DEFINITION

Treatment of end-stage organ disease by transplantation of solid organs. This module will focus on kidney and liver transplantation.

INDICATIONS

Increasing need for kidney and liver transplantation among HIV+ individuals

• Chronic kidney disease (CKD) is common due to HIV-specific causes (HIV-associated nephropathy, antiretroviral toxicity), hepatitis B and hepatitis C-related glomerulopathies, as well as traditional causes of hypertension, diabetes, and cardiovascular disease.[11]
• End-stage renal disease (ESRD) is increasing in prevalence with about 1.5% of the U.S. dialysis population being HIV+.[5]
• End-stage liver disease (ESLD) is also common due to hepatitis B and hepatitis C co-infection, alcohol-related liver disease, and non-alcoholic fatty liver disease.[12]
• HIV+ individuals with ESRD and ESLD have greater waitlist mortality than their HIV- counterparts and decreased access to transplant.

Outcomes of kidney transplantation

• Excellent overall patient and graft survival based on NIH HIV Multisite HIV Transplant Recipient Study[17] as well as U.S. Scientific Registry of Transplant national registry data[9].
• Increased incidence of allograft rejection, 2- to 4-fold higher than in HIV- individuals.[13]
• AIDS-related infections are rare.[7]
• Inferior outcomes for HIV/HCV co-infected recipients, although this may change with advent of direct-acting antivirals (DAAs) for hepatitis C.[9]

Outcomes of liver transplantation

• Acceptable patient and graft survival but lower for HIV+/HCV+ liver recipients compared to HCV+ monoinfected liver transplant recipients[15][6]. Outcomes are expected to improve with the availability of DAAs.
• Increased incidence of allograft rejection[6].
• AIDS related infections are rare[7].

CLINICAL RECOMMENDATION

The following guidelines are generally recommended for HIV+ solid organ transplant candidates:

Pre-transplant/Eligibility (based on NIH-funded HIV Transplant Recipient Study)[17][15]

• Kidney transplant candidates should have a CD4 count of at least 200 cells/uL.
• Liver transplant candidates should have a CD4 count of at least 100 cells/ul (lower threshold is tolerated since there may be lower overall counts from hypersplenism).
• HIV viral replication should be suppressed on antiretroviral therapy < 50 copies/mL. If antiretroviral therapy cannot be tolerated due to liver dysfunction, candidates can still be considered as long as an effective antiretroviral regimen is anticipated post-transplant.
• A history of progressive multifocal leukoencephalopathy or visceral Kaposi’s sarcoma has historically been considered a contraindication to transplant.
• Optimize antiretroviral therapy to avoid drug-drug interactions with immunosuppression. Avoid potent CYP3A4 inhibitors and inducers - see selected drug comments.
• Screen for HPV-related malignancies which have increased incidence and accelerated progression with post-transplant immunosuppression.

At transplant

• Induction immunosuppression is recommended as it is associated with lower rates of rejection and increased graft survival.[13][8]
• Antithymocyte globulin (ATG) induction should be considered for individuals with a high risk of rejection. Although it is associated with significant CD4 depletion immediately post-transplant, counts gradually recover over 1-3 years. Early uncontrolled studies reported an association between ATG and bacterial infections requiring hospitalization[21] but larger, more recent studies have not found an increased incidence of infection in those who received ATG[8].
• HIV-infected donor organs can now be considered for HIV+ recipients under research protocols as a result of the HIV Organ Policy Equity Act of 2013.[10]

Post-transplant

• Check CD4 count one-month post-transplant and every 3 months thereafter to guide opportunistic infection prophylaxis. Expect significant decrease in CD4 count for recipients of lymphodepleting immune induction.
• Check HIV viral load 1-month post-transplant and every 3 months thereafter.
• Standard/institutional CMV prophylaxis according to CMV serostatus.

• Pneumocystis prophylaxis is recommended for at least 1 year and until CD4 > 200 cells/uL. Some experts would use longer durations.
• For patients from an endemic area, Histoplasma and coccidioidomycosis prophylaxis is recommended until CD4 > 150 cells/uL.
• Lifelong secondary prophylaxis for Histoplasma and coccidioidomycosis is recommended based on expert opinion.
• Secondary prophylaxis for prior opportunistic infections is recommended for at least one month after transplant and for one month after treatment of allograft rejection with intensified immunosuppression.
• Continue to screen for HPV-related malignanices which have increased incidence and accelerated progression with post-transplant immunosuppression.

Selected Drug Comments

• Most transplant recipients will be on a maintenance immunosuppression regimen consisting of prednisone, mycophenolate mofetil, and a calcineurin inhibitor (CNI).
  • The CNI tacrolimus is preferred over cyclosporine due to lower rates of rejection with tacrolimus[13].

Avoid protease inhibitor- and cobicistat-containing antiretroviral therapy regimens[20]

• Cytochrome P450 inhibitors will markedly decrease metabolism of tacrolimus requiring infrequent and very low doses of calcineurin inhibitors
• This leads to an overall underexposure of immunosuppressants and may partially explain high rates of graft rejection seen in HIV+ transplant recipients.

Caution with some non-nucleoside reverse transcriptase inhibitors regimens

• Potent cytochrome P450 inducers such as efavirenz and etravirine will increase metabolism of calcineurin inhibitors. Co-administration can be managed but doses of calcineurin inhibitors will need to be adjusted if changing on or off an NNRTI based regimen.
• Rilpivirine and doravirine do not have significant interactions with calcineurin inhibitors.

Preferred: INSTI regimens

• No significant drug interactions
• Dolutegravir and bictegravir will inhibit tubular creatinine excretion but do not have any functional impact on glomerular filtration rate.

CCR5 antagonists, maraviroc (MVC)

• No significant drug interactions
• Theoretically, CCR5 blockade may decrease lymphocyte chemotaxis, inflammation, and organ rejection. This hypothesis is supported by epidemiological studies of HIV- kidney transplant recipients that demonstrated excellent long term allograft survival in recipients who did not express CCR5 as a consequence of a homozygous CCR5 delta 32 deletion[22], studies of HIV- liver transplant recipients homozygous for the CCR5 delta 32 mutation who had reduced acute rejection rates[23], and a randomized clinical trial of maraviroc in HIV- bone marrow transplant recipients which showed reduced rates of visceral graft-versus host disease[16]. A randomized clinical trial of MVC in HIV+ kidney transplant recipients is ongoing.

References

1. 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 Transplant. 2019.  [PMID:30773688]
2. Manzardo C, Londoño MC, Castells L, et al. Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study. Am J Transplant. 2018;18(10):2513-2522.  [PMID:29963780]
3. Locke JE, Gustafson S, Mehta S, et al. Survival Benefit of Kidney Transplantation in HIV-infected Patients. Ann Surg. 2017;265(3):604-608.  [PMID:27768622]
4. Locke JE, Mehta S, Sawinski D, et al. Access to Kidney Transplantation among HIV-Infected Waitlist Candidates. Clin J Am Soc Nephrol. 2017;12(3):467-475.  [PMID:28232406]
5. Boyle SM, Lee DH, Wyatt CM. HIV in the dialysis population: Current issues and future directions. Semin Dial. 2017;30(5):430-437.  [PMID:28608994]
6. Locke JE, Durand C, Reed RD, et al. Long-term Outcomes After Liver Transplantation Among Human Immunodeficiency Virus-Infected Recipients. Transplantation. 2016;100(1):141-6.  [PMID:26177090]
7. Roland ME, Barin B, Huprikar S, et al. Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls. AIDS. 2016;30(3):435-44.  [PMID:26765937]
8. Kucirka LM, Durand CM, Bae S, et al. Induction Immunosuppression and Clinical Outcomes in Kidney Transplant Recipients Infected With Human Immunodeficiency Virus. Am J Transplant. 2016;16(8):2368-76.  [PMID:27111897]
9. 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(9):2222-9.  [PMID:25791727]
10. Health Resources and Services Administration (HRSA), Department of Health and Human Services (HHS). Organ procurement and transplantation: implementation of the HIV Organ Policy Equity Act. Final rule. Fed Regist. 2015;80(89):26464-7.  [PMID:25985481]
11. Abraham AG, Althoff KN, Jing Y, et al. End-stage renal disease among HIV-infected adults in North America. Clin Infect Dis. 2015;60(6):941-9.  [PMID:25409471]
12. Smith CJ, Ryom L, Weber R, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384(9939):241-8.  [PMID:25042234]
13. 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(4):446-50.  [PMID:24162248]
14. Bickel M, Marben W, Betz C, et al. End-stage renal disease and dialysis in HIV-positive patients: observations from a long-term cohort study with a follow-up of 22 years. HIV Med. 2013;14(3):127-35.  [PMID:22994610]
15. Terrault NA, Roland ME, Schiano T, et al. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. 2012;18(6):716-26.  [PMID:22328294]
16. Reshef R, Luger SM, Hexner EO, et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012;367(2):135-45.  [PMID:22784116]
17. Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med. 2010;363(21):2004-14.  [PMID:21083386]
18. Subramanian A, Sulkowski M, Barin B, et al. MELD score is an important predictor of pretransplantation mortality in HIV-infected liver transplant candidates. Gastroenterology. 2010;138(1):159-64.  [PMID:19800334]
19. Murillas J, Rimola A, Laguno M, et al. The model for end-stage liver disease score is the best prognostic factor in human immunodeficiency virus 1-infected patients with end-stage liver disease: a prospective cohort study. Liver Transpl. 2009;15(9):1133-41.  [PMID:19718643]
20. Frassetto LA, Browne M, Cheng A, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant. 2007;7(12):2816-20.  [PMID:17949460]
21. Carter JT, Melcher ML, Carlson LL, et al. Thymoglobulin-associated Cd4+ T-cell depletion and infection risk in HIV-infected renal transplant recipients. Am J Transplant. 2006;6(4):753-60.  [PMID:16539632]
22. Fischereder M, Luckow B, Hocher B, et al. CC chemokine receptor 5 and renal-transplant survival. Lancet. 2001;357(9270):1758-61.  [PMID:11403814]
23. Heidenhain C, Puhl G, Moench C, et al. Chemokine receptor 5Delta32 mutation reduces the risk of acute rejection in liver transplantation. Ann Transplant. 2009;14(3):36-44.  [PMID:19644158]