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Critical Review

Cardiac Transplantation in HIV-Positive Patients: A Narrative Review

Wairimu, Faith MBBSa; Ward, Natalie C. PhDb,c; Liu, Yingwei MDc; Dwivedi, Girish MD, PhDa,b,c

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JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1, 2021 - Volume 87 - Issue 2 - p 763-768
doi: 10.1097/QAI.0000000000002647
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Abstract

INTRODUCTION

Before the introduction of combination antiretroviral therapy (cART), patients infected with HIV experienced poor prognosis including high rates of opportunistic infections, rapid progression to AIDS, and significant mortality. The introduction of cART enabled suppression of HIV viral replication and immune reconstitution, which delays disease progression and improves survival. An analysis of 88,504 patients with HIV, revealed that patients starting ART during 2008–2010 had lower all-cause mortality in the first year after starting therapy than those who started therapy in 2000–2003. Similar results were observed at 2 and 3 years after ART initiation, with results not explained by CD4 count or viral load. The increased life expectancy was believed to be reflective of transition to less toxic drugs, improved adherence, prophylactic measures, and management of comorbidities.1

This prolonged survival has transformed HIV from a rapidly fatal illness due to AIDS-related complications to a chronic disease.2–4 Consequently, the relative burden of other chronic diseases, including cardiovascular disease (CVD)5 and, in particular, end-stage heart failure, is now the leading cause of non-HIV death within this patient population.2,6–8 A recent statement by the American Heart Association has highlighted the increased risk of MI, stroke, and heart failure even with effective viral suppression in HIV patients. This is largely believed to be due to inflammation and immune dysregulation for atherosclerosis; however, very few studies have investigated the pathophysiology between HIV and heart failure.5 Furthermore, the Veterans Aging Cohort Study in 98,015 participants observed that individuals infected with HIV have an increased risk of heart failure, both with and without preserved ejection fraction. In addition, reduced ejection fraction occurred earlier in patients with HIV compared with non-HIV-infected patients.9 Also, antiretroviral side effects such as direct organ toxicity, dyslipidemia, and type 2 diabetes mellitus also increase the risk for atherosclerosis, which is twice as prevalent in HIV-positive compared with HIV-negative populations.10 Indeed, this increased prevalence of atherosclerosis could account for an increased incidence of ischemic cardiomyopathy and subsequent heart failure, which may eventually necessitate transplantation (Fig. 1). However, studies investigating CVD prevention and treatment as well as implementation of CVD treatment regimes in HIV patients are still required.5

F1
FIGURE 1.:
HIV-related factors associated with accelerated atherosclerosis, ischemic cardiomyopathy, and heart failure.

Historically, HIV infection was deemed an absolute contraindication for transplantation because of limited life expectancy, high-risk status of the patient, and concerns for posttransplantation immunosuppression, which could lead to infectious and neoplastic complications and acceleration of HIV progression.11,12 Since the development of cART, however, life expectancy for HIV-positive patients has significantly improved. In addition, there is a low incidence of opportunistic infections and the current antiretrovirals have an improved toxicity profile.

Furthermore, there has been an increasingly positive experience after renal and liver transplantation in HIV-positive patients, with similar life and graft survival albeit with an increased risk of rejection. Since 2007, 0.5%–0.6% of deceased liver transplant recipients and 0.7% of deceased kidney transplant recipients were HIV-seropositive. Since 2009, 0.3% of living donor liver transplant recipients and 0.3%–0.4% of living donor kidney transplant recipients were HIV-positive.13 The current status of cardiac transplants in HIV-positive patients, however, remains unclear. With this in mind, we conducted a literature review on cardiac transplantation in patients with HIV.

METHODS

An electronic literature search was conducted on Cochrane, Embase, MEDLINE, and Scopus from their inception to September 2020 to identify studies reporting on the effects of cardiac transplant in patients who were known to be HIV-positive. Search strategy included free-text words and the Medical Subject Headings terms for cardiac transplantation in patients with known HIV. The search used key words and MeSH terms and included the following terms: “heart transplantation,” “cardiac transplantation,” “HIV,” and “AIDS.” Only articles that published in English were included. Two reviewers (Y.L. and F.W.) independently reviewed titles and abstracts and retrieved studies that were believed to be relevant for inclusion. Six studies and 2 abstracts were identified for review.

RESULTS

This narrative review focused on cardiac transplantation in patients who were known to be HIV-positive. As early death from AIDS-specific causes diminishes, the relative burden of end-stage organ disease such as heart failure has increased, yet HIV-positive patients are rarely considered for cardiac transplantation. The projected life survival of a person newly diagnosed with HIV is 24.2 years,14 which is more than double the 11 years of anticipated survival after heart transplant in the general population.15 As a result, HIV-positive patients with end-stage heart failure could potentially benefit from cardiac transplantation because it removes the immediate threat of mortality and leads to further productive years. In a survey of heart transplant centers in the United States and Canada, more than half of the centers reported considering HIV-positivity as a contraindication to cardiac transplantation.16 The centers tended to be smaller, low volume centers, and the most commonly cited reasons were high-risk status, fear of HIV progression secondary to posttransplantation immunosuppression, and cART/immunosuppression drug–drug interactions.16 More recently, a prospective survey of 155 cardiac surgeons across Canada found that most would perform coronary artery bypass graft or valve surgery on patients with controlled HIV; however, most considered positive HIV status a prohibitive risk factor for cardiac transplantation.17

The first heart transplant in a patient known to be HIV-positive was performed in 2001 and reported in 2003, with other countries around the world subsequently reporting successful transplants (Table 1).18,19 The US Scientific Registry of Transplant Recipients database reported 20 heart transplants performed in HIV-positive patients from January 1999 to July 2004, with the one- and 3-year survival rates comparable with those observed in 9154 HIV-negative recipients.20 Overall, most patients were younger than 50 years (93%), and most were men. Apart from one patient who presented with Pneumocystis jirovecii pneumonia, followed by an AIDS diagnosis,19 all patients were on cART and had stable disease management with CD4-cell counts >200 cells/mm3 and no previous opportunistic infections or AIDS-defining illness. The most common indication for transplantation was reported as dilated cardiomyopathy. The average follow-up period was 2.5 years. Despite rejection being commonly reported, the outcome was satisfactory in most.20 A retrospective case series analysis of the nationwide Organ Procurement and Transplantation Network, which is managed by the United Network of Organ Sharing, identified 41 HIV-positive patients who underwent cardiac transplant. This study demonstrated that HIV-positive patients have excellent posttransplant survival up to 5 years of follow-up, including those patients who underwent bridge to transplantion with a ventricular assist device. The rates of cardiac allograft vasculopathy and malignancy at 5 years were similar to that seen in the overall heart transplant population, and standard immunosuppression was used safely in HIV-positive patients. Despite these positive findings, however, it was noted that cardiac transplant was offered to HIV-positive patients in only a limited number of centers (<80%) in the United States.21

TABLE 1. - Characteristics of Included Patients Known to be HIV-Positive Before Cardiac Transplantation; Modified From Ref. 18.
Year and Country Sex Age HIV Status at Tx CD4 Count at Time of Tx Immunosuppression Follow-up (mo) Rejection Outcome at End of Follow-up
2001, United States M 42 Positive 637 CyA/MMF/P/daclizumab 88 Yes NR Alive
2001, United States M 39 Positive >250 CyA/MMF/P 43 Yes 3A Dead
2005, United States M 47 Positive 443 CyA/MMF/P/daclizumab 40 Yes NR Alive
2007, United States M 29 Positive 536 CyA/MMF/P/daclizumab 14 Yes NR Alive
2007, Spain M 39 Positive >500 FK/MMF/P 84 Yes 3A Alive
2008, United States F 43 Positive 793 CyA/MMF/P/daclizumab 31 No Alive
2008, United States M 48 Positive 360 CyA/MMF/P/daclizumab 6 No Alive
2008, France M 32 Positive 700 NR 30 Yes 2R Alive
2008, United States M 47 Positive 360 NR 31 No Alive
2009, Italy M 36 Positive NR CyA/EVR/P/ATG 36 Yes 2R Alive
2009, United States F 42 Positive >450 FK/MMF/P 24 Yes NR Alive
2011, Italy M 42 Positive NR FK/P 19 No Alive
ATG, atithymocyte immunoglobulin; CyA, cyclosporin A; EVR, everolimus; FK, tacrolimus; MMF, mycophenolate mofetil; NR, not reported; 1R, mild; 2R, moderate; 3R, severe.

Although cardiac transplantation in HIV-positive patients is still in its infancy and long-term outcomes are yet to be determined, short-term survival seems to be comparable with the general population. Previous reports indicate one-, 2-, and 5-year survival rates of 100%, 100%, and 63%, respectively.16,22 The traditional belief that the required postorgan transplantation immunosuppression would be deleterious to HIV patients has not held true. After transplantation, reports suggest the patients' HIV status was stable with no progression, apart from the patient who presented with AIDS before transplantation. Furthermore, viral load was undetectable, CD4-cell count was normal to near normal, and no opportunistic infections were reported. The lack of notable progression to AIDS is in keeping with previous findings in the liver and kidney transplant populations.23,24

Safety, Tolerability, and Rejection

Both HIV and postorgan transplantation require complex medication regimens. Several significant interactions have been reported during concomitant use of antiretroviral drugs and immunosuppressants (Figs. 2 and 3).25–27 High rates of allograft rejection, up to 2–3 times the rate of HIV-negative recipients, have been previously reported in liver and kidney transplants.24,28,29 The increased rejection rates are believed to be in part due to altered levels of immunosuppressive drugs, namely calcineurin inhibitors and target of rapamycin inhibitors. Underlying HIV infection-related mechanisms may also play a part. Stock et al postulated that there may be a memory response despite low CD4+ T-cell counts. This may be related to allosensitization induced after transmission of HIV-containing human leukocyte antigen molecules from one host to another. In addition, the homeostatic expansion of T cells in HIV infection is often coupled with the acquisition of memory phenotype, which in turn is associated with increased responsiveness of the T cell and nonspecific enhancement of alloimmunity. Finally, previous infections can lead to the generation of memory alloreactive T cells as a result of cross-reactivity.28

F2
FIGURE 2.:
Mechanism of immunosuppression.
F3
FIGURE 3.:
Mechanism of action by antiretroviral therapy.

Protease inhibitors, which are part of the standard HIV regimen, are known to inhibit cytochrome P450 enzymes and P-glycoprotein, both of which are involved in tacrolimus and cyclosporine metabolism, leading to prolonged half-lives of these immunosuppressants. These enzymatic pathways are also involved in target of rapamycin inhibitor metabolism, a mainstay of immunosuppression in heart transplantation (Table 2).30 Serious concerns have been raised about maintaining the appropriate level of immunosuppression after transplantation, with over immunosuppression potentially increasing the risk of opportunistic infections and AIDS-defining illnesses and inadequate immunosuppression increasing the likelihood of organ rejection. The issue of immunosuppression metabolism may be mitigated by the use of a newer class of antiretrovirals known as integrase strand transfer inhibitors, which are metabolized by an alternate UDP-glucuronosyltransferase 1-mediated pathway. This group of drugs has fewer drug–drug interactions and is being used as alternatives in patients undergoing renal transplantation (Table 2).

TABLE 2. - Potential Interactions Between Commonly Used cART and Immunosuppression Therapies
HAART Class Tacrolimus MMF Prednisolone Everolimus and Sirolimus
Protease inhibitors:
Darunavir and Ritonavir
CYP450 3A4 inhibition
Increased levels
Not studied May increase effect Increased levels
Pharmacokinetic enhancer:
Cobicistat
CYP450 3A4 inhibition
Increased levels
Not studied May increase effects (eg, cushingoid and hyperglycemia) May increase levels
Nonnucleoside reverse transcriptase inhibitors (NNRTI):
Efavirenz
CYP450 3A4 inhibition
Increased levels
Not studied May increase effects May increase levels
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI):
Abacavir
May reduce levels Potential risk of lactic acidosis with didanosine, stavudine, and zidovudine
In vitro synergy with abacavir and tenofovir
Nil known May reduce levels
Fusion inhibitors:
Enfuvirtide

Chemokine co-receptor antagonists (CCR5):
Maraviroc
Not studied
Integrase inhibitors (INSTIs):
Elvitegravir and raltegravir
May increase levels Not studied May increase effect May increase levels
INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor.

Similarly, interactions with integrase inhibitors (raltegravir and dolutegravir) or the CCR5 inhibitor, maraviroc, are not expected because these agents are neither inhibitors nor inducers of CYP450 (Table 2). Going forward, the use of these newer agents, including fusion inhibitors, which have less pharmacokinetic interactions, less toxicity, and potential pharmacodynamic synergy, portends the possibility of improved pharmacological management for HIV-positive patients undergoing solid organ transplant.

During 1996–1999, most HIV patients started a protease inhibitor-based regimen, whereas after 2000, nonnucleoside reverse transcriptase inhibitor-based regimens were most common. The protease inhibitors indinavir, nelfinavir, and saquinavir were replaced by atazanavir, darunavir, and lopinavir. Of the nonnucleoside reverse transcriptase inhibitors, efavirenz was the most commonly used third regimen drug from 2000 onward. The NRTIs didanosine, stavudine, and zidovudine were replaced by abacavir and tenofovir.1 The optimal immunosuppression regimen for HIV-positive patients is unknown and most centers use the same regimens as for HIV-negative patients. Given the higher rates of cellular rejection (also seen in liver and kidney transplantation), it is recommended that immunosuppression doses not be reduced over long-term follow-up.

Despite the complex medication regimen necessary and the rational concerns regarding drug–drug interactions, medication dosing was well controlled in the reviewed cardiac studies. Patients were generally maintained on their pretransplant antiretroviral regimen together with immunosuppression therapy drugs and dosages similar to the general transplant candidates, although lower doses of cyclosporine were needed to attain therapeutic levels.31 The cases of rejection that were reported were responsive to glucocorticoids, which likely represent a marker of milder levels of rejection.

Because of the scarcity of donor organs, transplant organ allocation has always posed an ethical dilemma, requiring the concurrent consideration of need, efficacy, urgency, and equality. Even presuming a relatively worse outcome in HIV-positive patients, distributive justice should still consider HIV-positive patients and expected posttransplant survival should not be the sole criteria. Patients with other risk factors including age, female gender, racial minority, and diabetes all have worse outcomes, but they remain within the eligible transplant pool.32–34

CONCLUSIONS

Improved antiretroviral therapy has markedly extended the life expectancy of HIV-positive patients, allowing end-stage organ dysfunction such as heart failure the opportunity to present. Patients with HIV have twice the incidence of CVD as the general population yet are rarely considered for transplantation. The few HIV-positive patients who have received a cardiac transplant in the post-cART era have performed remarkably well with outcomes similar to the general population.

Given the equivalent rate of complications and survival, the current tendency to automatically exclude HIV-positive patients from consideration for cardiac transplantation represents a practice that may no longer be justifiable based on current medical evidence. Further education regarding the safety and feasibility of cardiac transplantation in HIV-seropositive patients is needed. There are presently few publications recounting experience within this population and evidence will likely remain limited because of ethical and pragmatic considerations. HIV-seropositive patients should undergo a case-by-case assessment because cardiac transplantation may be a potentially viable option in a carefully selective group.

ACKNOWLEDGMENTS

The authors would like to acknowledge Kathleen Lirio from Fiona Stanley Hospital Medical Illustration department for her artistic contribution to this chapter. The authors would also like to acknowledge Matthew Rawlins from Fiona Stanley Hospital Pharmacy department for his help in reviewing the potential interactions between commonly used antiretroviral and immunosuppression therapies.

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Keywords:

cardiovascular disease; HIV; cardiac transplant

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