Impact of antiretroviral therapy on clinical outcomes in HIV⁺ kidney transplant recipients: Review of 58 cases

Introduction

More than 500 kidney transplants in human immunodeficiency virus–infected (HIV⁺) recipients have been performed in the United States with acceptable outcomes^1–5. HIV infection is associated with a two- to three-fold increase in the risk of rejection³. Reduced exposure to immunosuppressive agents is considered the main mechanism for increased predisposition to rejection^3,6,7.

Drug-drug interactions between antiretroviral therapy (ART) and calcineurin inhibitors (CNI), such as tacrolimus, pose a significant clinical challenge. Protease inhibitors (PI) and cobicistat increase the levels of CNI, whereas nonnucleoside reverse transcriptase inhibitors (NNRTI) reduce the levels of these agents. In contrast to PI and NNRTI, integrase strand transfer inhibitors (INSTI), which are not a substrate of CYP450, have become the preferred antiretroviral in many centers to overcome the problematic pharmacokinetic interactions^6–9.

Although tenofovir disoproxil fumarate (TDF) has a good safety profile and is recommended as a first-line agent¹⁰, it can cause renal tubular dysfunction in HIV⁺ individuals¹¹ and tenofovir-related nephrotoxicity is always a concern in kidney transplant recipients.

Data on the impact of specific ART regimens on the clinical outcomes of HIV⁺ kidney transplant recipients is scarce. In the present study, we compared post-transplant outcomes by ART regimens in a group of 58 HIV⁺ kidney recipients transplanted at our institution over a 9-year period.

Methods

Results

Antiretroviral therapy

There were no ART restrictions in transplant eligibility for HIV⁺ candidates during the study period. The three most common regimens post-transplant were nucleoside reverse transcriptase inhibitors (NRTI) plus PI, NRTI plus INSTI, and NRTI plus NNRTI (Table 2).

Table 2. Distribution of ART regimens among 58 HIV⁺ kidney transplant recipients.

ART regimen	Pre-transplant	Post-transplant†	Post-transplant (12 months)
	n (%)	n (%)*	n (%)º
Single drug class combination
NRTI	1 (2)	1 (2)	1 (2)
Two drug class combination
NRTI + PI	30 (52)	23 (40)	11 (27)
NRTI + INSTI	2 (3)	12 (21)	8 (20)
NRTI + NNRTI	15 (26)	9 (16)	7 (17)
PI + INSTI	4 (7)	2 (3)	2 (5)
NNRTI + INSTI	1 (2)	1 (2)	0
NNRTI + PI	0	0	1 (2)
Three drug class combination
NRTI + PI + INSTI	2 (3)	6 (10)	4 (10)
NRTI + PI + NNRTI	2 (3)	1 (2)	0
NRTI + INSTI + NNRTI	1 (2)	2 (3)	4 (10)
NNRTI + INSTI + PI	0	1 (2)	2 (5)
Four drug combination
NRTI + INSTI + NNRTI + PI	0	0	1 (2)

ART, antiretroviral therapy; INSTI, integrase strand transfer inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitors.

^†Refers to the ART regimen the patient was discharged home with after the initial transplant hospitalization.

^ºData only available for 41 patients (due to death, loss of follow up, or insufficient documentation in medical record).

^*Individual percentage values are rounded and might not total 100%.

A total of 30 (52%) patients underwent ART modifications after transplant; 22 (38%) of them prior to discharge, and an additional 8 (14%) during the first year post-transplant. Adjustments in ART were primarily done to avoid drug-drug interactions or added nephrotoxicity. There was a significant increase in the proportion of patients receiving INSTI at time of discharge and at 12 months post-transplant compared to pre-transplant period: 41% (p<0.01) and 51% (p<0.0005) vs. 17%, respectively (Table 2 and Figure 1).

Figure 1. Frequency of HIV⁺ kidney transplant recipients receiving a given ART class in the pre-transplant (n=58), post-transplant (at time of discharge; n=58) and at 12 months post-transplant follow-up (n=41).

There was a significant increase in the proportion of patients receiving INSTI-containing regimens at time of discharge and 12 months post-transplant. ART, antiretroviral therapy; INSTI, integrase strand transfer inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitors.

Transplant outcomes by ART regimen

The patient and graft survival at three years were both 90% for the entire cohort. Transplant outcomes varied by ART regimen at the time of discharge after the initial transplant hospitalization. Patients receiving PI-containing regimens had lower patient survival at one and three years than patients receiving PI-sparing regimens: 85% vs. 100% (p=0.06) and 82% vs. 100% (p=0.03), respectively (Table 3 and Figure 2). Patients who received PI-containing regimens had twelve times higher odds of death at three years compared to patients who were not exposed to PIs (odds ratio [OR] 12.05; 95% confidence interval [CI] 1.31-1602; p=0.02). Hepatitis C and delayed graft function also increased the odds of death, but this finding did not reach statistical significance (Table 4). Three-year death-censored graft survival was lower in patients receiving PI vs. patients on PI-sparing regimens (82 vs 100%, p=0.03; Table 3 and Figure 2). On the contrary, patients receiving INSTI-containing regimens had higher three-year graft survival rates (100 vs. 82%, p=0.04; Table 3).

Table 3. One and three-year transplant outcomes by ART regimen^°.

	N (%)	Patient survival				Death-censored graft survival†				Biopsy-proven acute rejection				Severe infection†
		1y	p	3y	p	1y	p	3y	p	1y	p	3y	p	6m	p
Overall	58	91.4		89.7		93.1		89.7		13.8		17.2		26.3
TDF
Yes	19	89.5		89.5		94.7		94.7		15.8		10.5		31.6
No*	35	94.3	0.6	91.4	>0.99	91.4	>0.99	85.7	0.4	14.3	>0.99	22.9	0.4	23.5	0.52
NRTI
Yes	54	92.6		90.7		92.6		88.9		14.8		18.52		26.4
No	4	75	0.3	75	0.36	100	>0.99	100	>0.99	0	>0.99	0	>0.99	25
NNRTI
Yes	14	100		100		92.9		92.9		7.14		21.4		7.14
No	44	88.6	0.32	86.4	0.32	93.2	>0.99	88.6	>0.99	15.9	0.66	15.9	0.69	32.6	0.08
PI
Yes	33	84.5		81.8		87.9		81.8		21.2		18.2		39.4
No	25	100	0.06	100	0.03	100	0.12	100	0.03	4	0.12	16	>0.99	8.33	0.01
INSTI
Yes	24	95.8		95.8		100		100		8.33		8.33		21.7
No	34	88.2	0.39	85.3	0.38	88.2	0.13	82.4	0.04	17.7	0.45	23.5	0.17	29.4	0.5
Two drug regimensˆ
NRTI + INSTI	12	100		100		100		100		8.3		8.3		18.1
NRTI + NNRTI	9	100		100		100		100		0		11.1		0
NRTI + PI	23	82.6	0.16	78.3	0.1	86.9	0.41	78.3	0.1	21.7	0.36	21.7	0.65	39.1	0.07
NRTI + other*	21	100		100		100		100		4.8		9.5		10
NRTI + PI	23	82.6	0.11	78.3	0.05	86.9	0.23	78.3	0.05	21.7	0.19	21.7	0.42	39.1	0.04

ART, antiretroviral therapy; INSTI, integrase strand transfer inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitors; TDF, tenofovir disoproxil fumarate.

^ºRefers to the ART regimen the patient was discharged home with after the initial transplant hospitalization.

P values correspond to Fisher 's exact test. Numbers in bold represent statistical significance.

^†As defined previously⁴. See main text for details.

ˆRegimens listed here were three most common ART regimens post-transplant in this cohort.

*Includes NRTI + INSTI and NRTI + NNRTI.

Figure 2. Transplant outcomes in HIV⁺ kidney transplant recipients by administration of protease inhibitor (PI) at time of discharge.

Kaplan–Meier curves show the (A) 3-year patient survival, (B) 3-year graft survival, (C) 3-year rejection-free survival, and (D) 200-day infection-free survival in PI-sparing (blue) and PI-containing (red) groups. The number of patients in each group is shown in the bottom of each panel.

Table 4. Variables associated with three-year mortality.

VariableϮ	Alive at 3-years n=52 (%)	Death at 3-years n=6 (%)	Odds ratio (95% CI)	P-value*
Protease inhibitor use	27 (51.9)	6 (100)	12.1 (1.31-1602)	0.02
HCV co-infection	5 (9.62)	2 (33.3)	4.80 (0.70-28.3)	0.10
Tacrolimus levels at 4 weeks, median (IQR)	6 (4.1-8.5)	8.7 (5.9-11.9)	1.06 (0.91-1.20)	0.38
Recipient age, years, median (IQR)	48 (42-54)	48 (46-49)	1 (0.92-1.10)	0.91
Baseline CD4 <350 cells/mm3	15 (28.9)	1 (16.67)	0.66 (0.06-3.70)	0.66
Delayed graft function	4 (7.84)	2 (33.3)	5.86 (0.84-36.70)	0.07
Type 2 diabetes	11 (21.6)	6 (100)	0.27 (0.002-2.60)	0.31
Donor age, years, median (IQR)	40 (29-47)	24 (18-48)	0.95 (0.88-1.02)	0.16
Living donor	14 (26.9)	0	0.20 (0.002-1.92)	0.19
Time from HIV diagnosis, years, median (IQR)	10 (5-16)	12 (5-13)	0.98 (0.86-1.09)	0.72
Morbid obesity	9 (17.3)	0	0.35 (0.003-3.45)	0.43

^ϮData presented as absolute number (percentage), unless specified otherwise.

*P-value calculated using logistic regression with penalized likelihood estimation (null hypothesis of beta=0).

HIV, human immunodeficiency virus; IQR, interquartile range.

We next assessed transplant outcomes in patients receiving NRTI “backbone” combined with either NNRTI, PI or INSTI as a second drug class. Compared to a group of patients receiving NRTI plus INSTI or NRTI plus NNRTI, the 3-year patient and graft survival were lower in patients receiving NRTI plus PI (78 vs. 100%; p=0.05, Table 3 and Figure 3).

Figure 3. Transplant outcomes in HIV⁺ kidney transplant recipients by ART regimen at time of discharge.

Kaplan–Meier curves show the (A) 3-year patient survival, (B) 3-year graft survival, (C) 3-year rejection-free survival, and (D) 200-day infection-free survival in NRTI + INSTI (blue), NRTI + NNRTI (red) and NRTI + PI (green) groups. Number of patients in each group is shown in the bottom of each panel. ART, antiretroviral therapy; INSTI, integrase strand transfer inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitors.

Causes of graft loss among patients on PI-containing regimens were acute rejection in two (33%), thrombosis/hemorrhagic complications in two (33%), CNI toxicity in one (17%), and unidentified in another patient. The cumulative incidence of biopsy-proven acute rejection was 14 and 17% at one and three years post-transplant, respectively. There were no significant differences in rejection rates by ART (Figure 2 and Figure 3; Table 3).

Discussion

Consistent with previous studies of kidney transplantation in HIV^1–5, we observed excellent transplant outcomes without evidence of HIV disease progression. The most important finding of the present study is the association between PI use and adverse outcomes, namely reduced three-year patient and graft survival, and increased risk of serious non-opportunistic infections. These observations remained true in analyses restricted to patients receiving NRTI “backbone”; thus, even after excluding the potential influence of other agents included in the ART regimen, PI continued to be associated with poor outcomes. The immunosuppression protocol at our institution remained constant during the study period, and the proportion of patients transplanted in the 2006–2010 (and consequently the 2011–2015) eras was similar between PI and non-PI groups, suggesting that this observation was also independent of variation in transplant practices over time that might have impacted outcomes.

Biopsy-proven acute rejection and CNI toxicity accounted for half of the cases of graft loss in patients taking PI in the present study. Increased risk of allograft rejection in HIV⁺ individuals has been largely attributed to reduced exposure to immunosuppressive agents, due to drug-drug interactions with ART^3,6,7. However, in this small cohort, we did not observe an association between ART regimens and the incidence of rejection. CNI levels at 4, 12, 26 and 52 weeks were comparable across ART groups. Other factors, such as infection of the allograft, previous alloimmunization and immune activation, might also play a role in predisposition to rejection^3,5,6.

Non-opportunistic infections within six months post-transplant are common in HIV⁺ kidney recipients³, especially those with marginal pre-transplant CD4 counts⁴. Notably, the occurrence of serious infections in this cohort was almost five-fold higher in patients receiving PI.

This might be due to the effects of PI on tacrolimus levels, considering that the overwhelming majority of these patients were on PI-containing regimen and more-than-half had tacrolimus levels above target at the time of infection. PI could also influence the net state of immunosuppression by increasing the level or effect of other immunosuppressants, such as prednisone and mycophenolate.

Contrary to our expectations, the use of NNRTI or TDF did not influence kidney allograft survival. Tenofovir alafenamide (TAF) is a new formulation of tenofovir associated with less kidney (and bone) toxicity¹². Whether there is added clinical benefit of TAF over TDF in kidney transplant recipients remains to be established.

Consistent with recent reports^7–9, patients receiving INSTI-containing regimens had excellent patient survival (96%) and graft survival (100%) at three years, and the lowest rejection rates in this cohort (8%). Current guidelines recommend the use of NRTI plus INSTI as a first-line therapy for HIV¹⁰. INSTI pose no interactions with CNI or mTOR inhibitors. In addition, INSTIs have no interactions with direct-acting antivirals, which is important in the setting of hepatitis C co-infection, as that has been associated with poor outcomes^2,3. Thus, it has become our practice to preemptively switch HIV⁺ candidates pre-transplant or in the immediate post-transplant period to PI-sparing, preferably INSTI-based, ART regimens.

Although none of the patients studied here was on cobicistat, it is important to highlight that this pharmacokinetic enhancer, contained in several combination pills, can increase the levels of CNI¹³. HIV⁺ recipients and their community HIV providers should be educated about what ART medications to avoid, and when not possible, how to adjust CNI doses and monitor levels accordingly.

Our study is limited by the small number of patients and retrospective design; serum levels for other immunosuppressants, such as mycophenolate were not available. The association found in the present study between PI-containing ART regimens and adverse outcomes needs to be confirmed in larger studies. Until more data becomes available, the use of PI-sparing regimens in HIV⁺ kidney recipients seems to be the most prudent approach.

Data availability

Dataset 1: Rosa et al. Impact of ART in KT outcomes in HIV recipients: Raw data. doi, 10.5256/f1000research.10414.d146717¹⁴.