AbstractIntroduction

The management of complex interactions between antiretroviral therapy (ART) and calcineurin inhibitor (CNI) immunosuppression regimens in HIV+ to HIV+ renal transplant recipients can be challenging. Literature describing ART regimens and indications for regimen switching in these patients is limited.

Methods

This retrospective review included 53 HIV+ to HIV+ renal transplant recipients. Data on ART regimens, reasons for ART switching and timing of switches were described from day of transplant to study endpoint (end of study date, death or graft failure). The association between rejection and ART regimen (protease inhibitor (PI) based versus non-PI based regimen) was analysed using negative binomial regression.

Results

There were a total of 46 switches in 31/53 patients (58%). Protocol switches (n=17/46, 37%) accounted for most switches, of which the majority were from non-nucleoside reverse transcriptase inhibitors (NNRTIs) to PIs. Other common reasons for switching include cytochrome P450 enzyme induction from efavirenz (EFV) (9/46, 20%), tenofovir disoproxil fumarate (TDF) nephrotoxicity (8/46, 17%) or side effects (6/46, 13%). Of the 46 switches, nearly half (n=21, 46%) occurred during the transplant admission period, and around two thirds (n=28, 62%) were in the first year post transplant. There was an association between rejection and being maintained on a PI-based regimen (IRR 2.77 (95% CI 1.03-7.48), p=0.044).

Conclusion

Despite frequent switching of ART regimens, HIV viral loads remained supressed and graft function remained stable in most HIV-positive kidney transplant recipients in our cohort. There was however a concerning signal for increased rejection rates in those on a PI-based regimen.

IntroductionHIV positive patients with chronic kidney disease (CKD) were long considered to be poor candidates for organ transplantation. As outlined in Muller et al (2010), prior to 2008 South African chronic dialysis programmes did not accept HIV-positive patients. At this time, a large number of people with HIV associated nephropathy (HIVAN) and CKD had little or no access to kidney replacement therapy (KRT). This was in part due to the misconception that immunosuppressing a transplant recipient with an already compromised immune system to prevent rejection would be too risky. It was thought that it would predispose to diseases of over-immunosuppression, including infections and malignancies.1Muller E. Kahn D. Mendelson M. Renal transplantation between HIV-positive donors and recipients.,2Davids M.R. Jardine T. Marais N. Jacobs J.C. Sebastian S. South African renal registry annual report 2018.In 2008, Groote Schuur Hospital performed the first HIV-positive to HIV-positive transplant using deceased donors. Deceased donors were not required to be on antiretroviral therapy, have no history of opportunistic infection or cancer, and have normal renal function 1Muller E. Kahn D. Mendelson M. Renal transplantation between HIV-positive donors and recipients.. Soon thereafter this novel transplant programme resulted in the acceptance of HIV-positive patients onto state dialysis programmes in South Africa. The South African renal registry (2018) reported that of the 8948 patients receiving KRT, 11% were HIV positive2Davids M.R. Jardine T. Marais N. Jacobs J.C. Sebastian S. South African renal registry annual report 2018.. Our group and others have shown that HIV per se is not a barrier to transplantation and that clinical outcomes are good as long as HIV is controlled on a stable anti-retroviral therapy (ART) regimen.3Muller E. Barday Z. Mendelson M. Kahn D. HIV-positive–to–HIV-positive kidney transplantation—results at 3 to 5 years., 4Selhorst P. Combrinck C.E. Manning K. et al.Longer-Term Outcomes of HIV-Positive–to–HIV-Positive Renal Transplantation., 5Durand C.M. Florman S. Motter J.D. et al.HOPE in action: A prospective multicenter pilot study of liver transplantation from donors with HIV to recipients with HIV. The entry criteria for HIV-positive patients with CKD to be eligible for transplant include HIV viral load suppression on ART, stable HIV disease and no previous opportunistic disease (besides fully treated tuberculosis).Another reason for the reluctance to transplant these patients was the complexity of interaction between ART and immunosuppressive medication.6Izzedine H. Launay-Vacher V. Baumelou A. Deray G. Antiretroviral and immunosuppressive drug-drug interactions: an update. There is limited literature on the use of ARTs in HIV positive kidney transplant recipients who received organs from HIV positive donors, including the causes that necessitate ART switching. South Africa is a resource constrained country, thus in the first 5 years of the study, our protocol included switching patients from non-nucleoside reverse transcriptase inhibitors (NNRTIs) to Protease Inhibitors (PIs) to save cost on immunosuppression. Integrase strand transferase inhibitors (ISTIs) are now becoming more widely available, so only a few and mainly the more recently transplanted patients are on this class of ARVs.A few studies have found an association between graft loss and rejection, and protease inhibitor (PI) based regimes.7Sawinski D. Shelton B. Mehta S. et al.Impact of Protease Inhibitor–Based Anti‐Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients., 8Rollins B. Farouk S. DeBoccardo G. et al.Higher rates of rejection in HIV‐infected kidney transplant recipients on ritonavir‐boosted protease inhibitors: 3‐year follow‐up study., 9Sparkes T. Manitpisitkul W. Masters B. et al.Impact of antiretroviral regimen on renal transplant outcomes in HIV‐infected recipients. Calcineurin inhibitors such as tacrolimus are metabolized by cytochrome P-450 3A4 (encoded by the CYP3A4 gene) and are a substrate of P-glycoprotein (encoded by the ABCB1 gene). Both pathways can be inhibited by protease inhibitors (PIs).10Drug interactions with tacrolimus. Although combining these drugs allows for a dramatic reduction in the dose of CNIs, this may also paradoxically contribute to subtherapeutic dosing, by minimizing the absorption peak even if trough levels are similar to those not on PIs.11van Maarseveen E.M. Crommelin H.A. Mudrikova T. van den Broek M.P. van Zuilen A.D. Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.

The primary aim of this study was to describe ART regimens and reasons for switching in HIV positive recipients. The secondary aim was to evaluate any associations between ART regimens and rejection over the study period.

5. Other

Reasons for switching that could not be categorised according to the criteria above were included in ‘other’.

For the purposes of the secondary aim i.e. to assess the relationship between rejection and ART regimens, ART regimens were grouped into non-PI regimens (combination of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs)), and PI-based regimens that were maintained from the transplant admission period to end of study. The transplant admission period was defined as the time from the day of transplant to discharge from hospital.

Outcome definitionAll types of biopsy-proven rejection i.e. Active T cell–mediated rejection (TCMR), Acute ABMR (antibody-mediated rejection), chronic and suspicious (Borderline) for acute TCMR, were classified using BANFF diagnostic criteria15Roufosse C. Simmonds N. Clahsen-van Groningen M. et al.2018 reference guide to the Banff classification of renal allograft pathology. We included borderline (suspicious) for TCMR cases in the rejection category as all borderline rejection cases required treatment adjustment.Data Analysis

Data was extracted from ©DataFax/DFdiscover clinical data management software. Data was summarised as median with interquartile range (IQR) for continuous variables and frequency and percentages for categorical variables. Tacrolimus levels from transplant to end of study were compared by regimen (non-PI based versus PI-based) using the Wilcoxon rank-sum test. A negative binomial regression model was generated to analyse the association between rejection episodes and ART regimen maintained from transplant admission period to end of study, and was adjusted for exposure time. Five patients who switched to a PI in late follow up period (2 due to side effects and 3 due to NNRTI-induced CNI catabolism) were excluded in order to observe the magnitude of association when patients were on a consistent ART regimen. Incidence rate ratios (IRR) were presented with 95% CIs. All analysis was performed in Stata (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC).

Ethics

The University of Cape Town Human Research Ethics committee (HREC) granted permission for this study (414/2008), and all the participants provided written informed consent.

ResultsBaseline demographics are shown in table 1. This was a cohort of relatively young, majority African ethnicity kidney transplant recipients, all of whom had an undetectable HIV viral load at the time of transplant. The primary cause of renal failure in the majority of cases was HIV associated nephropathy (HIVAN).

Table 1Baseline demographics and clinical characteristics of recipients at discharge post renal transplantation

Abbreviations: ESRD, End-stage renal failure; HIVAN, HIV-associated nephropathy; ADPKD, Autosomal dominant polycystic kidney disease; IFTA, Interstitial fibrosis and tubular atrophy; ART, Antiretroviral treatment.

Baseline ART treatment at admission is shown in Table 2. The majority of patients were on an NNRTI based regimen (46/53 (86%)), which is aligned with national guidelines. Seven patients (13%) were switched on admission to a PI-based regimen at admission as per initial study protocol. Time on ART pre-transplant ranged from 4 months to 12 years (median 4.2 years, IQR 2.5-5.6).

Table 2| ART regimen pre-transplant

Abbreviations: ART, Antiretroviral treatment; NNRTI, non-nucleoside reverse transcriptase inhibitor; EFV, Efavirenz; ABC, Abacavir; TDF, Tenofovir disoproxil fumarate; 3TC, Lamivudine; d4T, Stavudine; AZT, Zidovudine; NVP,Nevirapine; PI, protease inhibitor; LPV/r, Lopinavir/Ritonavir.

ARV switches by indicationThere were a total of 46 switches in 31/53 patients (58%) (Table 3). In patients who switched, 19 (36%) required one switch, 12 (23%) required two switches and 1 (2%) required three switches. Of the 46 switches, protocol switches (n=17, 37%) accounted for the largest group. Seven patients had early protocol switches during their transplant admission to a PI-based regimen at the time of transplantation. The remaining protocol switches were from d4T or AZT (Zidovudine) to ABC (Abacavir).

Table 3| ARV switches by indicationa during transplantation admission and follow period

Abbreviations: ART, Antiretroviral treatment; D4T, Stavudine; ABC, Abacavir; EFV, Efavirenz; LPV/r, Lopinavir/Ritonavir; AZT, Zidovudine; NVP, Nevirapine; TDF, Tenofovir disoproxil fumarate; 3TC, Lamivudine; RTV, Ritonavir.

aRefer to methods for definitions of indications

bTransplant admission period was defined as the day 0 admission for transplant to discharge from hospital.

Note: Total column percentages may not equal 100% in some instances due to rounding

The most frequent non-protocol reasons for switching was NNRTI-induced CNI catabolism and nephrotoxicity due to TDF. All 6 switches due to ART side effects were due to AZT and EFV. Three recipients received kidney transplants from hepatitis B antigenaemic donors with raised viral load and were switched to TDF at transplant (day 1) as a precaution.

HIV viral loadThere were isolated HIV viral load blips in three patients that resolved within three months. One patient experienced recurrent blips 6 years post-transplant. All HIV viral load blips were investigated and attributed to poor ART adherence. Viral resistance was excluded with deep sequencing methods.4Selhorst P. Combrinck C.E. Manning K. et al.Longer-Term Outcomes of HIV-Positive–to–HIV-Positive Renal Transplantation.Timing of switchesOf the 46 switches, nearly half (n=21, 46%) occurred during the transplant admission period, and 28 switches (61%) were in the first year post-transplant. Figure 1 shows the frequency of switching over time by the indication for switching. Most switches in the transplant admission period were protocol switches (n=9) or to account for the effect of liver enzyme induction from EFV (n=6). The later protocol switches were mostly switches to phase out of d4T. Switches from TDF and d4T to ABC or 3TC (lamivudine) due to nephrotoxicity occurred throughout the time periods. Four of the six switches due to side effects were at transplant admission or first year post transplant.

Figure 1Frequency of switches from transplant by indication and time period Note: ‘Other’ category excluded from graphs

Rejection and ART regimen

There were a greater number of patients who were maintained on PI-based regimens from transplant admission to end of study that experienced rejection and recurrent rejection, compared to those maintained on NNRTI regimes. Of the total of 32 rejection episodes, around half were attributed to borderline rejection (15/32, 47%) and 17/32 (53%) were either active ABMR or acute TCMR.

Twelve patients (63%) maintained on PI-based regimen and 8 patients (28%) maintained on NNRTI-based regimens developed rejection (Table 4). Eight patients in the NNRTI group had 9 episodes of rejection, while in PI group 12 patients experienced 23 episodes. In the regression analysis, there was a positive association between rejection (IRR 2.77 (95% CI 1.03-7.48) and being maintained on a PI-based regimen.

Table 4| Incidence Rate Ratio for Rejection by ART regimen

Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; IRR, Incidence Rate Ratio

aFive patients who switched to a PI in late follow up period (2 due to side effects and 3 NNRTI-induced CNI catabolism) were excluded from this analysis in order to observe the magnitude of association when patients were on a consistent ART regimen from transplant admission.

bPatients maintained on NNRTI from transplant admission to end of study

cPatients maintained on PI from transplant admission to end of study

Tacrolimus levels

Tacrolimus trough levels from transplant to end of study were compared between PI-based regimen and non-PI based regimens regimes. Both regimens maintained levels in the clinical target range (6-10ng/mL), however the PI-based regimen (median 8.6ng/mL, IQR (8.0-9.3) was higher than non-PI based regimens (median 7.4ng/mL, IQR 6.4-8.7) (P=0.012).

Discussion

In this cohort of relatively young, majority African HIV positive kidney transplant recipients, frequent switching of antiretroviral therapy was observed during transplant admission and in the first year post transplantation. Despite this, HIV viral loads remained supressed and graft function remained stable in most of the cohort. Early protocol switches from EFV to LPV/r were the most frequently observed reason for a change in ART, while TDF-associated nephrotoxicity accounted for the most frequent reason for non-protocol switches. NNRTI-induced CNI catabolism that required a switch from EFV to LPV/r occurred more frequently during the transplant admission period. Other reasons for switching were few and heterogenous.

The initial use of PI-based regimens resulted in substantial cost savings due to a reduction in tacrolimus dosing. The cost of CNIs continue to be a major issue in a resource-constrained healthcare system such as South Africa’s public health sector. In our experience, concomitant use of a PI and tacrolimus leads to a dose reduction in tacrolimus of over 99% (average tacrolimus dose while on a PI is 0.5mg per week versus 10mg per day for those not on a PI). In patients using NNRTIs, induction of cytochrome P450 3A results in faster catabolism of tacrolimus and increased dose requirements.10Drug interactions with tacrolimus. In view of the high prevalence of CYP3A5 expression in South African transplant recipients, high tacrolimus dose requirements are often necessary and result in substantially increased immunosuppression costs.16

Muller WK, Dandara C, Manning K, et al. CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population. vol 110. 2020. 2020.

However, in view of patient safety concerns, the continued mandatory use of PIs was reconsidered in 2014.12Frassetto L. Floren L. Barin B. et al.Changes in clearance, volume and bioavailability of immunosuppressants when given with HAART in HIV‐1 infected liver and kidney transplant recipients.TDF has been well described to be associated with tubular nephrotoxicity17Tourret J. Deray G. Isnard-Bagnis C. Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword?.. Because of the limited availability of tenofovir alafenamide (TAF), which has been shown to be less toxic18Raffi F. Orkin C. Clarke A. et al.Brief report: long-term (96-week) efficacy and safety after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-infected, virologically suppressed adults., TDF is still part of first line ART therapy in national guidelines and has been shown to be robust in reducing HIV viral load. For this reason, it remained first line therapy in our HIV transplant cohort until 2014 when ABC became more widely available.Suspected nephrotoxicity due to TDF was the most frequent reason for non-protocol ART switches. PIs containing ritonavir have been shown to influence the risk of TDF associated nephrotoxicity by increasing exposure to tenofovir through inhibition of apical tubular cell tenofovir transporters.19Hamzah L. Jose S. Booth J. et al.Treatment-limiting renal tubulopathy in patients treated with tenofovir disoproxil fumarate.,20Yombi J.C. Pozniak A. Boffito M. et al.Antiretrovirals and the kidney in current clinical practice: renal pharmacokinetics, alterations of renal function and renal toxicity. AIDS. Where a sustained decline in eGFR was observed in the absence of other known causes, we assumed this to be due to TDF associated nephrotoxicity and switched away from TDF.Since AZT has a high side-effect profile21D'Andrea G. Brisdelli F. Bozzi A. AZT: an old drug with new perspectives., no patients on our study were switched to AZT. Of those who were initially on AZT, all have subsequently been switched to alternatives; three were due to bone marrow toxicity.HIV positive kidney transplant recipients are at higher risk for rejection, but the exact reason for this remains unclear. Possible reasons could include an altered immune response, the impact of the viral reservoir in the transplanted kidney and drug interactions between immunosuppressive treatments and ART.22

Muller E, Botha FC, Barday ZA, Manning K, Chin-Hong P, Stock P. Kidney Transplantation in HIV Positive Patients: Current Practice and Management Strategies. Transplantation. 2020;

Recent evidence has indicated that PIs may influence graft survival in HIV positive renal transplant recipients. Sawinsky et al report a 1.8 and 1.9 fold increased risk of graft loss and death respectively in 332 HIV positive kidney transplant recipients in the Scientific Registry of Transplant Recipients database.7Sawinski D. Shelton B. Mehta S. et al.Impact of Protease Inhibitor–Based Anti‐Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients. In a multivariable modified Poisson regression model in that study, there was also a trend to a higher risk of acute rejection in those on PIs, although the exact mechanism for poorer outcomes was not clear. Despite the inherent limitations in the interpretation of registry data, calls have been made to eliminate the use of PIs in ART for HIV positive transplant recipients.23

Stock PG. Strengths and weaknesses of using SRTR data to shape the management of the HIV‐infected kidney transplant recipient. Wiley Online Library; 2017.

One small retrospective study reported higher rejection rates in those on a PI-based regimen.8Rollins B. Farouk S. DeBoccardo G. et al.Higher rates of rejection in HIV‐infected kidney transplant recipients on ritonavir‐boosted protease inhibitors: 3‐year follow‐up study. During the study period, tacrolimus levels in the long term were similar in both groups. Interestingly, a further small retrospective study reported lower rejection rates in those on tacrolimus and a PI-based ART regimen.9Sparkes T. Manitpisitkul W. Masters B. et al.Impact of antiretroviral regimen on renal transplant outcomes in HIV‐infected recipients. However, in that study, there were significant baseline differences between the two groups and mean tacrolimus levels at 12 months were approximately 40% higher in those receiving PIs. In our study, the use of a PI-based ART regimen was associated with a nearly three-fold increase in rejection rates. While we targeted the same trough tacrolimus trough levels in all our patients, we found tacrolimus levels to be higher in those on PI-based regimens compared to NNRTI-based regimens by about 16%. Van Maarseveen et al. have shown that in patients on PI-based ART, the lack of 12 hour absorption peaks results in a flat area under the curve and 40% less tacrolimus exposure.11van Maarseveen E.M. Crommelin H.A. Mudrikova T. van den Broek M.P. van Zuilen A.D. Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study. This may account for the higher rejection rates seen in our study in those on PI-based ART, where despite higher trough levels, the lack of a post-dose peak would still result in less tacrolimus exposure. Fortunately, integrase strand transferase inhibitors (ISTIs) such as dolutegravir are now becoming more widely available in South Africa and initial evidence for the use of this class of drugs in HIV positive transplantation cohorts is encouraging. Importantly, they are not associated with any drug-drug interactions with current immunosuppressive agents and this simplifies the post-transplant management of such patients.24Azar M.M. Malinis M.F. Moss J. Formica R.N. Villanueva M.S. Integrase strand transferase inhibitors: the preferred antiretroviral regimen in HIV-positive renal transplantation.

Four recipients received kidney transplants from hepatitis B antigenaemic donors with raised viral load. All four recipients received intravenous hepatitis B immune globulin to maintain titres of more than 200IU/ml for a 2-week period. Two of the recipients were immune to hepatitis B at transplantation and never developed any evidence of active hepatitis B infection. The other two were hepatitis B non-immune and developed serological hepatitis B infection following transplantation, but hepatitis B viral load have remained supressed since transplantation to date and neither patient developed hepatitis per se. One was already on TDF and the other three required a switch to a TDF. All are still alive and remain hepatitis B surface antigen negative with viral loads that have remained below the detectable threshold.

Our study was limited by small sample size, heterogenous baseline ART regimens which evolved with time and the lack of supporting immunological data. However, the study reports prospectively over a period of 12 years, gives a broad overview of issues experienced with ART in the HIV positive transplant setting and is supported by comprehensive biopsy data. Furthermore, there has been no loss of follow-up and only 2 patients were excluded from the analysis because of early graft loss. Based on our preliminary findings in this cohort, further analysis on outcomes in a larger cohort is required to investigate the impact of PIs on rejection and tacrolimus levels.

Article InfoPublication History

Accepted: June 20, 2022

Received in revised form: June 14, 2022

Received: May 10, 2022

Publication stageIn Press Journal Pre-ProofFootnotes

Translational Statement

This study provides reassuring data that despite frequent switching of ART regimens in HIV+ kidney transplant recipients, viral suppression and graft function remained stable in most patients. There was a concerning signal for increased rejection rates in those on PI-based regimens. Adjusted analysis with inclusion of immunological and additional pharmacokinetic data is required to validate this finding. Newer ART drugs that do not interfere with CNI pharmacokinetics should be preferably used. However, in the absence of the availability of alternative ART treatment, targeting higher trough tacrolimus levels in patients on PI-based ART may be warranted.

Disclosures

None.

Acknowledgements

This project is funded by the National Institute of Health (NIH) (Grant number: 1U01AI152153).

Identification

DOI: https://doi.org/10.1016/j.ekir.2022.06.013

Copyright

© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.

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