as an option, and patients with HIV have higher waitlist mortality than others. One way to solve this problem would be to expand the donor pool to include HIV-infected individuals. The results of a South Africa study involving 27 HIV-to-HIV kidney transplants showed promise, with 3- and 5-year patient and graft survival rates similar to those of their HIV-uninfected counterparts. Similarly, individual cases of HIV-to-HIV liver transplantation from the United Kingdom and Switzerland have also shown good results. In the United States, HIV-to-HIV kidney and liver transplants are currently permitted only under a research protocol. Nevertheless, areas of ambiguity exist, including streamlining organ allocation practices, optimizing HIV-infected donor and recipient selection, managing donor-derived transmission of a resistant HIV strain, determining optimal immunosuppressive and antiretroviral regimens, and elucidating the incidence of rejection in HIV-to-HIV solid organ transplant recipients.

In Brief

The HIV Organ Policy Equity (HOPE) Act legalizing liver and kidney donation from one HIV-infected person to another in the setting of a clinical research protocol in the United States could expand to other organs, but there are some unanswered concerns and challenges to broad implementation.

The advent of protease inhibitors in 1996 transformed human immunodeficiency virus (HIV) from a progressively fatal illness to a manageable, chronic disease.¹ The current era has seen reductions in acquired immunodeficiency syndrome (AIDS)–related deaths, and a near-normal life expectancy is expected for most patients who achieve a normal CD4 count and viral load suppression on antiretroviral therapy (ART).² Currently, about half of all deaths in people on ART in Europe and North America are not caused by AIDS or its associated opportunistic infections, but rather by non–AIDS-defining cancers, cardiovascular and respiratory diseases, and end-stage liver and kidney failure.^1,3-5 Given co-infections with hepatitis B and C (HBV and HCV), hepatitis-associated glomerulonephritis, membranous nephropathy, drug-related nephrotoxicity (particularly tenofovir disoproxil fumarate) and HIV-associated nephropathy (HIVAN), end-stage renal disease (ESRD), and liver failure remain a significant cause of non-AIDS deaths.^3-6

Although the survival of HIV-infected patients with ESRD has improved since 1997, it is still very low compared with age-, gender-, and race-matched HIV-uninfected patients, with 1- and 2-year survival rates of 58 and 41% versus 87 and 79%, respectively.⁷ In addition, the dramatic decrease in AIDS-related mortality observed after the advent of combination ART in the mid-1990s seems to be greatly attenuated in the subset of HIV-infected patients who are undergoing dialysis.⁸ Despite improved survival after liver transplantation in HIV-infected individuals treated with ART, some transplant candidates do not survive to transplantation.⁹ Although pretransplant mortality has been linked to higher Model for End-Stage Liver Disease scores,¹⁰ preliver-transplant survival is significantly shorter in HIV-infected than HIV-uninfected liver transplant candidates, and a subset of HIV-infected candidates with early death before transplantation were shown to rapidly succumb to infection.⁹

Solid organ transplantation of HIV-infected individuals who are doing well on ART has been steadily increasing since the late 1990s.¹¹ Liver and kidney transplantation remain the most common transplant procedures performed in these patients.¹¹ Several studies have demonstrated acceptable short-term survival and no increased risk of HIV-related complications in kidney and non-HCV liver transplant recipients,^12-18 despite the use of lymphocyte-depleting induction agents such as thymoglobulin.^12,19-21 Although HIV-infected transplant recipients have high rates of acute rejection,^11-14 graft and patient-survival rates are generally comparable to those of their uninfected counterparts.^12,14,18-21 A notable exception is that of individuals with HCV co-infection, who experience more aggressive recurrence of HCV, rejection, and sepsis with resultant graft loss and death^18,22,23 in the era before the availability of direct-acting antivirals for the treatment of HCV. Indeed, in a national study of over 500 adult kidney transplant recipients with HIV, HIV-uninfected and HIV mono-infected kidney transplant recipients had similar graft and patient survival, whereas HIV/HCV co-infected recipients had worse outcomes.²⁴ Limited data with cardiac, lung, and pancreatic transplantation also seem to be promising.^25-27 Herein, we discuss the evolution and historical background, current practices, and areas of uncertainty related to HIV-to-HIV solid organ transplantation.

ORGAN SHORTAGE

There is a growing disparity between the number of patients waitlisted for organ transplant and the organs available.²⁸ For example, one study found that 46% of kidney transplant candidates who were older than 60 were projected to die before the availability of a deceased donor transplant.²⁹ This shortage, while impacting all patients with organ failure, may disproportionately affect HIV-infected persons, who have higher waitlist mortality compared to HIV-uninfected individuals.³⁰ Additionally, patients with HIV are less likely to be placed on the transplant waitlist in the United States³¹ and less likely to undergo transplantation.¹⁰ An intuitive solution would be to allow the use of HIV-infected deceased donors (HIVDD) for HIV-infected recipients, which can potentially lead to expansion of the donor pool by an additional 360 to 600 donors annually in the United States, based on the results of two studies.^30,32 Waiting times for HIV-infected recipients willing to accept organs from HIV-infected donors would then be anticipated to decrease from an excess of 7 years to less than 1 year.³³ African American individuals, who have the greatest risk of HIVAN and continue to suffer from poor access to renal transplantation, may experience the most benefit from the use of HIVDD.²⁸ This practice would also positively impact both HIV-infected and HIV-uninfected individuals on the same waitlist because HIV-infected transplant candidates would now be eligible for organs from both HIV-infected and HIV-uninfected donors, which would increase the size of the HIV-uninfected donor pool available for HIV-uninfected recipients.³⁴

LEGAL STATUS

The first HIV-to-HIV kidney transplants were performed in South Africa in 2008, not because of legislative changes but rather of sheer need.^19,35,36 HIVAN is the leading cause of ESRD in South Africa,³⁵ but in 2008, HIV infection was considered a contraindication for both state-funded dialysis and renal transplantation from HIV-uninfected donors in patients with ESRD.³⁶ South Africa did not, however, have any specific legal restrictions on using HIV-infected organ donors.³⁷ Thus, physicians at Groote Schuur Hospital South Africa, led by Dr. Elmi Muller, began performing HIV-to-HIV kidney transplants.³⁵ The first four patients faced a choice between an unproven, experimental procedure or death from renal failure, and chose to undergo transplantation from an HIVDD instead.^19,35 Subsequently, after the initial results were made available, the human research ethics committee of the Faculty of Health Sciences at the University of Cape Town undertook a comprehensive review of the data, and in 2009, the exclusion of HIV-infected individuals from renal transplantation was lifted, enabling receipt of organs from HIV-uninfected donors as well as HIV-infected donors as part of the study. The dialysis ban was also lifted but continues to be a limited resource.

In 2007, Switzerland began allowing transplantation from HIV-infected donors to HIV-infected recipients after an amendment of the bylaws of the Swiss Federal Act on Transplantation, though to date, the results of only one transplant, which took place in 2015, have been published.³⁸ HIV-to-HIV liver transplantation has also been performed in the United Kingdom,³⁹ where the National Health Service–Blood and Transplant permits the use of HIV-, HBV-, and HCV-infected organ donors at the discretion of the transplant team (Dr. David Mutimer, written communication, December 2016).

In the United States, legislation regarding HIV-to-HIV transplantation has recently changed. The use of HIV-infected organs was made illegal in 1988, when an amendment to the National Organ Transplantation Act (NOTA) was put forth and prevented the Organ Procurement Transplantation Network (OPTN) from acquiring organs from HIV-infected patients.^28,40,41 In 2011, Boyarsky et al. published their study showing that expanding the donor pool to include HIV-infected individuals would lead to around 500 to 600 additional donors.³² This, coupled with encouraging HIV-uninfected to HIV-infected transplant outcomes^12-14 and the South African experience,³⁵ resulted in widespread media coverage throughout 2011, followed by meetings with members of Congress in Capitol Hill between 2011 and 2012.⁴² The HIV Organ Policy Equity (HOPE) Act was introduced on February 14, 2013⁴² and aimed at legalizing liver and kidney donation from one HIV-infected person to another in the setting of a clinical research protocol. The HOPE act had bipartisan approval and was unanimously passed by the United States House of Representatives and signed into law by President Obama on November 21, 2013.^34,43

The HOPE act required that the following deliverables be met within 2 years of it being signed: (a) revision of the law that prohibited the recovery and use of HIV-infected organs, (b) creation of policies for the recovery and transplantation of organs from HIV-infected donors, and (c) development of research criteria related to HIV-to-HIV organ transplantation, a task that was delegated to the National Institutes of Health.⁴³ The first two requirements were met on November 21, 2015, and the research criteria were published on November 23, 2015.⁴³ These research criteria state that livers and kidneys from individuals with HIV may be transplanted into individuals who are already HIV-infected and are participating in clinical research approved by an institutional review board (IRB), until such time that participation in clinical research as a requirement for HIV-to-HIV transplants is no longer warranted. The use of living donors is permitted.⁴⁴

Under the HOPE act, the results of the HIV-to-HIV trials in the United States will be reviewed within 4 years of the date of enactment and annually thereafter, to determine whether the OPTN policies should be revised and whether continuing to require that HIV-to-HIV transplantation be conducted exclusively as clinical research is necessary.⁴³ To allow for the evaluation of this effort within a specific timeframe, the OPTN created what is known as an “open variance” for HIV-to-HIV transplants. A transplant center may apply to be part of this “open variance” as long as it complies with all OPTN requirements, provides documentation of local IRB approval, and submits regular data monitoring safety reports.^34,45 The Executive Committee approved an expiration date of January 1, 2018 for this open variance. When the Board of Directors meets in December 2017, they will decide if the variance should be extended, amended, or terminated.⁴³

Johns Hopkins University became the first site in the United States to conduct a clinical trial under the above criteria (NCT02602262) after receiving approval from OPTN in January 2016.³⁴ The objective of this trial is to evaluate the safety of HIV-to-HIV kidney and liver transplantation and to assess the survival benefit of accepting an HIV-infected organ compared with waiting for an HIV-uninfected donor.³⁴ The first HIV-to-HIV kidney transplant in the United States was subsequently performed in March 2016.⁴⁶ At the time of publication of this review, 13 transplant centers have enrolled with the OPTN to participate in HIV-to-HIV research studies, and approximately 80 candidates are currently listed to receive organs from HIV-infected donors.^43,47

CURRENT STANDARD FOR ANTIRETROVIRAL THERAPY

HIV RNA (viral load) and CD4 cell count are the two surrogate markers of ART response and HIV disease progression that have been used for decades.⁴⁸ The goal of ART is to achieve and maintain durable suppression of HIV RNA, below the level of detection of commercial assays (viral load <20‐75 copies/mL, depending on the assay used). Increases in CD4 counts are expected to occur in parallel to suppression of viremia. In the United States, ART is now recommended for all HIV-infected patients regardless of their viral load or CD4 count, though these guidelines vary from country to country. All HIV-infected individuals should have baseline HIV drug resistance testing, using genotypic assays.

The ART regimen for the treatment-naive patient generally consists of two nucleoside/tide reverse transcriptase inhibitors (NRTIs) in combination with a third active drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a protease inhibitor (PI) with a pharmacokinetic booster (cobicistat or ritonavir), or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (Table 1).⁴⁸ There are currently many excellent options for initial therapy, including fixed-dose co-formulations. Most first-line regimens include an INSTI as the third agent. Selection of a regimen for a particular patient should therefore be guided by factors such as virologic efficacy, toxicity (especially renal impairment), pill burden, dosing frequency, drug–drug interaction potential, resistance testing results, comorbid conditions, and cost. Most patients do well on lifelong standard ART. Patients with suboptimal adherence, however, are at a substantially increased risk of developing drug-resistant HIV, and the prevalence of antiretroviral resistance in ART-naive people (“transmitted resistance”) varies by country.¹ The management of a drug-resistant strain of HIV can be complex and requires the use of second- and third-line regimens, in consultation with a practitioner experienced in managing resistant HIV. Detailed recommendations can be found on the Department of Health and Human Services website and are updated regularly.⁴⁸

TABLE 1: HIV drugs used in the United States

Of particular importance to organ transplant recipients are drug interactions with calcineurin and mammalian target of rapamycin (mTOR) inhibitors related to the potent inhibition of the CYP3A4 system by the pharmacological boosters ritonavir and cobicistat.^11,49 Patients receiving boosted PI regimens typically require only 0.375 to 0.5 mg of tacrolimus once or twice a week to maintain therapeutic targets.¹¹ A similar degree of adjustment is necessary when boosted PIs are used with sirolimus. In addition, the pharmacokinetic curve of tacrolimus in HIV-infected patients receiving PIs does not show the normal peak-and-trough pattern but rather resembles a flat line with a half-life of up to 20 days, implying that “troughs” may not reflect true exposure to tacrolimus⁵⁰ Expert guidelines therefore recommend avoiding PIs in HIV-infected transplant recipients.¹¹ The potential for drug interactions also exist with the NNRTIs because of their ability to induce CYP3A4-mediated metabolism.¹¹ INSTIs, on the other hand, have no drug interactions, making them appealing options for transplant recipients.⁵¹ A list of relevant drug–drug interactions is summarized in Table 1.⁴⁸

OUTCOMES IN HIV-TO-HIV ORGAN TRANSPLANTATION

Limited prospective outcome data exist on HIV-to-HIV transplantation (Table 2).^19,38,39 The largest cohort study to date comes from South Africa, where Dr. Muller and her team initially reported 100% 1-year graft survival of four HIV-infected patients who received kidneys from HIVDD.³⁵ A follow-up study detailing the 3- and 5-year outcome data of these and an additional 23 patients was subsequently published.¹⁹ All recipients were virally suppressed (HIV RNA viral load <50 copies/mL) on standard ART regimens consisting of two NRTIs plus either an NNRTI (59%) or a ritonavir-boosted PI (41%). Median pretransplant CD4 count was 288 cells/mm³ (interquartile range 236‐511 cells/mm³). Overall, 11% of recipients were co-infected with HBV, but none had HCV. To reduce the risk of transmission of a resistant virus, donors were required to either be ART-naive or to have only been on first-line ART regimens; in all, only one donor was on ART. All patients received thymoglobulin induction and were maintained on tacrolimus, mycophenolate mofetil (MMF), and prednisone. In patients receiving NNRTIs, their pretransplant ART regimen was initially switched to a boosted-PI-based regimen to suppress donor viremia and lower the cost of tacrolimus by benefiting from the interaction with ritonavir. Concerns about calcineurin-inhibitor-related nephrotoxicity emerged, and these patients were placed back on NNRTIs. It should be noted that INSTIs are not widely available in South Africa because of cost.⁵²

TABLE 2: Summary of available studies on HIV-to-HIV solid organ transplantation, as of December 2016^19,38,39

Two of the 27 recipients had delayed graft function, one because of venous thrombosis on day 1 and the second because acute, refractory antibody-mediated rejection ensued that necessitated removal of the graft after 2 weeks. The other 25 patients all had well-functioning grafts at 1 year. Patient survival was 84% at 1 and 3 years and 74% at 5 years, and graft survival was 93% at 1 year and 84% and 3 and 5 years. These were comparable to the rates of patient and graft survival among HIV-uninfected recipients at their institution during the same time period (91% 1-year and 85% 5-year patient survival; 88% 1-year and 75% 5-year graft survival, respectively). Rejection rates were 8% and 22% at 1 and 3 years, respectively; six of the eight episodes of rejection were successfully treated with glucocorticoids, thymoglobulin, or plasmapheresis. Three patients had posttransplant biopsies that showed changes typical of early HIVAN, but none of them had clinically significant renal impairment or proteinuria.¹⁹

Posttransplant causes of death included pancreatitis, myocardial infarction, urosepsis caused by carbapenem-resistant Enterobacteriaceae, and invasive pulmonary aspergillosis. Other nonfatal infections included urinary tract infections, osteomyelitis, respiratory infections, gastroenteritis, meningitis, and extrapulmonary tuberculosis. Notably, there were no AIDS-defining opportunistic infections in any of the patients. No patient experienced increased HIV viremia, and viral levels have remained undetectable after transplantation.¹⁹

The report from the United Kingdom describes a patient who was virally suppressed (HIV RNA viral load <20 copies/mL) with a CD4 count of 420 cells/mm³ while receiving tenofovir, emtricitabine, and efavirenz.³⁹ He also had HCV and developed cirrhosis, complicated by hepatocellular carcinoma. HCV treatment details and status of HCV viremia of the recipient at the time of transplantation were not provided. As his tumor size would have soon precluded him from meeting transplant criteria in the United Kingdom, he agreed to undergo transplantation from an HIV- and HCV-infected donor in July 2011. The donor had HIV viremia, but HCV RNA was undetectable. ART was held on postoperative day 0 but resumed the next day via a nasogastric tube. A detectable HIV viral load was observed on day 2 after transplantation, earlier than predicted from viral kinetic studies of ART discontinuation in other settings. Subsequent analysis showed this virus was virtually identical to the donor’s virus. The patient’s ART was not changed, and viremia was suppressed within 7 weeks and has remained undetectable since. However, the patient also developed detectable HCV RNA viremia on day 16 after transplant (unknown whether this was donor- or recipient-derived), and cirrhosis recurred 3 years posttransplant. He achieved a sustained virologic response after therapy with sofosbuvir, simeprevir, and daclatasvir.

The third report comes from Switzerland and describes a patient with cirrhosis and HIV with an M184V mutation, which confers reduced susceptibility to the NRTIs emtricitabine and lamivudine. He was treatment-experienced but had been virally suppressed (HIV RNA viral load <50 copies/mL) for years, with a CD4 count of over 300 cells/mm³, most recently on a regimen of tenofovir, emtricitabine, and rilpivirine.³⁸ He also had HCV that spontaneously cleared and HBV that was treated with interferon-gamma, which was stopped because of intolerance. The donor was also virally suppressed but had multiple NRTI mutations, including M184V and various other mutations called thymidine analogue mutations (41L, 210W, and 215Y), which can affect all NRTIs. He had previously been on several ART regimens but was on tenofovir, emtricitabine, and dolutegravir at the time of death. Between November 2014 and June 2015, the recipient’s clinical condition rapidly deteriorated, and he therefore signed an informed consent to receive a liver from this HIV-infected donor. He received basiliximab induction, tacrolimus, MMF, and hepatitis B immunoglobulin. Rilpivirine, tenofovir, and emtricitabine were restarted on day 2 posttransplant, together with raltegravir and subcutaneous enfuvirtide to cover for the donor’s HIV resistance genotypes. ART was modified 3 months after transplantation to a fixed-dose combination of rilpivirine, tenofovir, emtricitabine, and dolutegravir. HIV, HBV, and HCV viral loads remained undetectable after transplantation. Postoperative course has been unremarkable, and no rejection episodes occurred during the 5-month follow-up period.

Finally, there are additional reports in the news media of HIV-to-HIV kidney and liver transplants from the United Kingdom and the United States, but no further details have been made available in medical journals yet.^46,53

AREAS OF UNCERTAINTY

Organ Allocation

Although the above data are promising and suggest that HIV-to-HIV organ transplantation may become more acceptable in the next few years, several unanswered questions and challenges remain. The expansion of the donor pool to include HIV-infected individuals may lead to alterations in organ allocation practices, to ensure that suitable organs from HIV-infected donors are not wasted. Furthermore, stringent procedures should continue to be followed to avoid the inadvertent transplantation of HIV-infected organs into HIV-uninfected recipients, though this has not happened in the setting of transplantation of HCV-infected organs.³⁴ The use of living donors may help assuage these concerns. However, although the HOPE Act permits the use of living donors, the American Society of Transplantation advises caution; just as uncontrolled hypertension and diabetes are contraindications to living donation, HIV infection may have long-term consequences to the health of the kidney donor.⁵⁴

Recipient Selection

Individuals with poorly controlled HIV would likely not be candidates for organ transplantation, even from HIV-infected donors, given that all recipients in the current reports have been virally suppressed.^19,38,39 An obvious concern would be that of adherence: a patient who is unable to adhere to a simple ART regimen would not be expected to adhere to complex immunosuppression and the required monitoring associated with transplantation. However, patients who are unable to take ART because of the presence of advanced liver failure may be an exception to this. It is also unclear whether allowances would be made for HIV-infected persons who have newly documented adherence but have failed to achieve viral suppression because of the presence of extensive drug resistance, especially if a living donor is an option for them. HIV-infected patients with previously treated opportunistic infections (with the exception of progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, primary central nervous system lymphoma, and visceral Kaposi’s sarcoma) have received kidneys from HIV-uninfected individuals (in the HIV-TR trial),¹² with no increases in opportunistic infections. In contrast, the South African study excluded any patient with a previous opportunistic infection.¹⁹ Although it appears intuitively logical to exclude recipients with active or untreated opportunistic infections, the timing of HIV-to-HIV organ transplantation in patients with previous opportunistic infections warrants further investigation.

Donor Selection

Criteria for the optimal HIV-infected donor are yet to be defined. In the South African trial, both donors and recipients were carefully selected to avoid the chance of resistance,¹⁹ whereas in the Swiss case, both donor and recipient had HIV strains with different resistance mutations.³⁸ If a deceased donor has been engaged in care, then determining the history of treatment, resistance, opportunistic infections, and other variables may theoretically be carried out relatively easily, though realistically, this type of information is unlikely to be readily available through third-party historians during donor assessment, and access to medical records may prove difficult during the donor evaluation process.⁵⁵ This would also be easier to accomplish if living donors are used. A more challenging scenario is the deceased HIV-infected donor who is not engaged in medical care, especially in high-income countries, where the rates of transmitted resistance range between 10 and 17%.¹ It is unlikely that the results of HIV genotyping would be available at the time of organ recovery, so implementing proper informed consent procedures in these situations is critical. A recent study showed that HIV-uninfected brain dead donors have reduced absolute numbers of CD4 and CD8⁺ cells related to strategies of deceased donor management (vasopressors, diuretics, steroids) and immune dysfunction from central nervous system injury, suggesting that CD4 counts may be an inconsistent metric for assessing the risk of opportunistic infections among HIV-infected donors.⁵⁵ In addition, the HOPE Research Criteria allow for the use of donors with any CD4 count.⁴⁴ Thus, reliance on established protocols to decrease the risk of donor-derived infections should continue.⁵⁶

Superinfection with a Resistant HIV Strain

Concerns have been voiced about transmitting a resistant strain of HIV through the transplanted organ.^19,34,36 It has been established that the transmission of a new strain of HIV from one individual to the other (“HIV superinfection”) does occur, though the true incidence varies.⁵⁷ Viremia caused by a superinfecting strain of HIV may only be detectable for a short period of time, and its viability will likely depend on several viral and host-related factors, including viral fitness. Indeed, resistant viruses are typically “less fit” than wild-type viruses and have less replicative capacity.⁵⁷ In addition to the potential ART-related complexities associated with superinfection with a resistant strain, HIV uses different receptors to enter cells: viruses are generally CCR5-tropic, CXCR4-tropic, or dual/mixed viruses.¹ CXCR4/mixed viruses are associated with rapid disease progression, and transmission of CXCR4 tropic virus to a patient with a CCR5 tropic virus may be problematic.³⁴

The available data on HIV superinfection are nonetheless reassuring. No cases of transmitted resistance have emerged from South Africa, though careful donor selection and the fact that transmitted resistance is low in South Africa likely contributed to this.¹⁹ The case from the United Kingdom does describe donor-derived HIV viremia, which occurred when the patient had only been off ART for 1 day. As this was too soon to be rebound viremia caused by the patient’s own virus, donor-derived superinfection was suspected and confirmed by sequencing.³⁹ The virus had no resistance mutations (Dr. David Mutimer, written communication, December 2016), and the viremia subsequently cleared with the patient’s standard pretransplant ART. The Swiss patient, on the other hand, already had a resistant strain and willingly accepted an organ from a patient with an even more resistant strain. Preemptively adjusting the recipient’s ART to treat both donor and recipient virus posttransplant prevented any detectable donor-derived viremia³⁸; notably, no pharmacological boosters (ritonavir or cobicistat) were used. These experiences imply that rapid onset of posttransplant HIV viremia, especially in the setting of transient ART interruptions, likely represents donor-derived superinfection as opposed to recipient-derived rebound viremia. Based on these very limited data, preemptive management of known donor-derived resistance by adjusting the recipient’s ART seems to be effective and may not be as problematic as expected given the availability of agents that do not interact with calcineurin inhibitors. Challenges may be encountered in donors whose salvage regimen consists of a boosted PI. The availability of data from additional HIV-to-HIV organ transplants will shed light on the true significance and optimal management of posttransplant HIV viremia and the factors that determine donor-derived versus recipient-derived viremia.

Antiretroviral Therapy

Management of ART in HIV-infected organ transplant recipients has historically been problematic because of the interactions between calcineurin inhibitors, mTOR inhibitors, and boosted PIs.¹¹ As mentioned above, the availability of integrase inhibitors and NNRTIs, especially in high-income settings, has minimized these concerns. However, the optimal long-term ART regimen is not known, though it makes intuitive sense to avoid regimens containing tenofovir disoproxil fumarate (TDF), given its association with nephrotoxicity (Table 1).⁵⁸ The availability of tenofovir alafenamide (TAF), which has similar efficacy as TDF but lower rates of nephrotoxicity, is a welcome addition to the antiretroviral armamentarium.

Acute Rejection, Graft Function, and Immunosuppression

Rejection rates among HIV-infected recipients have been reported to be up to three times as high as those of HIV-uninfected recipients.^12,20 The South African study showed 1- and 3-year rejection rates of 8 and 22%, respectively.¹⁹ One explanation for these high rates of rejection could be a result of CYP3A4 interactions between immunosuppressive agents and ART,¹² which can be generally avoided in the current era. Alternative explanations include dysregulations in innate and cell-mediated immunity.^11,12 In a study of 19 HIV-infected kidney transplant recipients from HIV-uninfected donors, despite the lack of detectable viremia, HIV-1 was documented in kidney allografts in 13 out of 19 patients.⁵⁹ In five of these patients, podocyte infection was associated with the development of proteinuria and increased loss of graft function, suggesting that HIV infection of the graft itself may adversely influence transplant outcomes.⁵⁹ Indeed, three patients had pathological changes consistent with early HIVAN in the South African study,¹⁹ and two patients in the HIV-TR study had newly diagnosed HIVAN despite suppressed viremia. Although this was hypothesized to have been related to the recipient’s CD4 count and donor and recipient ethnicity,¹² additional data are needed to determine the true incidence of rejection and HIVAN after HIV-to-HIV transplantation.

The optimal agent for maintenance immunosuppression in HIV-infected organ transplant recipients is uncertain. The HIV-TR trial showed that tacrolimus-based regimens are superior to cyclosporine in HIV-infected recipients.¹² Furthermore, another study showed a greater incidence of acute rejection at 1 year among patients on cyclosporine versus tacrolimus (58 vs. 21%, respectively, p = 0.003).⁶⁰ HIV-infected patients receiving sirolimus-based therapy had a 2.2-fold higher risk of acute rejection than those receiving calcineurin inhibitor–based regimens.²⁰ However, sirolimus enhances the activity of enfuvirtide, efavirenz, and maraviroc in vitro,⁶¹ suggesting a potential role for the use of mTOR inhibitors in cases of transplant-associated transmitted resistance. Belatacept is a calcineurin inhibitor–sparing agent that may be an attractive option in persons with HIV. A CD28 co-stimulation blocker approved for the maintenance immunosuppression in kidney transplant recipients, it results in significantly greater estimated gains in glomerular filtration rates compared to calcineurin inhibitor–based therapy,⁶² despite the increased risk of biopsy-proven acute rejection.⁶³ It was successfully used in an HIV-infected kidney transplant recipient (from an HIV-uninfected donor) with delayed graft function and resulted in normalization of renal function once tacrolimus was discontinued.⁶⁴

The ideal agent for induction in HIV-infected recipients, regardless of the HIV status of the donor, has also not been defined. An increased risk of graft loss was seen with thymoglobulin induction in HIV-infected recipients of HIV-uninfected kidneys in the HIV-TR trial,¹² though this was not observed in the South African study.¹⁹ In addition, a study of over 800 HIV-infected kidney transplant recipients showed lower rates of delayed graft function, less graft loss, and a trend toward lower mortality in those who received either thymoglobulin or interleukin-2 (IL-2)-receptor blocker induction.²¹ Those who received induction with thymoglobulin had the lowest risk of acute rejection. Furthermore, another study comparing over 500 HIV-infected kidney transplant recipients to over 90000 HIV-uninfected controls found that although acute rejection was greater among those with HIV, this difference was not seen among HIV-infected patients who received thymoglobulin for induction.²⁰ Notably, AIDS-associated opportunistic infections have not been observed with induction therapy. Thus, although it is evident that induction agents, including lymphocyte-depleting and nondepleting drugs, are commonly used and appear to have a beneficial effect on rejection without increasing the risk of infection, more data are required to determine the effects of induction immunosuppressive agents on infection, allograft, and patient outcomes.⁶⁵

FUTURE DIRECTIONS

The implementation of the HOPE Act is a welcome progress for the medical community in the United States. If the results are reassuring, performing HIV-to-HIV heart, lung, multivisceral, and other organ transplants may become feasible. We remain optimistic that the results of HIV-to-HIV transplantation in the United States will show positive results, mirroring the South African, British, and Swiss experiences. Should this turn out to be the case upon review of the data in 2018, and should the research requirement for HIV-to-HIV transplantation be lifted, we would then encourage widespread adoption of this practice across transplant centers nationwide.

ACKNOWLEDGMENTS

The authors thank Dr. Elmi Muller and Dr. David Mutimer for their insights on the legal status of HIV-to-HIV transplantation in South Africa and the United Kingdom, respectively. The authors would also like to thank Dr. Deborah McMahon (University of Pittsburgh) for her helpful review of the antiretroviral therapy section.