Integrase strand transferase inhibitors: the preferred antiretroviral regimen in HIV-positive renal transplantation

Abstract

In the era of antiretroviral therapy, people living with HIV/AIDS live longer and are subject to co-morbidities that affect the general population, such as chronic kidney disease. An increasing number of people living with HIV/AIDS with end-stage renal disease are candidates for renal transplantation. Prior experience demonstrated that HIV-positive renal transplant recipients had acceptable survival but graft survival was decreased and rejection rates were increased, possibly due to suboptimal management of immunosuppressive medications in the face of drug interactions with antiretroviral therapy, particularly protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Integrase strand transferase inhibitors are advantageous since they avoid drug–drug interactions with immunosuppressive drugs such as calcineurin inhibitors. We report clinical outcomes of 12 HIV-positive patients who underwent 13 kidney transplantations at our institution between 2000 and 2015. Cumulative survival was 75%, one-year and three-year survival were 100% and 63%. Integrase strand transferase inhibitor-based regimens were used in nine patients, of which eight survived. In patients on integrase strand transferase inhibitor, there was 100% graft survival and two had allograft rejection. In contrast, graft failure occurred in three patients on non-integrase strand transferase inhibitor-based regimens. Based on our study findings and on previously published data, we conclude that integrase strand transferase inhibitor-based therapy, preferably instituted prior to transplantation, is the preferred antiretroviral regimen in HIV-positive renal transplantation.

Keywords

Renal transplant HIV graft failure graft survival integrase strand transferase inhibitors

Introduction

With the advent of combination anti-retroviral therapy (ART), the average life expectancy of people living with HIV/AIDS (PLWHA) in the United States has approached and, in some cases exceeded, that of the general population.¹ As AIDS-related morbidity and mortality has declined, the impact of non-AIDS related diseases, has risen.² Renal insufficiency, which affects up to 30% of PLWHA,³ is most commonly the result of HIV-associated nephropathy (HIVAN) and may progress to end-stage renal disease (ESRD).⁴ In the current ART era, the prevalence of ESRD among HIV-infected individuals has ranged between 0.3% and 0.5%.^5–7 In 2007, the U.S. Renal Data System recorded over 3000 HIV-positive persons with ESRD.^8,9 In HIV-positive patients, renal replacement therapy is associated with 26% mortality in the first year¹⁰ as compared to 15%–20% in the general population.^11,12

Whereas, HIV seropositivity was previously considered a contraindication to renal transplantation, recent multicenter studies have reported good outcomes in recipients with well-controlled HIV, specifically in terms of patient survival (one year = 94.6%, three year = 88.4%), graft survival (one year = 90.4%, three year = 73.7%) and control of HIV disease.^13–16 These outcomes have approximated those of HIV-negative populations whose one-year patient and graft survival exceed 90%.¹⁷ In light of these findings, there has been a substantial increase in renal transplantations in PLWHA worldwide,⁹ but these efforts have been hindered by high-rejection rates (30%–50%), more than double those of HIV-negative recipients.^{7,13,15,18,19}

The increased rejection rates have been postulated to be in part due to altered levels of immunosuppressive drugs, namely, calcineurin inhibitors (CNI) and target of rapamycin inhibitors (mTOR), which result from drug interactions with antiretrovirals. Specifically, protease inhibitors (PIs) inhibit the P450 cytochrome enzymes while certain non-nucleoside/tide reverse transcriptase inhibitors (NNRTIs)²⁰ induce them. Integrase strand transfer inhibitors (INSTIs) were introduced in 2007²¹ and recent Department of Health and Human Services (DHHS) guidelines for the use of antiretrovirals in HIV-infected adults endorse INSTIs in five of six recommended first line regimens for ART-naive patients.²² Since they are metabolized by an alternate pathway (UDP glucuronosyltransferase 1-mediated), INSTIs have few drug–drug interactions and have been proposed as a suitable alternative in patients undergoing renal transplants.²³ Moreover, numerous studies have shown favorable outcomes with the use of INSTI-based regimens in the setting of renal transplantation as compared to PIs and NNRTIs.^15,23–25 Despite the favorable pharmacology, accumulating data, and widespread use, there are no consensus guidelines recommending the use of INSTIs in this setting.

In this study, we describe the clinical outcomes of HIV-infected patients following kidney transplantation at our institution, with a particular focus on our experience with anti-retroviral and immunosuppressive regimens and their impact on graft rejection and survival.

Methods

We performed a retrospective chart review of HIV-positive patients who either underwent kidney transplantation at YNHH or were followed at YNHH after transplantation at another institution between 1 January 2000 and 31 December 2015. The majority of transplants were performed after 2010. The Yale New Haven Hospital (YNHH) kidney transplant program has been operating since 1967 and began performing transplants in HIV patients in 2010. The transplant program requires that each potential candidate undergo evaluation within the HIV clinic. The HIV-specific criteria for transplant are as published: CD4 ≥ 200 cells/mL, an undetectable viral load and no active opportunistic infections.²⁶ Hepatitis C was not an exclusion criterion; however, our program transplanted only co-infected individuals with liver biopsy staging less than or equal to F2 by METAVIR staging.

Electronic medical records and paper charts were used to extract data on patient demographics, medical comorbidities, including the cause of underlying ESRD prompting transplantation, HIV-related parameters (date of initial HIV diagnosis, history of AIDS or AIDS-defining opportunistic diseases, pre- and post-transplantation CD4 count [cells/mL], viral load [HIV RNA copies/mL] levels and ART). The COBAS Ampliprep/COBAS Taqman version 2.0, quantitative HIV RT-PCR platform was used and detects to a viral load of <20 copies/mL. The 2014 CDC criteria for AIDS (Stage 3 HIV-infection) were employed (CD4 count < 200 cells/mL or history of AIDS-defining illness).²⁷ Transplant-related parameters (donor vs. living-related kidney transplant, CMV donor and recipient serostatus, donor criteria, induction and maintenance immunosuppressive therapy, serum levels of tacrolimus, presence of delayed graft function (DGF), episodes of acute or chronic rejection, graft and patient outcomes) were reviewed. Maintenance immunosuppressive regimens included relevant medications within four weeks of transplantation. A therapeutic serum tacrolimus trough level was defined as 8–10 ng/ml within 30 days after transplantation and 5–7 ng/ml > 30 days post-transplant, following our institution's protocol. Kidney biopsies were performed only when rejection was suspected based on clinical or laboratory findings. Acute (within 90 days of transplant) and chronic renal allograft rejection were assessed in accordance with the BANFF working classification of renal allograft pathology.²⁸ DGF was defined as acute renal failure requiring dialysis within seven days of transplantation.²⁹ Graft failure was defined as chronic allograft nephropathy leading to the resumption of chronic renal replacement therapy. Definitions of standard criteria donors and expanded criteria donors are as published.³⁰

The incidence of DGF, allograft rejection and graft failure were calculated as well as overall patient mortality. Tacrolimus trough levels were expressed as a median and interquartile range (IQR). Statistical analyses were not performed due to the small number of patients. The institutional review board of Yale University approved this study.

Results

Baseline (pre-transplant) characteristics

During the study period, 14 renal transplantations were performed among 13 HIV-positive patients. One patient received two renal transplants separated by eight years and therefore is represented twice in our dataset (designated as Patient 2 and 11). One patient, who developed renal vein thrombosis complicated by septic shock, died within 30 days of transplantation and was excluded from the analysis; leaving 13 episodes of transplantation in 12 patients available for analysis. As shown in Table 1, the majority of patients were male (n = 9), black (n = 10), with a median age at transplant of 52 years (range = 38–73). Hypertension was the most common underlying cause of ESRD (n = 5), and hemodialysis (n = 10) was the most common form of renal replacement therapy.

Table 1.

Baseline characteristics of 12 HIV-infected kidney transplant recipients.

Characteristic	N = 12
Gender
Male	9
Female	3
Race/ethnicity
Black	10
White	1
Hispanic	1
Age at transplant
Mean in years (Range)	53 (38–73)
Median in years	52
Cause of ESRD
Hypertension	5
HIVAN	3
Glomerulonephritis	1
Renal cell carcinoma	1
Toxemia of pregnancy	1
Unknown	1
Hepatitis C infection	2
Type of dialysis
Hemodialysis (HD)	10
Peritoneal dialysis	2
Pre-transplant HIV-specific characteristics
Time since HIV diagnosis
Mean in years (Range)	16 (7–21)
Median in years	19
HIV status
HIV positive only	9
CDC-defined AIDS	3
HIV risk factors
Heterosexual	8
MSM	2
IDU	2
Pre-transplant ART regimen
NNRTI-containing	2
Efavirenz	1
Nevirapine	1
PI-containing	4
Lopinavir/ritonavir	2
Darunavir/ritonavir	2
INSTI-containing	7
Raltegravir	6
Dolutegravir	1
NRTI backbone
Abacavir-containing	6
Tenofovir-containing	5
Zidovudine-containing	1

ESRD: end-stage renal disease; HIVAN: HIV-associated nephropathy; HD: hemodialysis; CDC: Center for Disease Control; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor; NRTI: nucleoside reverse transcriptase inhibitors; MSM: men who have sex with men; IDU: intravenous drug users.

Pre-transplant HIV-specific characteristics are shown in Table 1. Excluding the one patient who was diagnosed with HIV two years post-transplant, the average time from HIV diagnosis to kidney transplantation was 16 years. Three patients had a previous history of CDC-defined AIDS but at time of transplant listing, all patients met HIV-specific criteria for transplant (as listed in Methods section). The most common self-reported risk factor for HIV acquisition was heterosexual intercourse (n = 8). At the time of evaluation at the HIV clinic prior to transplant, INSTI-containing regimens (n = 7; raltegravir = 6, dolutegravir = 1) were most commonly used, followed by PI-containing regimens (n = 4; lopinavir/ritonavir = 2; darunavir/ritonavir = 2) and NNRTI-containing regimens (NNRTI; n = 2; efavirenz = 1, nevirapine = 1). In one patient, the ART regimen contained both INSTI and PI. The nucleoside reverse transcriptase (NRTI) backbones were mostly abacavir (n = 6) or tenofovir (n = 5) combined with either lamivudine or emtricitabine.

HIV-specific post-transplant ART and outcomes

Table 2 contains a detailed account of HIV-specific peri-transplant parameters and outcomes. In nine cases, the ART regimens before and after transplant were the same. Notably, seven contained INSTI pre-transplantation, representing a pre-emptive change in the majority of cases. Overall, among 13 transplant episodes, INSTI-based regimens were most common after transplantation (n = 9) followed by NNRTI-based regimens (n = 2), PI-based regimen (n = 1) and PI/INSTI combination regimen (n = 1) in addition to the dual-nucleoside reverse transcriptase inhibitor (NRTI) backbone. In three cases after transplantation, ART was switched to INSTI-containing regimens (2 PI → INSTI, 1 NNRTI → INSTI). Among four patients who were on PI or NNRTI-containing regimens post-transplant, two patients (Patients 1 and 2) received their transplants before the availability of INSTIs; one patient (Patient 4) required ART containing a PI due to highly resistant virus requiring a salvage regimen and one patient (Patient 10) resumed a PI-based regimen after developing a drug rash secondary to raltegravir.

Table 2.

HIV-specific peri-transplantation antiretroviral treatment and outcomes in 12 renal transplant recipients.

Patient	Pre-transplant ART regimen	Post-transplant ART regimen	Year of transplant	Pre- transplant HIV viral load (copies/ml)	Pre-transplant CD4 count (cells/mL)	Nadir CD4 count (cells/mL) (time of nadir post transplant)	Peak CD4 count (cells/mL)(time of peak post-transplant)	Most recent CD4 count (time post-transplant)	Post-transplant follow-up time (years)
1*	N/A	ABC/3TC/ZDV/EFV	2000	N/A	N/A	179 (24 months)	1064 (117 months)	753 (134 months)	11.3
2 °	ABC/3TC/EFV	ABC/3TC/EFV	2006	ND	NA	790 (61 months)	854 (67 months)	854 (67 months)	9.2
3	TDF/3TC/NVP	TDF/3TC/RAL	2010	ND	536	181 (29 months)	445 (1.4 months)	181 (29 months)	2.4
4	ABC/FTC/DRV/r/RAL	ABC/3TC/DRV/r/RAL	2010	ND	938	127 (10.4 months)	862 (38.5 months)	862 (38.5 months)	4.0
5	TDF/3TC/LPV/r	TDF/3TC/RAL	2011	ND	658	304 (32 months)	1050 (18 months)	753 (56 months)	4.8
6	ABC/3TC/RAL	ABC/3TC/RAL	2012	ND	592	245 (28 months)	636 (39 months)	636 (39 months)	3.6
7	TDF/FTC/RAL	TDF/FTC/RAL Then ABC/3TC/RAL	2012	ND	577	333 (2 months)	540 (5.8 months)	403 (11 months)	3.6
8	ABC/3TC/RAL	ABC/3TC/RAL	2012	ND	500	194 (6 months)	451 (0.6 months)	342 (34 months)	3.0
9	TDF/3TC/LPV/r	ABC/3TC/RAL	2013	ND	385	146 (9 months)	295 (21 months)	269 (17 months)	2.7
10	AZT/FTC/DRV/r	AZT/FTC/DRV/r	2014	ND	395	170 (0.5 months)	170 (0.5 months)	170 (0.5 months)	1.3
11**	ABC/3TC/RAL	ABC/3TC/RAL	2014	ND	971	10 (3.3 months)	48 (6.8 months)	48 (6.8 months)	1.3
12	TDF/FTC/DTG	ABC/3TC/DTG	2015	ND	318	107 (6 months)	172 (9 months)	172 (9 months)	0.9
13	ABC/3TC/RAL	ABC/3TC/RAL	2015	ND	338	53 (0.3 months)	203 (1.2 months)	203 (1.2 months)	0.7

ART: antiretroviral therapy; RAL: Raltegravir; DTG: Dolutegravir; 3TC: Lamivudine, TDF: Tenofovir; ABC: Abacavir; EFV: Efavirenz; FTC: Emtricitabine; ZDV: Zidovudine; DRV/r: Darunavir/Ritonavir; NVP: Nevirapine; LPV/r: Lopinavir/ritonavir; N/A: not applicable; ND: not detectable; NA: not available.

Diagnosed with HIV two years after transplantation.

Retransplant.

Transplant performed at outside institution.

The median post-transplant follow-up time for patients was 3.2 years (range = 8 months–11.3 years). During this period, the median CD4 nadir was 179 cells/mL (range = 10–790), while the median peak CD4 was 451 cells/mL (range = 49–1064). Three patients (Patients 3, 11, and 12) had prolonged CD4 lymphocytopenia of < 200 cells/mL of > 6 months post-transplant. All patients remained virally suppressed (HIV RNA < 40 copies/mL) and the median CD4 count pre-transplant was 536 cells/mL.

Transplant-specific parameters and outcomes

Specific transplant characteristics and outcomes are shown in Table 3. The majority of transplants occurred after 2007 (n = 11). Deceased donor kidney transplants (DDKT) were performed in nine cases and living-related kidney transplants (LRKT) in four cases. The donor-recipient (D/R) cytomegalovirus (CMV) serostatus was as follows: R + in 10, D+/R− in 2, unknown in 1 case. Two kidneys were procured from extended criteria donors.

Table 3.

Transplant-specific characteristics and patient and graft outcomes.

Patient	Date of transplant	Type of kidney transplant	CMV D/R serostatus	Induction immune- suppressive therapy	Maintenance immune- suppressive therapy	DGF	Episodes of rejection	Graft outcomes	Tacrolimus level within 30 days post-transplant	Episodes of infection post-transplant requiring admission	Outcome
1	2000	DDKT	D?/R+	ATG	Tacrolimus 3 mg/d MMF 2000 mg/d Prednisone 5 mg/d	No	Chronic allograft nephropathy Grade II-III (55 months post-transplant)	Graft failure (98 months post-transplant)	Subtherapeutic	Intraabdominal abscesss due to enterocutaneous fistula leading to septic shock/bacteremia VZV encephalitis CLABSI due to MRSA	Death from septic shock (145 months post-transplant)
2	2006	DDKT	D?/R?	ATG	Tacrolimus 18 mg/d Azathioprine 75 mg/d Prednisone 5 mg/d	No	Acute cellular rejection (classification unknown) Chronic allograft nephropathy Grade I with features of CNI toxicity (26 months post-transplant)	Graft failure (57 months post-transplant)	Subtherapeutic	None	Alive
3	2010	LRKT	D?/R+	Basiliximab	Tacrolimus 8 mg/d MMF 1500 mg/d Prednisone 5 mg/d	No	No	Functioning until death	Therapeutic	None	Death from respiratory failure of unclear etiology – possible lymphangitic spread of malignancy (29 months post-transplant)
4	2010	LRKT	D+/R+	Basiliximab	Tacrolimus 1 mg every 7–9 days Prednisone 5 mg/d	No	Chronic allograft nephropathy Grade II, Minimal Change Disease and CNI toxicity (10 months post-transplant)	Graft failure (37 months post-transplant)	Therapeutic	None	Death, of unclear etiology (50 months post-transplant)
5	2011	DDKT	D+/R+	ATG	Tacrolimus 2.5 mg/d Prednisone 5 mg/d	No	No	Functioning but with new CKD (likely from HTN/DM2)	Therapeutic	Pulmonary aspergillosis	Alive
6	2012	DDKT	D+/R+	Basiliximab	Tacrolimus 2.5 mg/d MMF 2000 mg/d Prednisone 5 mg/d	No	No	Functioning	Therapeutic	Influenza A pneumonia Bacteremia and UTI due to E. faecalis Cellulitis due to laceration	Alive
7	2012	LRKT	D+/R-	Basiliximab	Tacrolimus 3 mg/d MMF 2000 mg/d Prednisone 5 mg/d	Yes	Chronic allograft injury Grade I, mild features CNI toxicity (6 months post-transplant)	Functioning	Therapeutic	None	Alive
8	2012	DDKT	D+/R+	Basiliximab	Tacrolimus 8 mg/d MMF 2000 mg/d Prednisone 10 mg/d	Yes	No	Functioning	Therapeutic	None	Alive
9	2013	DDKT	D-/R+	ATG	Tacrolimus 8 mg/d MMF 2000 mg/d Prednisone 10 mg/d	Yes	No	Functioning	Therapeutic	Upper respiratory infection due to human metapneumovirus infection	Alive
10	2014	LRKT	D?/R+	Basiliximab	Belatacept 750 mg IV every 2 weeks MMF 2000 mg/d Prednisone 5 mg/d	No	No	Functioning	N/A	AICD lead infection, UTI and bacteremia due to E. faecalis	Alive
11*	2014	DDKT	D-/R+	Alemtuzumab	Belatacept 750 mg IV every 2 weeks MMF 2000 mg/d Prednisone 5 mg/d	No	No	Functioning	N/A	None	Alive
12	2015	DDKT	D-/R+	Basiliximab	Tacrolimus 7 mg/d Prednisone 5 mg/d	No	No	Functioning	Therapeutic	UTI due to E.coli with obstruction and bilateral hydronephrosis	Alive
13	2015	DDKT	D+/R-	ATG	Tacrolimus 7 mg/d MMF 1000 mg/d	No	Acute cellular rejection borderline BANFF	Functioning	Therapeutic	Klebsiella pneumonia bacteremia, UTI and infected peri-nephric collection	Alive

MMF: mycophenolate mofetil; ATG: antithymocyte globulin; DGF: delayed graft function; DDKT: deceased donor kidney transplant; LRKT: living related kidney transplant; CNI: calcineurin inhibitor; N/A: not applicable; CLABSI: central line associated bloodstream infection; MRSA: methicillin resistant Staph aureus; DM: diabetes mellitus; HTN: hypertension; UTI: urinary tract infection.

Retransplant

Of 12 patients included in this series, 9 were alive at the end of the study period. The median time from transplant to death of the three deceased patients was 50 months (range = 29–145). Survival data were as follows: cumulative survival (9/12 = 75%), one-year survival (12/12 = 100%) and three-year survival (5/8 = 63%). We do not currently have sufficient cumulative data to calculate five-year survival.

Induction immunosuppressive therapy consisted of basiliximab (n = 7), antithymocyte globulin (n = 5) and alemtuzumab (n = 1). Maintenance immunosuppressive therapy included low-dose prednisone (n = 12), tacrolimus (n = 11), mycophenolate mofetil (MMF; n = 9), belatacept (n = 2) and azathioprine (n = 1). The most common maintenance regimen consisted of tacrolimus, MMF and prednisone but two of the three most recent transplants employed belatacept. Three patients developed DGF post-operatively; all ultimately recovered and had functioning grafts long term.

Graft failure occurred in three patients (Patients 1, 2 and 4) at a median of 57 months post-transplant (range = 37–98). Two patients, who were transplanted prior to 2007, were on NNRTI-based regimens (Patients 1 and 2) and one on mixed INSTI/PI-based regimen (Patient 4) at time of allograft failure. Maintenance therapy included tacrolimus in all. Graft failure was linked to progressive chronic allograft rejection in all three cases.

Tacrolimus trough levels in the first post-transplant year are shown in Table 4 for eight patients who were on INSTI-only containing regimens and one patient who was on a PI-containing regimen. All patients on INSTI-only based therapy achieved target tacrolimus trough levels throughout the first year, with a median tacrolimus trough level between 7 and 8 ng/mL for the cohort. Time to first therapeutic tacrolimus trough level was 6 days for patients on INSTI-only regimens. In contrast, tacrolimus trough levels were higher for the single patient on PI-containing regimen (Patient 4), ranging between 12 and 20 ng/mL. Patient 4, who required continuation of salvage ART containing darunavir/ritonavir and raltegravir because of HIV genotype constraints, required marked dose reduction of tacrolimus (0.5 mg every 7–9 days). This patient developed biopsy-proven chronic allograft nephropathy, recurrent minimal change disease and CNI toxicity at 10 months post-transplant and subsequent graft failure at 37 months.

Table 4.

Tacrolimus trough levels in first post-transplant year by ART-regimen type.

Patients°	Tacrolimus trough level median [IQR] (ng/mL)							Time to first therapeutic Tacrolimus level*
Patients°	0–30 days post-transplant	Target range (ng/mL)	31–90 days post-transplant	91–120 days post- transplant	121–180 days post- transplant	181–365 days post-transplant	Target range (ng/mL)	Time to first therapeutic Tacrolimus level*
INSTI-only based ART (n=8)	7 [5–10]	8–10	8 [6–10]	8 [7–11]	7 [6–9]	7 [6–8]	5–7	6 days
Patient 3	6 [5–9.5]	8–10	7 [6–7]	6	6 [6–7]	6 [5–6]	5–7	5 days
Patient 5	6 [3–10]	8–10	7 [6–8]	8 [7–9]	7 [5–8]	5 [5–8]	5–7	5 days
Patient 6	NA	8–10	8 [7–10]	8 [7–9]	6 [5–9]	7 [6–10]	5–7	NA
Patient 7	6 [6–10]	8–10	8 [5–8]	20	NA	6 [6–7]	5–7	7 days
Patient 8	8 [6–9]	8–10	11 [10–12]	9 [8–9]	9	8 [7–8]	5–7	5 days
Patient 9	8 [6–9]	8–10	10 [9–13]	NA	11 [11–12]	7 [6–8]	5–7	8 days
Patient 12	7 [7–8]	8–10	7 [5–9]	17	8	7 [6–7]	5–7	NA
Patient 13	8 [6–12]	8–10	8 [6–11]	10 [9–11]	7 [7–9]	7 [7–9]	5–7	6 days
PI-containing ART (n = 1; Patient 4)	NA	8–10	13	20	13	12 [10–17]	5–7	NA

ART: anti-retroviral therapy; IQR: interquartile range; NA: not available.

°Patients 1 and 2 excluded because of lack of data on tacrolimus levels in first year post-transplant. Patients 10 and 11 excluded because maintenance immunosuppressive therapy was belatacept-based.

Within first 14 days post-transplant.

Both patients receiving efavirenz-containing regimens (Patients 1 and 2) were excluded from Table 4 because tacrolimus levels from the first-year post-transplant were unavailable. Additionally, Patient 2 was diagnosed with HIV and started on ART 2 years post-transplant. However, in subsequent years, both had varying levels of tacrolimus, generally below or in the low therapeutic range. While on an efavirenz-based regimen, Patient 1 had tacrolimus levels ranging between 3–5 ng/mL, as compared to 3–14 ng/mL prior to starting ART. Patient 2 required dose escalation of tacrolimus to 18 mg/day to achieve therapeutic levels, with tacrolimus levels ranging between 3–8ng/mL prior to initiation of dialysis.

Among the nine survivors, all had functioning grafts. Of these, eight were on INSTI-based regimens. Patients who were on tenofovir, emtricitabine or lamivudine required dose adjustment of their ART based on post-transplant renal function. Patients who were on abacavir-based regimens did not require renal dose adjustment.

Renal allograft rejection was histopathologically confirmed in five patients, including two episodes of acute rejection and four cases of chronic rejection (Patient 2 had evidence of acute followed by chronic rejection). Chronic rejection occurred at a median of 18 months post-transplant (range = 6–55). Three episodes of rejection occurred in patients on non-INSTI based regimens (Patients 1, 2 and 4) while two episodes occurred in patients on INSTI-based regimens (Patients 7 and 13). For patients 4, 7 and 13, tacrolimus trough levels obtained within two weeks of allograft rejection were elevated: 16 ng/mL, 17 ng/mL and 9 ng/mL, respectively. Patient 1 had tacrolimus levels of 3–5 ng/mL within two weeks of rejection while levels for Patient 2 were not available.

Infections requiring inpatient admission occurred in seven patients and included bacterial, viral and fungal causes. The most common etiologies were bacteremia, urosepsis and respiratory infections. One patient died of septic shock, and two patients died of unclear etiologies. There were no HIV-related opportunistic infections. The donor/recipient Epstein Barr Virus (EBV) serostatus for both patients on belatacept (Patients 10 and 11) was D+/R+. For Patient 11, EBV DNA PCR was undetectable at time of transplant and eight months post-transplant. Patient 10 had no available EBV DNA PCR results. Neither patient developed post-transplant lymphoproliferative disorder during the study.

Discussion

In the era of antiretroviral therapy, PLWHA are living longer and are subject to co-morbidities that affect the general population, including chronic renal disease. An increasing number of PLWHA who progress to ESRD are suitable candidates for life-prolonging renal transplantation. Post-transplant management of HIV-infection with PI and NNRTI-based ART is complicated by reciprocal drug interactions with immunosuppressive therapy, especially CNI, because of inhibition or induction of P450 cytochrome enzymes. Despite appropriate CNI dose-adjustments, variations in drug serum levels are difficult to control and have been linked to increased graft rejection in HIV-positive renal transplant recipients.^9,31 In the largest study of 150 HIV-positive renal transplant patients to date, higher than expected rates of rejection were reported (31% and 41% at one and three years, respectively).¹⁵ The authors speculated that increased rates of rejection may have been secondary to altered CNI levels since only one-third of patients on PI or NNRTI-based regimens underwent CNI dose adjustments.

Since their introduction in 2007, INSTIs have been proposed as preferred post-transplant ART because of a favorable pharmacologic profile with decreased potential for drug interactions.^15,23–25 In the study by Stock et al.,¹⁵ the majority were on PIs or NNRTIs with only 4% of participants receiving INSTIs; these patients were also receiving PI, NNRTI or maraviroc, making it impossible to draw conclusions about INSTI-based therapy. In a series of 27 HIV-positive renal transplant patients in France predominantly on PI or NNRTI-based regimens (93%), 70% required post-transplant ART modification due to drug interactions with CNIs.¹⁶ In a study of HIV-positive renal transplant patients on raltegravir (n = 9) vs. PI or NNRTI-based (n = 24) regimens, acute rejection and graft failure were significantly lower in the former group.³² In two other small studies, INSTI-based regimens were associated with target trough levels of CNI, lack of episodes of rejection and satisfactory graft function.^14,23 Despite these studies, there are no definite consensus guidelines recommending INSTI use in the transplant setting.

Our series corroborates these favorable findings using INSTI-based ARV therapy. There were no cases of graft failure among nine patients on INSTI-based regimens in our study. In addition, only two of nine patients (22%) on INSTI-based regimens developed episodes of rejection at three years. This is in contrast with a three-year graft rejection rate of 41% in the Stock et al.¹⁵ cohort of 150 HIV-infected patients (who were predominantly on PI and NNRTI-based regimens). Our series included fewer patients, but notably, the three-year graft rejection figure in the above study was derived from only one-third of patients who were followed up to three years.

In the aforementioned studies employing INSTI-based regimens, most patients underwent switch to an INSTI-based regimen after transplantation. In contrast, the majority of patients in this study underwent a preemptive switch prior to transplantation. It is possible that the use of NNRTI and PI-based regimens, even in the immediate post-transplant period, may lead to an increased risk for rejection by altering drug CNI levels at a critical period, despite diligent monitoring. In our study, tacrolimus trough levels for patients on INSTI-only regimens remained within the therapeutic target ranges over the first post-transplant year. We documented CNI toxicity in only one patient (Patient 7) on INSTI-based therapy. Interestingly, this patient also had histopathologic evidence of allograft rejection, despite elevated tacrolimus trough levels. Though reasons for this are unclear, it suggests that factors other than direct drug–drug interactions may be involved including wide fluctuations in drug levels, not fully captured by single time points.

Overall, patients on INSTI-based ART maintained therapeutic levels of CNI, had favorable overall graft outcomes and achieved long-term HIV-viral suppression. Although our cohort was limited in numbers, our findings support the approach of a pre-emptive switch to an INSTI-based regimen (raltegravir or dolutegravir). There has been precedent for switches from PI or NNRTI based regimens to INSTI-based regimens, which demonstrated maintenance of viral suppression after switching, particularly in patients without prior virologic failure.^33,34 Given its high barrier to resistance, one pill once a day formulation and accumulating evidence of strong efficacy,³⁵ dolutegravir may be a particularly good choice for HIV-positive renal transplant candidates and recipients in the future. Notably, dolutegravir leads to mild increases of serum creatinine, through blockade of tubular secretion but this does not represent a nephrotoxic effect and does not affect glomerular filtration rate.³⁶ The third currently available INSTI, elvitegravir, should not be used in the setting of HIV-positive renal transplantation because it is co-formulated with cobicistat, a strong CYP3A4 inhibitor with many potential drug–drug interactions. Unlike other NNRTIs, rilpivirine does not induce P450 metabolism and should theoretically leave CNI drug levels unaffected; however, data on the use of rilpivirine after renal transplantation is lacking.³⁷ Due to decreased nephrotoxicity, the novel NRTI, tenofovir alafenamide, has the potential to replace tenofovir disoproxil fumarate in this population, but studies are needed to confirm its safety in this setting.

Our experience also suggests that in the event that a PI or NNRTI-based regimen is unavoidable, alternative maintenance immunosuppressive agents could be considered. Belatacept, a fusion protein with monoclonal antibody against CD80 and CD86, may be used to successfully avoid drug–drug interactions and has shown outcomes superior to cyclosporine in a recent study.³⁸ Data on the use of belatacept in HIV-positive renal transplant patients are lacking but two patients in our study who are receiving it have favorable outcomes thus far. The mTOR inhibitor, sirolimus, is theoretically a good choice because of its in vitro synergy with antiretroviral agents that inhibit viral entry.³⁹ However, in a large study of renal transplant patients, sirolimus use was associated with a 2.2-fold higher risk of acute rejection compared with CNI-based maintenance therapy among HIV-positive patients, prompting the authors to caution against its use in this population.³¹ Given that sirolimus also has significant drug–drug interactions with PIs and NNRTIs, we speculate that this may have played a role in the reported adverse outcomes. Based on the available evidence, we propose the following algorithm for managing HIV-infected patients undergoing renal transplantation (Figure 1).

Figure 1.

Algortithm for selecting ART and immunosuppressive therpy in HIV + renal transplantation.

In summary, we believe that INSTI-based therapy should be the preferred ART in patients with HIV who undergo renal transplantation, primarily because of decreased drug–drug interactions with immunosuppressive medications such as CNIs, enabling easier monitoring of immunosuppressive medications and superior graft outcomes. However, larger and more controlled trials are needed to better assess long-term outcomes of INSTI-based therapy in order to elucidate factors related to graft survival other than direct reciprocal drug interactions. Finally, immunosuppressive agents such as belatacept which may circumvent issues related to drug–drug interactions with ART may emerge as viable alternatives.

Footnotes

Author Contributions

All authors contributed significantly to this work. The authors have no conflicts of interest. Also, there was no funding to support the preparation of this manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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