- Email: [email protected]
Kidney Transplantation in HIV-Infected Recipients: Therapeutic Strategy and Outcomes in Monocentric Experience
Kidney Transplantation in HIV-Infected Recipients: Therapeutic Strategy and Outcomes in Monocentric Experience A. Baisia,*, F. Navaa, B. Baisib, E. Rubbiania, G. Guaraldic, F. Di Benedettod, M. Giovannonie, A. Solazzoa, D. Bonucchif, and G. Cappellia a University of Modena and Reggio Emilia, University Hospital Policlinico of Modena, Modena, Italy; bUniversity of Modena and Reggio Emilia, Division of Urology, University Hospital Policlinico of Modena, Modena, Italy; cUniversity of Modena and Reggio Emilia, Division of Infectious Diseases, University Hospital Policlinico of Modena, Modena, Italy; dUniversity of Modena and Reggio Emilia, Division of Liver-Bilio-Pancreatic Surgery and Liver Transplantation, University Hospital Policlinico of Modena, Modena, Italy; eUniversity of Modena and Reggio Emilia, Division of Angiology and Vascular Surgery, University Hospital Policlinico of Modena, Modena, Italy; and f Nephrology of Area Nord, Carpi, Italy
ABSTRACT Background. In Human immunodeficiency virus (HIV)-positive patients undergoing kidney transplantation, outcomes and immunosuppression (IS) protocol are not yet established due to infectious and neoplastic risks as well as to pharmacokinetic interactions with antiretroviral therapy (TARV). Methods. We report a retrospective, 1-center study on 18 HIVþ patients undergoing, between October 2007 and September 2015, kidney transplantation (13 cases) or combined kidney-liver transplant (5 cases). Inclusion criteria for transplant were based on the Italian National Transplant Center protocol. IS regimen was based on quick tapering of steroids and the use of mTOR inhibitors (mTORi) with low dose of calcineurin inhibitors (CNI). In the early post-transplant period, TARV was based on enfuvirtide, raltegravir, plus 1 or more nucleoside analogues. Results. In a mean follow-up of 3.1 years, patient survival rate at 1 and 3 years was, respectively, 86.6% and 84.6%, whereas graft survival was 81.2% and 78.6%. Cumulative rejection rate was 20.0% and 26.6% (1- and 3-year results). Median eGFR (MDRD) was 58.8 mL/min and 51.9 mL/min at 1 and 3 years. We had 9 cases of clinically relevant infections (2 Pneumocystis jirovecii pneumonia, 1 pulmonary aspergillosis, 2 severe sepsis, and 4 HCV reactivation) as well as 1 case (5.5%) of HIV reactivation. Conclusions. IS therapy based on mTORi and low CNI dose ensures good graft survival, low rate of acute rejection, limited drug toxicity, and control of HIV disease. TARV has no significant interaction with IS therapy.
U
NTIL the end of the 1990s, human immunodeficiency virus (HIV)-infected patients with an end-stage organ disease were excluded from transplant programs because of poor prognosis. The introduction of highly active antiretroviral therapy (HAART) has reduced morbidity and mortality rates. Many patients with HIV-related kidney diseases, once dying before entering end-stage renal disease (ESRD), now survive for many years and progressing to renal replacement therapy. As a result of the combined effect of new and more effective anti-retroviral (ARV) therapies and a better opportunistic infection prophylaxis, ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 333e336 (2016)
solid-organ transplantation is an effective therapeutic option also in this group of patients [1e4]: no differences in patient and graft survival rates have been reported between HIV-positive and -negative kidney recipients [5e7]. Many issues are still unclear, such as the increased acute rejection
*Address correspondence to Alberto Baisi, MD, Università di Modena e Reggio Emilia, Divisione di Nefrologia, Dialisi e Trapianto Renale, Largo del Pozzo 71, Modena 41124, Spain. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.038
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rate, the interaction between ARVs and immunosuppressive (IS) drugs, and the control of HIV replication to prevent opportunistic infections [8e12]. METHODS This was a single-center, retrospective study of kidney transplants or combined kidney-liver transplants performed in HIV-infected adult patients receiving an immunosuppressive therapy based on mTOR inhibitor (mTORi) and low dose of cyclosporine (CsA), between March 2008 and March 2015, and who were followed through September 2015. All patients fulfilled inclusion and exclusion criteria as well as specific policies provided by the Italian National Kidney Transplant Program in HIV (human immunodeficiency virus)þ patients, as shown in Table 1. Hepatitis B (HBV)- and/or C virus (HCV)-coinfected HIVþ patients required standard hepatic workout. Interferon and/or ribavirin therapy (when indicated) had to be completed before waiting list enrollment. All recipients received induction therapy with a standard dose of basiliximab; 500 mg intravenous (IV) methylprednisolone (MP) was given intra-operatively, followed by oral prednisolone progressively tapered from 16 mg to complete withdrawal within the 3rd month. Immunosuppression protocol included a delayed CsA (2.5 mg/kg bid when creatinine was <3.0 mg/dL) targeted to maintain CsA (C2 level) at initial value of 1000 ng/mL. At post-operative day (pod) 21, everolimus (EVL) 0.75 mg bid was introduced (EVL 0.75 mg bid; target EVL trough blood levels [TLC]: 8e10 ng/mL and CsAC2: 400e500 ng/mL); steroid was tapered to 4 mg/day within 45 days. After 6 months, EVL and CsA blood levels were targeted to EVLTLC 6 to 8 ng/mL and CsAC2, 250 to 350 ng/mL. After the first 6 case, mycophenolic acid (MPA) 720 mg bid was added until pod 21. Patients with combined liver-kidney transplantation received initial therapy with CsA and steroid. At pod 30, CsA was substituted with sirolimus (SIR) (SIRTLC, 8e12 ng/mL).
Table 1. Inclusion and Exclusion Criteria Inclusion criteria Documented HIV infection Ability to provide/obtain informed consent Patients never treated with ARVs with CD4 cell count circulating stably 200 cell/mm3 Patients on ARVs with CD4 cell count 200 cell/mm3 stable for at least 12 months and plasma HIV-RNA VL undetectable at the time of inclusion on waiting list Compliance to/willingness to continue ARVs and prophylaxis of opportunistic infections, if indicated If female, pregnancy test (b-HCG) negative (monthly monitoring) Exclusion criteria History of AIDS-defining opportunistic infections in the previous 2 years History of neoplasm (with the exception of in situ cervical neoplasia and baso-cellular carcinoma with a documented disease-free period of more than 5 years; recovery from malignant disease must be certified by an oncologist) Detectable peripheral blood HHV8 DNA VL Breast-feeding underway Abbreviations: ARVs, anti-retroviral drugs; VL, viral load; b-HCG, beta-human chorionic gonadotropin; AIDS, acquired immune deficiency syndrome; HHV8, human herpes virus 8.
Prescription and monitoring of ARVs was managed by physicians with expertise in HIV treatments. To avoid drug interactions between protease inhibitors and IS, ARV was given in the immediate post-operative period with enfuvirtide (T20) in combination with 2 nucleoside analogues or 1 nucleoside analogue and raltegravir (RAL), which was administered within 48 hours. Once steady state of IS was achieved (on average, pod 30), T20 was stopped and HAART was modified on the basis of HIV pre-transplant genotype profile, individual drug tolerability, and clinical conditions. For Pneumocystis jirovecii prophylaxis, we used a 6-month course of trimethoprim-sulfametoxazol. For CMV prophylaxis, all patients received IV ganciclovir or oral valganciclovir for a 3-month treatment; in the case of donor/recipient CMV status, specific antiCMV immunoglobulins were added. In the follow-up period, we monitored CMV, Epstein-Barr virus (EBV), human herpes virus (HHV) 6, HHV8, Polyoma BK and JC viruses, HBV, HCV, and Aspergillus spp. according to the Italian National Kidney Transplant Program in HIV-infected people guidelines. Biopsy-proven acute rejection was treated with 3 MP pulses. Graft loss was defined as return to dialysis or death with a functioning kidney. Delayed graft function (DGF) was defined as the need of hemodialysis during the first post-transplant week. Outcome measures included patient and graft survivals, acute rejection episodes, DGF, glomerular filtration rate (e-GFR according to MDRD), HIV immuno-virological response [HIV RNA viral load (VL) and CD4 cell count], and incidence of opportunistic infections and viral reactivations (CMV, EBV, HHV8, HHV6, Polyoma BK, and JC viruses).
RESULTS
The study included 13 HIV-positive patients submitted to deceased-donor kidney transplantation and 5 patients on combined kidney-liver transplantation. The median followup was 3.1 years. Median age of donors was 41 years, with interquartile range (IQR) 28 to 53. Recipient medium age was 49 years (IQR, 43e51), with 12 male 18 female. Causes of renal disease were HIV-associated nephropathy (HIVAN) in 6 of 18 (33%), hypertension in 1 of 18 (5%), diabetic nephropathy in 2 of 18 (11%), focal segmental glomerulosclerosis in 2 of 18 (11%), chronic pyelonephritis in 1 of 18 (5%), and unknown in 6 of 18. In combined liverkidney transplantation, viral hepatitis was HCV-related in 4 patients and HBV-related in 1 patient. All patients were on stable HAART at the time of transplantation with plasma HIV RNA viral load below detection limit (<40 c/mL). At enrollment, median CD4þ count was 321 per mm3 (IQR, 217e534), whereas at transplant, median CD4þ count was 441 per mm3 (IQR, 308e580). Survival rates at 1 year and 3 years were, respectively, 86.6% and 84.6% for patients and 81.2% and 78.6% for grafts. One patient died for sudden cardiac death 2 months after transplantation, without graft failure; 1 patient with liver-kidney transplantation died of candida systemic infection 3 months after transplantation. DGF occurred in 4 patients (22%); 1 of them presented an early rhabdomyolysis with acute kidney injury delaying CsA introduction. This patient developed a severe biopsyproven acute rejection (IIb according to Banff 97 criteria)
KIDNEY TRANSPLANT IN HIV-INFECTED RECIPIENTS
on pod 24 requiring transplantectomy on pod 31 after highdose MP, plasmapheresis, and high-dose immunoglobulins. At the end of the follow-up, median MDRD eGFR at 1 year and 3 years were, respectively, 58.8 19.2 mL/min and 51.9 19.2 mL/min. Acute rejection cumulative incidence was 20.0% at 1 year and 26.6% at 3 years. Anti-retroviral combination therapies before and after transplantation are shown in Table 2. HIV reactivation occurred in 1 patient (5%). Clinically relevant infections occurred in 9 cases: 2 P. jirovecii pneumonia, 1 pulmonary aspergillosis, 2 Escherichia coli sepsis; 4 HCV reactivations occurred in combined liver-kidney transplant recipients with HCV-related hepatitis. A viral load increase of CMV, EBV, HHV8, HHV6, and Polyoma BK and JC was documented by means of the PCR method in almost all patients; it required specific treatment or immunosuppression dose adjustment, and no complications of clinical significance occurred. No neoplasms were reported. DISCUSSION
The mean limitation of this study is the relatively small number of HIVþ transplanted patients. However, our data support kidney transplantation in HIV-positive recipients as feasible and effective renal-replacement therapy. An important issue is the fitting of immunosuppression in the context of anti-retroviral therapy in HIVþ population mainly in the early post-transplant period, when the risks of pharmacokinetic interactions and organ rejection are higher. The IS scheme is based on mTORi and low-exposure CsA, a well-recognized combination with excellent results reported in HIV patients [13,14]. This strategy allows prevention of
335
chronic drug-induced renal toxicity while reducing risk of viral infections and neoplasms and keeping protection from rejection. As already shown in the standard recipient of kidney transplant [15], the association EVL-CsA allows minimization of the steroid maintenance dose or allows its withdrawal. It is likely that this almost steroid-free immunosuppression may reduce the risk of cardiovascular disease, osteopenia/osteoporosis, aseptic bone necrosis, and ocular complications in the long term, as reported by previous registry studies [16] and randomized trials [17]. Results obtained in our patients, in terms of patient and graft survivals, are in the range of all deceased donor kidney transplants performed in our center since 1998: graft survival (%) of 91.35 1.45 and 86.55 1.85 at 1 and 3 years, respectively; patients survival (%) at 1 and 3 years 96.85 0.95 and 94.05 1.35. Cumulative incidence of acute rejections at 1 and 3 years (20.0% and 26.6%, respectively) is higher than in HIVnegative recipients. All acute rejection was steroidresponsive, except for a case of acute rejection resistant to steroid pulses and plasmapheresis; this occurrence prompted us to introduce the short-term MPA course into the protocol. A possible explanation for this higher incidence of acute rejection could be a condition of T-cell cross-reactivity caused by HIV infections [18]. Strict bacteriological and virological monitoring has allowed control of the development of opportunistic infections. Viral reactivations, as assessed by laboratory data, frequently occurred after post-transplant immunosuppression, but only in a few cases did viremia exceed the threshold of clinical significance. ARVs based on T20 and RAL, in the early posttransplant period, follow the concept of a therapeutic
Table 2. Anti-Retroviral Combination Therapies Before and After Transplantation Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
HAART Before Transplantation
3TCþABCþATV 3TCþABCþSQV 3TCþTDFþEFV 3TCþTDFþATV 3TCþTDFþATVþRTV ABCþRTVþfAPV 3TCþRALþT20 RALþDRVþRTVþETV No HAART 3TCþABCþATV RTVþLPV 3TCþRALþT20 DRVþRTVþTDFþFTC DRVþRTVþRAL 3TCþfAPVþRAL DRVþRTVþRAL 3TCþATVþRAL 3TCþABCþNEV
HAART Early Post-Transplantation
Immunosuppressive Therapy Early Post-Transplantation
3TCþTDF 3TCþABC 3TCþRAL 3TCþRAL 3TCþRAL RALþT20 RALþT20 RALþT20 No HAART RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20
CsAþEVL CsAþEVL CsAþEVL CsAþEVL Transplantectomy CsAþEVL EVL EVL CsAþEVL CsA CsA CsA CsAþEVL CsAþEVL FK506 CsA CsAþEVL CsAþEVL
HAART Maintenance Post-Transplantation
3TCþATVþRAL 3TCþABCþRALþRTV MVCþRAL 3TCþATVþRAL 3TCþTDF 3TCþRALþATZ 3TCþRALþATVþRTV RALþDRVþRTVþETV 3TCþRALþMVC 3TCþRTVþATVþRAL 3TCþRALþATZþRTV 3TCþRALþATV Death 3TCþRALþMVC 3TCþRALþfAPV Death RALþT20þRPV RALþRPV
Abbreviations: HAART, highly active anti-retroviral therapy; 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; TDF, tenofovir; CsA, cyclosporine; EVL, everolimus; RAL, raltegravir; SQV, saquinavir; RTV, ritonavir; DRV, darunavir; EFV, efavirenz; MVC, maraviroc; fAPV, fosamprenavir; T20, enfuvirtide; ATZ, zidovudine; ETV, entecavir; LPV, lopinavir; FTC, emtricitabine; FK506, tacrolimus; NEV, nevirapine; RPV, rilpivirine.
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interval focused on prevention of pharmacokinetic interactions to avoid organ rejection and drug toxicity still keeping viral control. Through a low genetic barrier, this ARV is used for a limited time because they do not allow long-term management of HIV infection; RAL and T20 did not interfere with EVL, SIR, and CsA through blood levels, confirming the low potential for pharmacokinetic interactions with IS therapy. In summary, according to our data, kidney transplant in HIV-positive recipients is an efficient renal replacement therapy. IS based on mTORi and a low exposure to CsA linked to ARVs with T20 and RAL in the immediate postoperative period allowed good graft survival, a low rate of rejection, and HIV replication control. REFERENCES [1] Stock PG, Roland ME. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation 2007;84:563e71. [2] Blumberg EA, Stock P. Solid organ transplantation in the HIV-infected patient. Am J Transplant 2009;4:S131e5. [3] Miró JM, Torre-Cisnero J, Moreno A, et al. GESIDA/ GESITRA-SEIMC, PNS and ONT consensus document on solid organ transplant (SOT) in HIV-infected patients in Spain (March 2005). Enferm Infecc Microbiol Clin 2005;23:353e62. [4] Roland ME, Stock PG. Comprehensive guidelines translate research findings into clinical policy for HIV-infected transplant candidates and recipients. Enferm Infecc Microbiol Clin 2005;23: 331e4. [5] Ahuja TS, Grady J, Khan S. Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States. J Am Soc Nephrol 2002;13:1889e93. [6] Abbott KC, Swanson SJ, Agodoa LY, et al. Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression. J Am Soc Nephrol 2004;15:1633e9. [7] Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med 2004;363: 2004e14.
BAISI, NAVA, BAISI ET AL [8] Frassetto L, Baluom M, Jacobsen W, et al. Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virus-infected liver and kidney transplant recipients. Transplantation 2005;80:13e7. [9] Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995;13:129e34. [10] 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;7:2816e20. [11] Stock PG, Roland ME, Carlson L, et al. Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 2003;76:370e5. [12] Pelletier SJ, Norman SP, Christensen LL, et al. Review of transplantation in HIV patients during the HAART era. Clin Transplant 2004:63e82. [13] Salvadori M, Scolari MP, Bertoni E, et al. Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial. Transplantation 2009;88:1194e202. [14] Tedesco Silva H, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standardexposure CsA in renal-transplant recipients. Am J Transplant 2010;10:1e13. [15] Montagnino G, Sandrini S, Iorio B, et al. A randomized exploratory trial of steroid avoidance in renal transplant patients treated with everolimus and low-dose cyclosporine. Nephrol Dial Transplant 2008;23:707e14. [16] Opelz G, Döhler B, Laux G. Collaborative Transplant Study: long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 2005;5: 720e8. [17] Montagnino G, Tarantino A, Segoloni GP, et al. Long-term results of a randomized study comparing three immunosuppressive schedules with cyclosporine in cadaveric kidney transplantation. J Am Soc Nephrol 2001;12:2163. [18] Brehm MA, Markees TG, Daniels KA, et al. Direct visualization of cross-reactive effector and memory allo-specific CD8 T cells generated in response to viral infections. J Immunol 2003;170: 4077e86.
ABSTRACT Background. In Human immunodeficiency virus (HIV)-positive patients undergoing kidney transplantation, outcomes and immunosuppression (IS) protocol are not yet established due to infectious and neoplastic risks as well as to pharmacokinetic interactions with antiretroviral therapy (TARV). Methods. We report a retrospective, 1-center study on 18 HIVþ patients undergoing, between October 2007 and September 2015, kidney transplantation (13 cases) or combined kidney-liver transplant (5 cases). Inclusion criteria for transplant were based on the Italian National Transplant Center protocol. IS regimen was based on quick tapering of steroids and the use of mTOR inhibitors (mTORi) with low dose of calcineurin inhibitors (CNI). In the early post-transplant period, TARV was based on enfuvirtide, raltegravir, plus 1 or more nucleoside analogues. Results. In a mean follow-up of 3.1 years, patient survival rate at 1 and 3 years was, respectively, 86.6% and 84.6%, whereas graft survival was 81.2% and 78.6%. Cumulative rejection rate was 20.0% and 26.6% (1- and 3-year results). Median eGFR (MDRD) was 58.8 mL/min and 51.9 mL/min at 1 and 3 years. We had 9 cases of clinically relevant infections (2 Pneumocystis jirovecii pneumonia, 1 pulmonary aspergillosis, 2 severe sepsis, and 4 HCV reactivation) as well as 1 case (5.5%) of HIV reactivation. Conclusions. IS therapy based on mTORi and low CNI dose ensures good graft survival, low rate of acute rejection, limited drug toxicity, and control of HIV disease. TARV has no significant interaction with IS therapy.
U
NTIL the end of the 1990s, human immunodeficiency virus (HIV)-infected patients with an end-stage organ disease were excluded from transplant programs because of poor prognosis. The introduction of highly active antiretroviral therapy (HAART) has reduced morbidity and mortality rates. Many patients with HIV-related kidney diseases, once dying before entering end-stage renal disease (ESRD), now survive for many years and progressing to renal replacement therapy. As a result of the combined effect of new and more effective anti-retroviral (ARV) therapies and a better opportunistic infection prophylaxis, ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 333e336 (2016)
solid-organ transplantation is an effective therapeutic option also in this group of patients [1e4]: no differences in patient and graft survival rates have been reported between HIV-positive and -negative kidney recipients [5e7]. Many issues are still unclear, such as the increased acute rejection
*Address correspondence to Alberto Baisi, MD, Università di Modena e Reggio Emilia, Divisione di Nefrologia, Dialisi e Trapianto Renale, Largo del Pozzo 71, Modena 41124, Spain. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.038
333
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rate, the interaction between ARVs and immunosuppressive (IS) drugs, and the control of HIV replication to prevent opportunistic infections [8e12]. METHODS This was a single-center, retrospective study of kidney transplants or combined kidney-liver transplants performed in HIV-infected adult patients receiving an immunosuppressive therapy based on mTOR inhibitor (mTORi) and low dose of cyclosporine (CsA), between March 2008 and March 2015, and who were followed through September 2015. All patients fulfilled inclusion and exclusion criteria as well as specific policies provided by the Italian National Kidney Transplant Program in HIV (human immunodeficiency virus)þ patients, as shown in Table 1. Hepatitis B (HBV)- and/or C virus (HCV)-coinfected HIVþ patients required standard hepatic workout. Interferon and/or ribavirin therapy (when indicated) had to be completed before waiting list enrollment. All recipients received induction therapy with a standard dose of basiliximab; 500 mg intravenous (IV) methylprednisolone (MP) was given intra-operatively, followed by oral prednisolone progressively tapered from 16 mg to complete withdrawal within the 3rd month. Immunosuppression protocol included a delayed CsA (2.5 mg/kg bid when creatinine was <3.0 mg/dL) targeted to maintain CsA (C2 level) at initial value of 1000 ng/mL. At post-operative day (pod) 21, everolimus (EVL) 0.75 mg bid was introduced (EVL 0.75 mg bid; target EVL trough blood levels [TLC]: 8e10 ng/mL and CsAC2: 400e500 ng/mL); steroid was tapered to 4 mg/day within 45 days. After 6 months, EVL and CsA blood levels were targeted to EVLTLC 6 to 8 ng/mL and CsAC2, 250 to 350 ng/mL. After the first 6 case, mycophenolic acid (MPA) 720 mg bid was added until pod 21. Patients with combined liver-kidney transplantation received initial therapy with CsA and steroid. At pod 30, CsA was substituted with sirolimus (SIR) (SIRTLC, 8e12 ng/mL).
Table 1. Inclusion and Exclusion Criteria Inclusion criteria Documented HIV infection Ability to provide/obtain informed consent Patients never treated with ARVs with CD4 cell count circulating stably 200 cell/mm3 Patients on ARVs with CD4 cell count 200 cell/mm3 stable for at least 12 months and plasma HIV-RNA VL undetectable at the time of inclusion on waiting list Compliance to/willingness to continue ARVs and prophylaxis of opportunistic infections, if indicated If female, pregnancy test (b-HCG) negative (monthly monitoring) Exclusion criteria History of AIDS-defining opportunistic infections in the previous 2 years History of neoplasm (with the exception of in situ cervical neoplasia and baso-cellular carcinoma with a documented disease-free period of more than 5 years; recovery from malignant disease must be certified by an oncologist) Detectable peripheral blood HHV8 DNA VL Breast-feeding underway Abbreviations: ARVs, anti-retroviral drugs; VL, viral load; b-HCG, beta-human chorionic gonadotropin; AIDS, acquired immune deficiency syndrome; HHV8, human herpes virus 8.
Prescription and monitoring of ARVs was managed by physicians with expertise in HIV treatments. To avoid drug interactions between protease inhibitors and IS, ARV was given in the immediate post-operative period with enfuvirtide (T20) in combination with 2 nucleoside analogues or 1 nucleoside analogue and raltegravir (RAL), which was administered within 48 hours. Once steady state of IS was achieved (on average, pod 30), T20 was stopped and HAART was modified on the basis of HIV pre-transplant genotype profile, individual drug tolerability, and clinical conditions. For Pneumocystis jirovecii prophylaxis, we used a 6-month course of trimethoprim-sulfametoxazol. For CMV prophylaxis, all patients received IV ganciclovir or oral valganciclovir for a 3-month treatment; in the case of donor/recipient CMV status, specific antiCMV immunoglobulins were added. In the follow-up period, we monitored CMV, Epstein-Barr virus (EBV), human herpes virus (HHV) 6, HHV8, Polyoma BK and JC viruses, HBV, HCV, and Aspergillus spp. according to the Italian National Kidney Transplant Program in HIV-infected people guidelines. Biopsy-proven acute rejection was treated with 3 MP pulses. Graft loss was defined as return to dialysis or death with a functioning kidney. Delayed graft function (DGF) was defined as the need of hemodialysis during the first post-transplant week. Outcome measures included patient and graft survivals, acute rejection episodes, DGF, glomerular filtration rate (e-GFR according to MDRD), HIV immuno-virological response [HIV RNA viral load (VL) and CD4 cell count], and incidence of opportunistic infections and viral reactivations (CMV, EBV, HHV8, HHV6, Polyoma BK, and JC viruses).
RESULTS
The study included 13 HIV-positive patients submitted to deceased-donor kidney transplantation and 5 patients on combined kidney-liver transplantation. The median followup was 3.1 years. Median age of donors was 41 years, with interquartile range (IQR) 28 to 53. Recipient medium age was 49 years (IQR, 43e51), with 12 male 18 female. Causes of renal disease were HIV-associated nephropathy (HIVAN) in 6 of 18 (33%), hypertension in 1 of 18 (5%), diabetic nephropathy in 2 of 18 (11%), focal segmental glomerulosclerosis in 2 of 18 (11%), chronic pyelonephritis in 1 of 18 (5%), and unknown in 6 of 18. In combined liverkidney transplantation, viral hepatitis was HCV-related in 4 patients and HBV-related in 1 patient. All patients were on stable HAART at the time of transplantation with plasma HIV RNA viral load below detection limit (<40 c/mL). At enrollment, median CD4þ count was 321 per mm3 (IQR, 217e534), whereas at transplant, median CD4þ count was 441 per mm3 (IQR, 308e580). Survival rates at 1 year and 3 years were, respectively, 86.6% and 84.6% for patients and 81.2% and 78.6% for grafts. One patient died for sudden cardiac death 2 months after transplantation, without graft failure; 1 patient with liver-kidney transplantation died of candida systemic infection 3 months after transplantation. DGF occurred in 4 patients (22%); 1 of them presented an early rhabdomyolysis with acute kidney injury delaying CsA introduction. This patient developed a severe biopsyproven acute rejection (IIb according to Banff 97 criteria)
KIDNEY TRANSPLANT IN HIV-INFECTED RECIPIENTS
on pod 24 requiring transplantectomy on pod 31 after highdose MP, plasmapheresis, and high-dose immunoglobulins. At the end of the follow-up, median MDRD eGFR at 1 year and 3 years were, respectively, 58.8 19.2 mL/min and 51.9 19.2 mL/min. Acute rejection cumulative incidence was 20.0% at 1 year and 26.6% at 3 years. Anti-retroviral combination therapies before and after transplantation are shown in Table 2. HIV reactivation occurred in 1 patient (5%). Clinically relevant infections occurred in 9 cases: 2 P. jirovecii pneumonia, 1 pulmonary aspergillosis, 2 Escherichia coli sepsis; 4 HCV reactivations occurred in combined liver-kidney transplant recipients with HCV-related hepatitis. A viral load increase of CMV, EBV, HHV8, HHV6, and Polyoma BK and JC was documented by means of the PCR method in almost all patients; it required specific treatment or immunosuppression dose adjustment, and no complications of clinical significance occurred. No neoplasms were reported. DISCUSSION
The mean limitation of this study is the relatively small number of HIVþ transplanted patients. However, our data support kidney transplantation in HIV-positive recipients as feasible and effective renal-replacement therapy. An important issue is the fitting of immunosuppression in the context of anti-retroviral therapy in HIVþ population mainly in the early post-transplant period, when the risks of pharmacokinetic interactions and organ rejection are higher. The IS scheme is based on mTORi and low-exposure CsA, a well-recognized combination with excellent results reported in HIV patients [13,14]. This strategy allows prevention of
335
chronic drug-induced renal toxicity while reducing risk of viral infections and neoplasms and keeping protection from rejection. As already shown in the standard recipient of kidney transplant [15], the association EVL-CsA allows minimization of the steroid maintenance dose or allows its withdrawal. It is likely that this almost steroid-free immunosuppression may reduce the risk of cardiovascular disease, osteopenia/osteoporosis, aseptic bone necrosis, and ocular complications in the long term, as reported by previous registry studies [16] and randomized trials [17]. Results obtained in our patients, in terms of patient and graft survivals, are in the range of all deceased donor kidney transplants performed in our center since 1998: graft survival (%) of 91.35 1.45 and 86.55 1.85 at 1 and 3 years, respectively; patients survival (%) at 1 and 3 years 96.85 0.95 and 94.05 1.35. Cumulative incidence of acute rejections at 1 and 3 years (20.0% and 26.6%, respectively) is higher than in HIVnegative recipients. All acute rejection was steroidresponsive, except for a case of acute rejection resistant to steroid pulses and plasmapheresis; this occurrence prompted us to introduce the short-term MPA course into the protocol. A possible explanation for this higher incidence of acute rejection could be a condition of T-cell cross-reactivity caused by HIV infections [18]. Strict bacteriological and virological monitoring has allowed control of the development of opportunistic infections. Viral reactivations, as assessed by laboratory data, frequently occurred after post-transplant immunosuppression, but only in a few cases did viremia exceed the threshold of clinical significance. ARVs based on T20 and RAL, in the early posttransplant period, follow the concept of a therapeutic
Table 2. Anti-Retroviral Combination Therapies Before and After Transplantation Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
HAART Before Transplantation
3TCþABCþATV 3TCþABCþSQV 3TCþTDFþEFV 3TCþTDFþATV 3TCþTDFþATVþRTV ABCþRTVþfAPV 3TCþRALþT20 RALþDRVþRTVþETV No HAART 3TCþABCþATV RTVþLPV 3TCþRALþT20 DRVþRTVþTDFþFTC DRVþRTVþRAL 3TCþfAPVþRAL DRVþRTVþRAL 3TCþATVþRAL 3TCþABCþNEV
HAART Early Post-Transplantation
Immunosuppressive Therapy Early Post-Transplantation
3TCþTDF 3TCþABC 3TCþRAL 3TCþRAL 3TCþRAL RALþT20 RALþT20 RALþT20 No HAART RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20 RALþT20
CsAþEVL CsAþEVL CsAþEVL CsAþEVL Transplantectomy CsAþEVL EVL EVL CsAþEVL CsA CsA CsA CsAþEVL CsAþEVL FK506 CsA CsAþEVL CsAþEVL
HAART Maintenance Post-Transplantation
3TCþATVþRAL 3TCþABCþRALþRTV MVCþRAL 3TCþATVþRAL 3TCþTDF 3TCþRALþATZ 3TCþRALþATVþRTV RALþDRVþRTVþETV 3TCþRALþMVC 3TCþRTVþATVþRAL 3TCþRALþATZþRTV 3TCþRALþATV Death 3TCþRALþMVC 3TCþRALþfAPV Death RALþT20þRPV RALþRPV
Abbreviations: HAART, highly active anti-retroviral therapy; 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; TDF, tenofovir; CsA, cyclosporine; EVL, everolimus; RAL, raltegravir; SQV, saquinavir; RTV, ritonavir; DRV, darunavir; EFV, efavirenz; MVC, maraviroc; fAPV, fosamprenavir; T20, enfuvirtide; ATZ, zidovudine; ETV, entecavir; LPV, lopinavir; FTC, emtricitabine; FK506, tacrolimus; NEV, nevirapine; RPV, rilpivirine.
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interval focused on prevention of pharmacokinetic interactions to avoid organ rejection and drug toxicity still keeping viral control. Through a low genetic barrier, this ARV is used for a limited time because they do not allow long-term management of HIV infection; RAL and T20 did not interfere with EVL, SIR, and CsA through blood levels, confirming the low potential for pharmacokinetic interactions with IS therapy. In summary, according to our data, kidney transplant in HIV-positive recipients is an efficient renal replacement therapy. IS based on mTORi and a low exposure to CsA linked to ARVs with T20 and RAL in the immediate postoperative period allowed good graft survival, a low rate of rejection, and HIV replication control. REFERENCES [1] Stock PG, Roland ME. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation 2007;84:563e71. [2] Blumberg EA, Stock P. Solid organ transplantation in the HIV-infected patient. Am J Transplant 2009;4:S131e5. [3] Miró JM, Torre-Cisnero J, Moreno A, et al. GESIDA/ GESITRA-SEIMC, PNS and ONT consensus document on solid organ transplant (SOT) in HIV-infected patients in Spain (March 2005). Enferm Infecc Microbiol Clin 2005;23:353e62. [4] Roland ME, Stock PG. Comprehensive guidelines translate research findings into clinical policy for HIV-infected transplant candidates and recipients. Enferm Infecc Microbiol Clin 2005;23: 331e4. [5] Ahuja TS, Grady J, Khan S. Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States. J Am Soc Nephrol 2002;13:1889e93. [6] Abbott KC, Swanson SJ, Agodoa LY, et al. Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression. J Am Soc Nephrol 2004;15:1633e9. [7] Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med 2004;363: 2004e14.
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