Heart or lung transplant outcomes in HIV-infected recipients

Heart or lung transplant outcomes in HIV-infected recipients

ARTICLE IN PRESS http://www.jhltonline.org ORIGINAL CLINICAL SCIENCE Heart or lung transplant outcomes in HIV-infected recipients Christine E. Kova...

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ORIGINAL CLINICAL SCIENCE

Heart or lung transplant outcomes in HIV-infected recipients Christine E. Koval, MD,a Maryjane Farr, MD,b Jill Krisl, PharmD,c Ghady Haidar, MD,d Marcus R. Pereira, MD,e Nabin Shrestha, MD,a Maricar F. Malinis, MD,f Nicolas J. Mueller, MD,g,h Margaret M. Hannan, MD,i Paolo Grossi, MD,j and Shirish Huprikar, MDk From the aDepartment of Infectious Diseases, Cleveland Clinic, Cleveland, Ohio; bDivision of Cardiology, Columbia University Irving Medical Center, New York, New York; cDepartment of Pharmacy, Houston Methodist Medical Center, Houston, Texas; dDivision of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; e Division of Infectious Diseases, Columbia University Irving Medical Center, New York, New York; fDivision of Infectious Diseases, Yale University Medical Center, New Haven, Connecticut; gDepartment of Infectious Diseases and Hospital Epidemiology, Zurich, Switzerland; hSwiss Transplant Cohort Study, Basel, Switzerland; iDepartment of Clinical Microbiology, Mater Misericordiae University Hospital, Dublin, Ireland; jDepartment of Infectious and Tropical Diseases, University of Insubria, Varese, Italy; and the kDivision of Infectious Diseases, Mt. Sinai Hospital, New York, New York.

KEYWORDS: heart transplant; heart/lung transplant; HIV infection; lung transplant; transplant rejection

BACKGROUND: Limited published data exist on outcomes related to heart and/or lung transplantation in human immunodeficiency virus (HIV)-infected individuals. METHODS: We conducted a multicenter retrospective study of heart and lung transplantation in HIVinfected patients and describe key transplant- and HIV-related outcomes. RESULTS: We identified 29 HIV-infected thoracic transplant recipients (21 heart, 7 lung, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared with an International Society for Heart and Lung Transplantation registry cohort, we demonstrated similar 1-, 3-, and 5-year patient and allograft survivals for each organ type with a median follow up of 1,064 (range, 184−3,745) days for heart and 1,540 (range, 116−3,206) days for lung recipients. At 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Risk factors for rejection were inconclusive, likely because of small numbers, but may be related to cautious early immunosuppression and infrequent use of induction therapy. Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs). Median CD4 counts changed from baseline to 1 year from 399 to 411 cells/ml for HTRs and 638 to 280 cells/ml for LTRs. Acquired immunodeficiency syndrome−related events, including infections and malignancies, were rare. Rates of severe renal dysfunction suggest a need to modify nephrotoxic anti-retrovirals and/or immunosuppressants. CONCLUSIONS: HIV-infected HTRs and LTRs have similar survival rates to their HIV-uninfected counterparts. Although optimal immunosuppression is not defined, it should be at least as aggressive as that for HIV-uninfected recipients. Such data may help pave the way for the use of hearts and lungs from HIV-infected donors in HIV-infected recipients through HIV Organ Policy Equity Act protocols. J Heart Lung Transplant 000;000:1−10 Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved.

Reprint requests: Christine Koval, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, G21, Cleveland, Ohio 44122. Telephone: +1-216636-1873. Fax: +1-216-445-9446. E-mail address: [email protected]

Since the advent of combination active anti-retroviral therapy (cART), prognosis for human immunodeficiency virus (HIV)-infected patients has markedly improved and acquired immunodeficiency syndrome (AIDS)-related deaths have

1053-2498/$ - see front matter Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved. https://doi.org/10.1016/j.healun.2019.09.011

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decreased. With longer life expectancy, chronic medical conditions such as cardiovascular diseases, cirrhosis, and renal disease are on the rise and often lead to end-stage organ disease.1,2 Cardiovascular disease is among the top 3 causes of non−AIDS-related mortality in HIV-infected individuals.1 For patients with HIV with end-stage renal and liver diseases, organ transplantation has become the standard of care.3 Published studies demonstrate acceptable short- and long-term outcomes for kidney and liver transplantation in HIV-infected patients.3,4 Surprisingly, infection-related outcomes have been reassuring, whereas higher rates of rejection have been described compared with HIV-uninfected transplant recipients3,5,6. There are limited data on thoracic transplantation in HIV-infected patients. Previously published case reports, case series, and 2 recently published manuscripts of Scientific Registry of Transplant Recipients (SRTR)-reported data describe acceptable outcomes for over 50 heart transplant recipients (HTRs) and 4 lung transplant recipients (LTRs).7−15 Nevertheless, most heart and/or lung transplant centers have not performed transplantation in HIV-infected patients.16 A survey conducted on attitudes toward heart transplantation revealed mixed perception regarding transplantation for the HIV-infected.16 Increased awareness of acceptable outcomes among HIVinfected patients could improve access to thoracic transplant for such patients. Hence, we conducted a multicenter retrospective study of heart and/or lung transplantation in HIVinfected patients and describe key transplant- and HIV-related outcomes. Moreover, we sought to describe patient characteristics and detailed HIV management strategies not currently available in transplant registries.

Methods We conducted a retrospective multicenter study involving HIVinfected adults that underwent heart, lung, or heart and/or lung transplant with at least 1 year of follow up. Participating transplant centers were identified through the American Society of Transplantation and International Society for Heart and Lung Transplantation (ISHLT) memberships with approval of the society’s executive committees. Institutional review board approval was granted at participating sites. Data were generated as standard of care for most sites between 2000 and 2016, collected retrospectively, de-identified, and electronically transmitted securely via REDCap. Data from Switzerland were prospective as part of the Swiss Transplant Cohort. Collected data included recipient demographics, underlying pulmonary or cardiac disease, pre-transplant HIV history and comorbid diseases, available donor data, transplant information, immunosuppression regimens (but not dosing or target drug levels), cART, post-transplant infections, biopsyproven rejections, allograft and patient survival, CD4+ T-cell counts, and plasma HIV RNA. HIV RNA assays became more sensitive, with the undetectable range reported from <400 to <20 copies/ml. Infections were possible, probable, or proven and categorized by organism type. Rejection was biopsy-proven. Grading for heart transplant biopsies encompassed the 1990 and the 2004 ISHLT grading systems. Effort was made to convert 1990 grades to 2004 grades with mild rejection distinguished from moderate and severe. Cellular- and antibody-mediated rejection were reported as separate entities when possible.

Statistical analysis Rates of patient survival, graft rejection, and infection were calculated at 1-year follow up. Estimated rate of patient survival was calculated over a 7-year period using the Kaplan−Meier method and compared with the total population of primary HTRs and LTRs reported publicly in the ISHLT data registry from 1990 to 2015. Categorical variables were compared using Fisher’s exact test and continuous variables using the Mann−Whitney U test.

Results Patient characteristics are listed in Table 1. There were 21 heart, 7 lung, and 1 heart and/or lung transplants reported in 29 recipients from 14 sites in the US and Europe. Five HTRs were previously reported, and all US cases likely were published recently from SRTR data.14,15 Median follow up was 1,064 days (range, 184−3,745) for HTRs and 1,540 days (range, 116−3,206) for LTRs. Median age was 48 years (range, 27−58) for HTRs and 57 years (range, 37−70) for LTRs. Median time on the wait list was 82 days (range, 9−757) for HTRs and 42 days (range, 4−200) for LTRs. Median baseline CD4+ T-cell counts were 398 cells/ml for HTRs and 536 cells/ml for LTRs. Two HTRs had detectable (117 and 1,044 copies/ml) HIV RNA at time of transplantation; all others were transplanted with undetectable HIV RNA. All were on a 3-drug cART regimen at transplantation, divided fairly evenly between integrase inhibitor−, protease inhibitor−, and non-nucleoside reverse transcriptase inhibitor−based regimens. The cART regimen was changed for 5 HTRs and 1 LTR (4 to integrase inhibitors) because of possible drug interactions with immunosuppressive agents. Tenofovir disaproxil fumarate was included in 12 of 21 (57%) and 3 of 7 (42%) cART regimens for HTRs and LTRs post-transplantation, respectively. Prior opportunistic infections were present in 6 patients, 2 with multiple significant past opportunistic infections (including cytomegalovirus [CMV], Pneumocystis jirovecii pneumonia, Mycobacterium avium complex, and Mycobacterium tuberculosis infections). One had curative treatment for hepatitis C virus before transplantation. Induction therapy was provided for 28% of HTRs compared with 42% of LTRs, with basiliximab most frequent. Anti-thymocyte globulin (ATG) was used for one HTR and one LTR. Three quarters of the HTRs and all LTRs received tacrolimus. Most were on a calcineurin inhibitor (CNI), mycophenolate mofetil, and prednisone. HTR- and LTR-specific characteristics are listed in Table 2a. Underlying heart disease was due to non-ischemic cardiomyopathy for 17 of 21 (81%) and ischemic cardiomyopathy for 4 of 21 (19%). Ventricular assist devices (VADs) were present in 12, five for longer than 12 months. Pretransplant VAD-specific infections occurred in seven. At time of organ offer, twelve were at home and seven were hospitalized in the intensive care unit. Inotropes were being used in eight and two were supported on intra-aortic balloon pump. LTR-specific characteristics are listed in Table 2b. Underlying lung disease was due to interstitial lung disease and/or idiopathic pulmonary fibrosis in 4 patients, chronic

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Koval et al. Table 1

Heart or lung transplant in HIV-infected

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Baseline and Donor Characteristics

Characteristic Recipient Transplant year, median (range) Age, median Biological gender, male Race/ethnicity, white Location at time of transplant offer Intensive care Hospital, not ICU Outpatient CD4 T-cell count, cells/ml, median (IQR) HIV RNA viral load, undetected Prior opportunistic infectiona CMV IgG Ab positive Hepatitis B core Ab positiveb Hepatitis C Ab positivec ART regimen Integrase inhibitor−based Protease inhibitor−based NNRTI-based Other Antibody induction ATG Basiliximab Calcineurin-based regimen Tacrolimus Cyclosporine Donor Age, median (n = 15, 4, 1) Gender, male (n = 15, 4, 1) CDC increased risk Race/ethnicity, white (n = 10, 3, 0)

Heart (n = 21)

Lung (n = 7)

Heart and/or lung (n = 1)

2012 (2000−2016) 48 15 (71) 7 (33)

2012 (2009−2016) 57 7 (100) 7 (100)

2016 54 1 —

7 (33) 2 (10) 12 (57) 399 (153−1,580) 19 (90) 4 (19) 21 (100) 6 (28) 1 (5)

— — 7 (100) 638 (264−1,296) 7 (100) 2 (28) 7 (100) 2 (28) —

— — 1 78 1 — 1 — —

8 (38) 4 (19) 8 (38) 1 (5) 6 (28) 1 (5) 5 (24)

3 (42) 3 (42) 2 (28) — 3 (42) 1 (14) 2 (28)

1 — — — — — —

16 (76) 5 (24)

7 (100) —

1 —

33 11 (73) — 3 (30)

40 3 (75) — 3 (100)

19 1 — —

Abbreviations: Ab, antibody; ATG, anti-thymocyte globulin; ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; CMV, cytomegalovirus; HIV, human immunodeficiency virus; ICU, intensive care unit; IgG, immunoglobulin G; IQR, interquartile range; NNRTI, non-nucleoside reverse transcriptase inhibitor. Data are reported as n (%) unless otherwise noted. a Cytomegalovirus, Pneumocystis jirovecii pneumonia, Kapsosi sarcoma, Mycobacterium avium complex, thrush, varicella zoster virus, Mycobacterium tuberculosis. b Hepatitis B virus surface antigen negative. c Hepatitis C treated successfully pre-transplant.

obstructive pulmonary disease, cystic fibrosis, and Langerhans histiocytosis. Pulmonary hypertension accounted for organ failure in the heart and/or lung transplant recipient (H/ LTR). Median lung allocation score for the 6 patients for whom it was reported was 47 (range, 32−59). Three underwent single lung transplant and 4, bilateral transplant. All recipients were at home at the time of organ offer.

Outcomes

outcomes were not significantly different. However, for HTRs, 3- and 5-year survival (64%) for the HIV-infected patients diverged from the registry cohort. Three- and 5-year survival were 80% and 75% for LTRs. Cause of death for HTRs included glioblastoma, sepsis, medical non-adherence, AIDS-related complications in a cART non-adherent patient (high HIV RNA and low CD4 count and erosive candida esophagitis), candidemia, and allograft failure. For LTRs, adenovirus and Klebsiella pneumoniae infection were reported causes of death.

Survival Rejection Table 3 describes key outcomes, and Figure 1a and b depict Kaplan−Meier survival curves. Overall, survival was similar to that reported from ISHLT registries for heart and lung transplantation (p = 0.947 and p = 0.949). One-year survival was 90% and 86% for HTRs and LTRs, respectively. Long-term

At least 1 episode of biopsy-proven and treated acute cellular rejection (ACR) was reported in 14 of 21 (67%) HTRs by 1 year post-transplant (Table 4). Eight (38%) experienced moderate to severe ACR. Mild ACR only occurred in 6 of 21

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Table 2

Heart Transplant Recipient Characteristics

Characteristic Underlying heart disease, n = 21 Non-ischemic cardiomyopathy Ischemic cardiomyopathy VAD support, n = 21 LVAD RVAD Duration of LVAD support, n = 12 1−12 months >1 year LVAD-specific infection, n = 12 Superficial driveline infection Deep driveline infection Pump pocket infection Other Defibrillator, n = 21 Inotropes, n = 21 Balloon pump, n = 21

n (%) 17 (81) 4 (19) 12 (57) 12 1

Malignancy 8 (75) 4 (25) 7 (58) 3 2 1 1 18 (86) 8 (38) 2 (9.5)

Abbreviations: LVAD, left ventricular assist device; RVAD, right, ventricular assist device; VAD, ventricular assist device.

Table 2b

Lung Transplant Recipient Characteristics

Characteristic Underlying lung disease, N= = 7 ILD/IPF,(%) COPD, (%) Cystic FibrosisCystic fibrosis, (%) Other Type of transplant Double lung Single lung

Candida infection. For LTRs, there were 14 total infections, 11 bacterial (mostly pulmonary in origin), 1 viral, and 2 fungal. All recipients were CMV immunoglobulin G−positive, and there were no significant CMV infections. Table 6 describes the infections in each group. Figure 2 describes the timing of infection post-transplant. Late infections (from 6 to 12 months) were more common in the HTRs. The H/LTR had neither infection nor rejection.

n (%) 4 (57) 1 1 1 4 (57) 3 (43)

Abbreviations: COPD, chronic obstructive pulmonary disorder; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis

(29%). However, one of these required multiple courses of steroids, and 4 were treated for suspected antibody-mediated rejection. Therefore, 13 of 21 (62%) had significant rejection requiring aggressive therapies. Two had evidence of allograft vasculopathy at 1 year. Risk for rejection did not appear to be significantly associated with induction regimen, cART regimen, choice of CNI, or median drop in CD4 count or percentage at 1 year (Table 5). ACR was reported in 2 of 7 (28%) LTRs by 1 year (Table 4). For these patients, rejection occurred at day 16 and recurred twice in one patient and 6 times in the other. The latter was treated 5 times with steroids, once with ATG and then with cyclophosphamide. This patient developed Grade 1 bronchiolitis obliterans syndrome and was hospitalized at 1 year post-transplant. This patient had received basiliximab induction.

Infection Infections occurred in 8 of 21 (39%) HTRs and 7 of 9 (86%) LTRs at 1 year post-transplant. There were 17 infections in 8 HTRs, including 9 bacterial, 7 viral, and 1

Six malignancies (5 HTRs and 1 LTR) occurred through follow up, with 2 in the first year. Most were non-melanoma skin cancers, but they also included glioblastoma and prostate cancer. None were AIDS-defining malignancies. There were no cases of post-transplant lymphoproliferative disorder.

HIV outcomes For HTRs, viral suppression was maintained at 1 year for all patients and for 14 of 18 at last follow up. All LTRs and the H/LTR maintained viral suppression at 1 year and at last follow up. CD4 counts were initially higher in LTRs than HTRs (median, 683 cells/ml vs 399 cells/ml, respectively), but remained lower for LTRs than HTRs through follow up (197 cells/ml vs 469 cells/ml, respectively) (Table 7). As previously noted, 1 HTR died at 3 years of AIDS-related complications and graft failure because of non-adherence and poor follow up. This patient had detectable viral load at transplant but undetectable levels at 1 year. The other patient with detectable HIV viral load at transplant had intermittent low-grade viremia post-transplant and lived 10 years post-transplant.

Post-transplant morbidities There was 1 new diagnosis of diabetes in an HTR. Median creatinine in HTRs at last follow up was 1.35 mg/dl, with 4 having severe renal dysfunction and 2 on hemodialysis. Median creatinine for LTRs was 2.5 mg/dl, with 4 having severe renal dysfunction (>2.5 mg/dl) and 1 on hemodialysis. Figure 3a and b demonstrates creatinine changes from baseline for HTRs and LTRs, respectively. At 1 year most HTRs were home, either working (5 of 17; 29%) or not working (10 of 17; 59%) for income. Similarly, most LTRs were home, either working (1 of 7; 14%) or not working (4 of 7; 57%) for income.

Discussion These results demonstrate very good outcomes for heart and/or lung transplantation in HIV-infected recipients, validating and expanding upon previous reports in the field. This includes 2 recent publications of similar groups of HIV-infected HTRs from the SRTR database, one reporting 41 HTRs transplanted between 2004 and 2017 and the other reporting 35 of these same HTRs transplanted between 2004 and 2016.14,15 Of the patients in this study, 19 HTRs were part of these registries. Rates of patient survival at 1 year are in line with data for HIV-uninfected recipients.

Koval et al. Table 3

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Heart or lung transplant in HIV-infected

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Outcomes after Transplantation

Outcome Survival 1 year 3 year (heart n = 15, lung n = 5) 5 year (heart n = 11, lung n = 4) Infection, 1 year Median infection events, 1 yearb (range) Rejection, 1 year Mild ACR Moderate ACR AMR Allograft vasculopathy, CAV, BOS Creatinine, 1 year, median (range) CD4 T-cell count, cell/ml, median (range) (n = 12, 4, 1) Functional status (n = 17, 7, 1) Acute care Home, not working for income Home, working for income Died

Heart n = 21a

Lung n = 7a

Heart and/or lung n = 1a

19 (90) 11 (73) 7 (64) 8 (39) 1 (1−4) 14 (67) 9 (42) 8(38) 4(19) 2 (9) 1.3 (0.83−2.7) 411 (74−847)

6 (86) 4 (80) 3 (75) 6 (86) 2 (1−5) 2 (28)

1 — — — — —

2 (28) — 1 (14) 1.8 (1.2−4.6) 280 (100−392)

— — — 0.91 272

— 10 (59) 5 (29) 2 (10)

1 (14) 4 (57) 1(14) 1(14)

— — 1 —

Abbreviations: ACR, acute cellular rejection; AMR, antibody-mediated rejection; BOS, bronchiolitis obliterans syndrome; CAV, cardiac allograft vasculopathy Data reported as n (%) unless otherwise specified. a Unless otherwise specified, % is based on total number of transplants performed. b Of those with any infection or rejection event at 1 year.

For LTRs, the numbers are few, but the 3- and 5-year survival are similar to HIV-uninfected recipients. Of importance is the somewhat divergent 3- and 5-year patient survival in HIV-infected HTRs relative to more contemporary cohorts (years 2009−2015 of similar age range) of HTRs.17 These are not statistically significant differences but may raise concerns for some programs. Cause of death was not uniform and included infection, non-adherence to medical therapies, malignancy, and allograft failure. These disparate causes do not decisively point to a targeted remedy to reduce mortality but also do not suggest HIV infection as a cause for the divergence. The greatest finding of concern was early rejection rates for HIV-infected HTRs. The 1-year rejection rate (including moderate ACR, recurrent mild ACR, or treated suspected antibody-mediated rejection) of 62% observed in these HTRs is much higher than the treated rejection rate of 10%−23% for the overall heart transplant population from 2004 to 2015.17 Such early rejection may lead to diminished longer-term graft and patient survival and might have impacted the 5-year outcomes seen here.17 The rejection rate is also higher than reported for HIVinfected HTRs from SRTR data that included many of these same patients.14,15 Our data (collected retrospectively) may reflect a more accurate measure of those treated for significant rejection. If including only moderate ACR, our rate of 38% mirrors the 39% reported by Madan and is still higher than rates reported for the larger HTR population.15 Higher rejection rates for HIV-infected kidney and liver transplant recipients have been reported repeatedly from

large studies and have been a key feature of ongoing investigations.3,5,6,18−20 Recognition of immune activation in the setting of HIV infection was underappreciated in the transplant arena and remains somewhat poorly characterized in the clinical setting. In contrast, a cautious approach to immunosuppression (owing to concern for increased infection risk) has long been posited to account for increased rejection rates. Data from the SRTR indicates that HIV-infected kidney recipients are less likely to receive induction immunosuppression and less likely to receive ATG or alemtuzumab.20,21 Similarly, maintenance immunosuppression in HIV-infected kidney transplant recipients is less likely to be CNI-based and more likely to be sirolimus-based.20 Use of ATG appears to abrogate the differences in ACR between HIV-infected and HIV-uninfected kidney transplant recipients and suggests that similarly aggressive immunosuppression be provided to HIVinfected kidney transplant recipients.20 Excessively cautious use of immunosuppression may also be the case for the HTR rejections reported here. Although we did not find significant differences in rejection rate within our HIV-infected group based on induction regimen or choice of CNI, this may reflect our small sample size. Very few of our HTR programs reported intentional use of less immunosuppression for HIV-infected than uninfected recipients. We were not able to capture details of maintenance regimens (anti-proliferative drug dosing or target CNI drug levels), as these differ across programs and a comparison to matched HIV-uninfected HTRs would be important. However, similar to Chen et al.,14 we described less frequent ATG use (4%−8%) in HIV-infected HTRs

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Figure 1 Survival for HIV-infected recipients and ISHLT data registry cohort for primary transplant recipients from 1990 to 2015. (a) Heart transplant and (b) lung transplant. HIV, human immunodeficiency virus; ISHLT, International Society for Heart and Lung Transplantation.

compared with 19.49% of HIV-uninfected HTRs, suggesting differences in induction strategies between groups. Drug interactions affecting maintenance immunosuppression exposure have also been considered a possible cause for higher rejection rates.22 Protease inhibitors and cobicistatcontaining regimens can markedly impact dosing of CNIs and mammalian target of rapamycin inhibitors and may lead to delays in achieving steady state concentrations. HIV integrase inhibitors do not impact cytochrome P450-3A enzymes required for CNI metabolism and are viewed as less apt to contribute to rejection risk.23 We did not capture CNI drug

levels to assess the impact of drug interactions. However, we did not see lower rejection rates in those receiving integrase inhibitors compared with protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Although CNI management in the setting of integrase inhibitors is more facile, it is unlikely the only cause for rejection risk. Infections occurred for a large percentage of HIVinfected LTRs, on the higher end of the 40%−72% reported for the lung transplant population as a whole.24,25 Most were due to bacterial pneumonia and occurred evenly through 1 year, as opposed to the clustering typically

Koval et al.

Rejection Episodes in First Year Post-Transplant

Calcineurin inhibitor

BL CD4 cells/ml

3rd HIV drug

Time to rejection, days

47/M 61/M 57/M 49/M 37/M 39/M 58/M 56/M 47/M 29/F 27/F 58/F 50/F 48/M

— Basiliximab ATG Basiliximab Basiliximab — — — — — — — — Basiliximab

Tacro Tacro CSA CSA Tacro Tacro Tacro Tacro CSA CSA Tacro Tacro Tacro Tacro

315 673 711 391 805 397 153 399 260 539 1,110 701 347 1,580

EFV RTG RTG RTG RTG RTV EFV ETV EFV NA RTG RTG EFV DTG

25 7 37 52 88 25 14 8 24 7 6 178 7 13

56/M 57/M

Daclizumab Basiliximab

Tacro Tacro

264 1,496

RTV, LPV RTG, ETV, MRV

16 16

Heart

ACR mild

ACR moderate

AMR

Graft fxn

n = 13

n = 20 2 2 1

n=4

EF % 60 55

1 1 1

41 60 57 65 60

2 4 4 4 1 5 1 1 1 1

1

5

3 2

1 1 1 1

55 65 65

CIT, hours

Alive

3.7 4 2 3.5 3.3 2 3.1 NR 3.1 3.2 2.5 4.4 1.2 4.2

Y Y Y Y Y N N Y N N N Y Y Y

NR 6.9

Y Y

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Antibody induction

Patient, age/sex

Heart or lung transplant in HIV-infected

Table 4

Lung good BOS

Abbreviations: ACR, acute cellular rejection; AMR, antibody-mediated rejection; ATG, anti-thymocyte globulin; BL, baseline; BOS, bronchiolitis obliterans syndrome; CIT, cold ischemic time; CSA, cyclosporine; DTG, dolutegravir; EF, ejection fraction; EFV, efavirenz; ETV, etravirine; F, female; fxn, function; HIV, human immunodeficiency virus; LPV, lopinavir; M, male; MRV, maraviroc; N, no; NA, not applicable; NR, not recorded; RTG, raltegravir; RTV, ritonavir; Tacro, tacrolimus; Y, yes.

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Table 5

Risk for Rejection in Heart Transplant Recipients

Risk Any induction IL2R (basiliximab) ATG HIV regimen (third drug)a NNRTI Protease inhibitor Integrase inhibitor Cyclosporine Median CD4 count/% at 1 year

Rejection n = 14

No rejection n=7

5 (36) 4 (28) 1

2 (28) 1 (14) —

5 (36) 1 (7) 7 (50) 4 (29) 403/34

3 (42) 3 (42) 2 (28) — 414/42

p-value 1.00 0.62 1.00 0.27

0.26 0.56

Abbreviations: ATG, anti-thymocyte globulin; HIV, human immunodeficiency virus; IL2R, IL-2 receptor antagonist; NNRTI, non-nucleoside reverse transcriptase inhibitor. a In addition to 2 nucleoside/nucleotide analogues.

Table 6 Probable and Proven Infections Reported at 1 Year Post-Transplant

Infection Patients with infection Total infections Bacterial Respiratory Escherichia coli Klebsiella spp. NTM Staphylococcus aureus Pseudomonas spp. Anaerobe Unknown org Surgical site GI Bone and joint Bloodstream, primary Other site Viral Adenovirus Respiratory virus, NOS Influenza Varicella Fungus/yeast Mucocutaneous Respiratory

Heart n = 21

Lung n=7

Heart and/or lung n=1

9 17

6 16

0 0

— — — —

2 1 1 2

— — — —

— — 1 1 1 1 1 4

1 1 1 — 1 — — —

— — — — — — — —

1 2 3 1

1 — — —

— — — —

1 —

— 2

— —

Abbreviations: GI, gastrointestinal; NOS, not otherwise specified; NTM, non-tuberculous mycobacteria; org, organism; spp., species.

described in the first few months after lung transplant.25 Comparable infection rates occurred in HIV-infected and uninfected HTRs, though the distribution occurred later in the year, inverse to the early post-transplant clustering described for HIV-uninfected HTRs.26,27 Although this delay in infection was not investigated further, it is possibly

Figure 2 Incident infections from time period following organ transplant for heart transplant recipients and lung transplant recipients.

a result of therapies for early rejection requiring repeated hospital admissions. HIV infection remained controlled for most patients in the series. However, some patients developed viremia and 1 patient died of AIDS-related complications owing to cessation of cART. This underscores the proper selection of patients, as is typical of all transplant candidates, but perhaps more so because of the added medication adherence required for the HIV population. Though 1 patient survived to 10 years post-transplant with low grade HIV viremia at the time of transplant and intermittently detectable viral load thereafter, viral suppression should be the goal (and should be achievable) for all HIV-infected transplant candidates. No episodes of AIDS-defining malignancies or infections were described despite the remarkable drop in T-cell numbers for LTRs while on transplant related immunosuppression. The fact that HTRs did not drop their CD4+ T-cell count as dramatically as LTRs may reflect the more cautious approach to immunosuppression previously discussed. Overall rates of malignancy (20%) were similar to and somewhat higher than those reported for HTRs and LTRs, respectively, in data sets from western countries.27,28 Although our low numbers limit definitive conclusions, rates of severe renal dysfunction were high compared with those reported for the HIV-uninfected.17,29,30 Such data may inform selection and timing of CNI use and selection of cART (use of tenofovir alafenamide fumarate rather than the more nephrotoxic tenofovir disaproxil fumarate most common to the era reported in this series). The HIV Organ Policy Equity (HOPE) Act was signed in to law in 2013 and allows for organs from HIV-infected donors to be used in HIV-infected recipients under approved protocols. By the end of 2018, over 100 livers and kidneys were transplanted from 49 HIV-infected deceased donors at centers around the US (unos.org). Such expansion of the donor pool is important to heart and lung transplant candidates as well. The data presented in this study provide a foundation to consider HIV-infected donor heart and lung transplants under HOPE Act protocols. In summary, both heart and lung transplantation are successful treatment modalities in selected HIV-infected patients with advanced heart and/or lung disease. Such success can occur even in those patients with prior opportunistic infections. HIV can be well controlled coincident with transplant

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Koval et al. Table 7

Heart or lung transplant in HIV-infected

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HIV-Related Outcomes Following Heart and/or Lung Transplantation

Outcome

Heart

Lung

1 year follow up Median CD4 T-cell count, cells/ml, (range) HIV RNA viral load, undetected, n (%) Last follow up, days Median CD4 T-cell count, cells/ml, (range) HIV RNA viral load, undetected, n (%)

411 (74−837) 15 (100) 1,064 (184−3,745) 469 (112−884) 14 (77)

280 (100−392) 7 (100) 1540 (16−3,208) 197 (21−557) 7 (100)

Heart and/or lung 272 1 365 272 1

Figure 3 Serum creatinine concentrations (mg/dl) at BL, 1 year, and last follow up visit after transplant. (a) Heart transplant recipients and (b) lung transplant recipients. BL, baseline.

immunosuppression using a variety of cART regimens. Although CD4 cell counts are likely to fall substantially after lung transplantation, this is without clear clinical consequence. For HIV-infected thoracic organ transplant recipients, much like the abdominal organ transplant recipients, rejection is a particular risk. Until more sophisticated correlates are made, immunosuppression for HIV-infected recipients should be at least as potent as for HIV-uninfected recipients. Advanced data registries that capture detailed immunosuppression and HIV management strategies are required for centers to provide optimal care for this unique patient population. Such data will be particularly important as the use of hearts and lungs from HIV-infected donors becomes possible through HOPE Act protocols.

Disclosure statement P.G. reports personal fees from Gliead, Biotest, Merck, Sharp & Dohme, and Shire. The authors report no other financial conflicts. We thank our contributors including Katie Stankowski, PharmD, Cameron Wolfe, MD, PhD, Blair Weikart, MD, Cynthia Gay, MD, Sean Pinney, MD, Alessandro Palleschi, MD, Camille Kotton, MD, David Epstein, MD, and Ryan Levine.

References 1. Kendall CE, Wong J, Taljaard M, et al. A cross sectional population based study measuring comorbidity among people living with HIV in Ontario. BMC Public Health 2014;14:161.

2. Ingle SM, May MT, Gill MJ, et al. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy Among HIV-infected patients. Clin Infect Dis 2014;59:287-97. 3. Blumberg EA, Rogers CC. American Society of Transplantation Infectious Diseases Community of Practice. Solid organ transplantation in the HIV-infected patient: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transpl 2019: e13499. 4. Locke JE, Mehta S, Reed RD, et al. A national study of outcomes among HIV-infected kidney transplant recipients. J Am Soc Nephrol 2015;26:2222-9. 5. Carter JT, Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected kidney transplant recipients. N Engl J Med 2010;363:2004-14. 6. Malat GE, Ranganna KM, Sikalas N, Liu L, Jindal RM, Doyle A. High frequency of rejections in HIV-positive recipients of kidney transplantation: a single center prospective trial. Transplantation 2012;94: 1020-4. 7. Bertani A, Grossi P, Vitulo P, et al. Successful lung transplantation in an HIV- and HBV-positive patient with cystic fibrosis. Am J Transplant 2009;9:2190-6. 8. Calabrese LH, Albrecht M, Young J, et al. Successful cardiac transplantation in an HIV-1-infected patient with advanced disease. N Engl J Med 2003;348:2323-8. 9. Castel MA, Perez-Villa F, Miro JM. Heart transplantation in HIV-infected patients: more cases in Europe. J Heart Lung Transplant 2011;30:1418. 10. Durante-Mangoni E, Maiello C, Sbreglia C. A European first: successful heart transplant in a human immunodeficiency virus-positive recipient. J Heart Lung Transplant 2011;30:845. 11. Kern RM, Seethamraju H, Blanc PD, et al. The feasibility of lung transplantation in HIV-seropositive patients. Ann Am Thorac Soc 2014;11:882-9. 12. Uriel N, Jorde UP, Cotarlan V, et al. Heart transplantation in human immunodeficiency virus-positive patients. J Heart Lung Transplant 2009;28:667-9.

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The Journal of Heart and Lung Transplantation, Vol 00, No 00, Month 2019

13. Ag€ uero F, Castel MA, Cocchi S, et al. An update on heart transplantation in human immunodeficiency virus-infected patients. Am J Transplant 2016;16:21-8. 14. Chen C, Wen X, Yadav A, Belviso N, Kogut S, McCauley J. Outcomes in human immunodeficiency virus-infected recipients of heart transplants. Clin Transpl 2019;33:e13440. 15. Madan S, Patel SR, Saeed O, et al. Outcomes of heart transplantation in patients with human immunodeficiency virus. Am J Transplant 2019;19:1529-35. 16. Lund LH, Khush KK, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation. Thirty-fourth Adult Heart Transplantation Report—2017;Focus Theme: allograft ischemic time. J Heart Lung Transplant 2017;36:1037-46. 17. Husson J, Stafford K, Bromberg J, et al. Association between duration of human immunodeficiency virus (HIV)-1 viral suppression prior to renal transplantation and acute cellular rejection. Am J Transplant 2017;17:551-6. 18. Muthukumar T, Afaneh C, Ding R, et al. HIV-infected kidney graft recipients managed With an early corticosteroid withdrawal protocol: clinical outcomes and messenger RNA profiles. Transplantation 2013;95:711-20. 19. Carter JT, Melcher ML, Carlson LL, Roland ME, Stock PG. Thymoglobulin-associated CD4+ T-cell Depletion and Infection Risk in HIVInfected Renal Transplant Recipients. Am J Transplant 2006;6:753-60. 20. Locke JE, James NT, Mannon RB, et al. Immunosuppression regimen and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014;97:446-50. 21. Kucirka LM, Durand CM, Bae S, et al. Induction immunosuppression and clinical outcomes in HIV-infected kidney transplant recipients. Am J Transplant 2016;16:2368-76.

22. Sawinski D, Shelton BA, Mehta S, et al. Impact of protease inhibitorbased anti-retroviral therapy on outcomes for HIV+ kidney transplant recipients. Am J Transplant 2017;17:3114-22. 23. Tricot L, Teicher E, Peytavin G, et al. Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. Am J Transplant 2009;9:1946-52. 24. Palacio F, Reyes LF, Levine DJ, et al. Understanding the concept of health care associated pneumonia in lung transplant recipients. Chest 2015;148:516-22. 25. Aguilar-Guisado M, Givalda J, Ussetti P, et al. Pneumonia After lung transplantation in the RESITRA cohort: A multicenter prospective study. Am J Transplant 2007;7:1989-96. 26. Rojas-Contreras C, De la crus-Ku G, Valcarcel-Valdivia B. Noninfectious and infectious complications and their related characteristics in heart transplant recipients at a national institute. Exp and Clin Transplant 2018;16:191-8. 27. Hsu RB, Chang CI, Tsai MK, et al. Low incidence of malignancy in heart-transplant recipients in Taiwan: an update and comparison with kidney transplant recipients. Eur J Cardio-Thorac Surg 2010;37:111721. 28. Berastegui C, LaPorta R, Lopez-Meseguer M, et al. Epidemiology and risk factors for cancer After lung transplantation. Transplant Proc 2017;49:2285-91. 29. Lachance K, White M, de Denus S. Risk factors for chronic renal insufficiency following cardiac transplantation. Ann Transplant 2015;20:576-87. 30. Sole A, Zurbano F, Borro JM, Monforte V, Ussetti P, Santos F. Prevalence and diagnosis of chronic kidney disease in maintenance lung transplant patients: ICEBERG study. Transplant Proc 2015;47:196671.