Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

Abstract

Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.

Introduction

S ince the introduction of combination antiretroviral therapy (cART) and the concomitant associated prolonged survival of HIV-infected patients,¹ HIV infection is no longer considered to be a contraindication for transplantation. The yearly number of solid organ transplantation (SOT) procedures in HIV-infected patients has grown² and the decrease in mortality due to AIDS-defining illnesses has been countered with an increase in mortality due to chronic diseases such as end-stage renal disease (ESRD) and liver failure.¹ The increased prevalence of ESRD in the HIV population is likely related to the toxicity of some antiretroviral medications as well as the development of HIV-associated nephropathy.³ Furthermore, patients coinfected with hepatitis C virus (HCV) and HIV experience a more rapid progression of liver fibrosis than patients with HCV alone.⁴ With emerging data supporting the role of SOT as an option for HIV-infected patients with ESRD and cirrhosis,^5,6 one would expect the number of centers accepting these patients as eligible SOT candidates to grow. A careful balance of just the right amount of immunosuppression is necessary in the HIV-infected SOT population. Overimmunosuppression may increase the risk of opportunistic infections and the development of an AIDS-defining illness. On the other hand, underimmunosuppression could ultimately result in allograft rejection. The management of cART and immunosuppressive therapy is extremely challenging, as witnessed by high allograft rejection rates observed in this immune system dysregulated population,⁵ but also increased risk of infections, high rates of drug toxicity and the profound drug–drug interactions between cART and immunosuppressants.^6
–8

As transplantation in the HIV population becomes increasingly common there is a need to optimize the pharmacologic management of this population. Specifically, there is a need for cART regimens that have less potential for drug–drug interactions and minimal overlapping toxicities when used in combination with common immutnosuppressive regimens. On the road toward optimal results of SOT in HIV-infected patients there are many hurdles to overcome, but it also offers the unique opportunity to study the pharmacodynamic synergy between cART and immunosuppressants to achieve optimal viral suppression and transplantation outcomes. In this review we provide a brief overview of the recent successes of SOT in the HIV population in addition to an update on the pharmacokinetic and pharmacodynamic interactions between cART and immunosuppressants.

Recent successes in transplantation of HIV-infected recipients

Hundreds of renal transplants have been performed in HIV-infected patients worldwide during the last two decades, and 1- to 3-year patient and graft survival rates have been comparable to that of HIV-negative recipients.⁹ Regarding liver transplantation in HIV a recent meta-analysis of transplant centers in the United States, France, Spain, Italy, and England and results from a large cohort study suggest that the 1- to 5-year survival is comparable to individuals without HIV.^10,11

Characteristics that place HIV-HCV coinfected patients at an increased risk of graft loss were identified in a recent publication by Terrault et al.¹⁰ These risk factors include a BMI of less than 21 at study enrolment, combined kidney liver transplant, HCV-positive donor, and increased donor age (by decade). When patients with these risk factors were excluded from the analysis, patient and graft survival rates in the HIV-HCV coinfected population were similar to those reported in the national Scientific Registry of Transplant Recipients (SRTR) for older liver transplant recipients (≥65 years) and for all liver transplant recipients in the United States during a similar time frame. Combined kidney–liver transplantation in HIV-infected patients has been associated with very poor outcome and was reported as one of the strongest predictor of mortality.¹² It is therefore not recommended to perform kidney–liver transplantations because of these findings. Experience with simultaneous pancreas–kidney and lung transplantation is limited, but the first results are similar to those seen in non-HIV–infected population and do not indicate HIV-infected patients should be excluded.^13
–15 Finally, the startling success of a stem cell transplant in the “Berlin patient,” cured of AIDS using an allogeneic CCR5 delta32 donor¹⁶ and at least one other recently reported case from Utrecht, The Netherlands,¹⁷ should be mentioned here. Although these reports do not concern solid organ transplantations, they will almost definitely result in more HIV-infected patients with similar drug–drug interactions issues.

Despite the acceptable patient and graft survival rates, life expectancy should not be overlooked before accepting an HIV-infected patient for SOT. A minimal life expectancy of 5 years is required.¹⁸ Further criteria state that prior opportunistic infections are not a strict exclusion criterion, but patients must have a CD4⁺ count above 100 and 200 cells per microliter for liver and kidney transplant recipients respectively, an HIV-1 RNA viral load suppressed with treatment, and demonstrable compliance to a stable cART regimen for over 6 months. The criteria used to select HIV-infected patients for SOT are similar in North America and Europe.^9,11

Although patient and graft survival in the renal transplant population are excellent, the largest trial performed in these patients did find a relatively high one year rejection rate of 31%.⁵ In fact, disturbingly high rejection rates have been reported by a great number of SOT studies in HIV-infected recipients.^9,11 Similar results were seen in the recent HIV-HCV coinfection study.¹⁰ In this series, the incidence of acute rejection requiring treatment was significantly higher in the HCV-HIV coinfected patients than in the HCV patients (39% versus 24% at year 3, HR=2.1, p=0.01). Of note, more than half of the rejection episodes in the coinfected group occurred within the first 21 days posttransplant.

As the number of yearly performed SOTs in HIV-infected patients is steadily increasing, and there is a shortage in donor organs, the focus should be on reducing the number of posttransplantation complications.

Immunosuppressants in HIV-infected solid organ transplant recipients and their metabolic pathways

To ensure the long-term success of transplantation in HIV-infected patients, life-long virologically effective cART as well as immunosuppresive therapy are necessary. Current posttransplantation immunosuppressive protocols may include combinations of an antibody induction agent, a glucocorticoid, a calcineurin inhibitor (CNI), a mammalian target-of-rapamycin (mTOR) inhibitor, and an antimetabolite.¹⁹ In the early posttransplantation phase an induction agent is usually combined with a glucocorticoid, a CNI, and an antimetabolite. Whether and which induction agent is utilized strongly depends on the local transplantation protocol, but generally patients at high risk of allograft rejection receive induction antibodies. Since HIV-infected patients are considered to be at high risk of rejection they should recieve induction therapy.^5,20 Induction with a monoclonal antibody, for instance basiliximab, may be preferred over a polyclonal antibody such as rabbit antithymocyte globulin (rATG) because of the deep and broad lymphocytopenia caused by the latter.⁵ Since no relevant pharmacokinetic interactions with cART are to be expected based on their pharmacokinetic interaction profiles, use of a monoclonal or polyclonal antibody would be acceptable.

Maintenance immunosuppression protocols vary depending on center preferences. The prefered CNI in the HIV-infected SOT population is often debated. Although it has never been demonstrated in vivo,^21,22 cyclosporine is preferred at some centers because of the in vitro data supporting its antiviral activity against HIV.23 Other centers prefer the more potent anti-rejection activity of tacrolimus. The antimetabolites mycophenolate mofetil or enteric-coated mycophenolate sodium are commonly used as life-long adjuncts to the CNIs. The mTOR inhibitors sirolimus and everolimus are sometimes used when patients do not tolerate the CNIs or antimetabolites. Use of mTOR inhibitors is often very center specific. Furthermore, given the known high risk of rejection, HIV-infected renal transplant recipients are not considered ideal candidates for early corticosteroid withdrawal. Corticosteroids are often continued as part of the life-long immunosuppressive protocol at low to moderate doses. The majority of immunosuppressants utilized in the posttransplant setting are primarily metabolized by hepatic cytochrome P450 3A enzymes (CYP3A) or uridine diphosphate glucuronosyltransferase (UGT) and eliminated by the transmembrane transporter P-glycoprotein (Pgp). Most of these agents have been reported to have clinically relevant interactions with antiretroviral drugs that either induce or inhibit CYP3A, Pgp, or UGT (Table 1).

Table 1.

Antiretroviral and Immunosuppressive Drugs: Routes of Metabolism or Elimination and Inhibiting/Inducing Properties

		Drug as a substrate for
		CYPs	Transporters	Other	Drug as an inhibitor/inducer of CYPs or transporters
NRTIs	3TC	—	—	Renal	—
	ABC	—	—	Renal, UGT, ADH	—
	AZT	—		Renal, UGT	—
	D4T	—	—	Renal	—
	ddI	—	—	Renal	—
	FTC	—	—	Renal	—
	TDF	—	—	Renal	—
NNRTIs	EFV	3A, 2B6	—	—	3A ↑, 2B6 ↑, 2C9/19 ↑
	ETV	3A, 2C9, 2C19	—	UGT	3A ↑, 2C9 ↓, 2C19 ↓
	NVP	3A4	P-gp	—	3A ↑, 2B6 ↑
	RPV	3A4	—	—	—
Protease inhibitors	ATZ	3A4	P-gp, MRP	—	3A ↓, P-gp ↓
	DRV	3A4	P-gp, MRP	—	3A ↓, P-gp ↓
	IDV	3A4, 2D6	P-gp, MRP	—	3A ↓, P-gp ↓
	NFV	3A4	P-gp	—	3A ↓, P-gp ↓
	RTV-boosted PIs	3A4	P-gp	—	3A ↓, 2D6 ↓, 1A2 ↑, 2C9 ↑, Pgp ↓
ARVs of new classes	MVC	3A4	—	—	—
	T20	—	—	Hydrolysis	—
	RAL	—	—	UGT, bile and renal	—
Glucocortioids		3A4	P-gp, MRP	—	3A ↑
Antimetabolites	AZA	—	—	HGPRT, TPMT	—
	MPA	—	—	UGT	—
Calcineurin inhibitors	CsA	3A4	P-gp, MRP	—	—
	TAC	3A4	P-gp	—	—
mTor inhibitors	EVR	3A4	P-gp	—	—
	SRL	3A4	P-gp	—	—

CYP, cytochrome P450, NRTIs, nucleoside reverse transcriptase inhibitors; NNRTIs, nonnucleoside reverse transcriptase inhibitors; AVRs, antiretroviral drugs; 3TC, lamivudine; ABC, abacavir; AZT, zidovudine; D4T, stavudine; DDI, didanosine; FTC, emtricitabine; TDF, tenofovir; DLV, delavirdine; EFV, efavirenz; ETV, etravirine; NVP, nevirapine; ATZ, atazanavir; DRV, darunavir; IDV, indinavir; NFV, nelfinavir; RTV, ritonavir; MVC, maraviroc; T20, enfuvirtide; RAL, raltegravir, AZA, azathioprine; MPA, mycophenolic acid; CsA, cyclosporine; TAC, tacrolimus; EVR; everolimus, SRL, sirolimus; ADH, alcoholdehydrogenase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; TMPT, thiopurine methyltransferase and UDPGT, UDP-glucuronosyltransferase; MRP, multi-drug resistance protein. An upwards arrow indicates induction and a downwards arrow indicates inhibition.

Tacrolimus or cyclosporine are CNIs that are frequently prescribed as part of the posttransplant immunosuppressive regimen. Both metabolized by CYP3A and eliminated by Pgp offering potential for strong interactions with cART.²⁴ The same pharmacokinetic interactions with cART apply to mTOR inhibitors because they are also eliminated via Pgp and CYP3A.²⁵ Mycophenolic acid, an antimetabolite, is primarely metabolized by UGT. The metabolic capacity of UGT is only marginally affected by cART.²⁶ Finally, cART can also interact with the metabolic pathway of glucocortoids through either inhibition or induction of CYP3A enzymes.²⁷

Interactions between cART and immunosuppressants

In order to optimize transplant patient and graft outcomes in HIV-infected patients, it is essential to carefully manage the profound pharmacokinetic interactions between cART and immunosuppressants. The degree of pharmacokinetic interactions vary both across classes of cART and within classes. The interactions with cART may result in supratherapeutic or subtherapeutic levels of immunosuppressive agents. Pharmacodynamic interactions, on the other hand, can have a positive as well as a negative effect on graft function and/or virologic response. Since 2007 therapeutic options for the treatment of HIV have improved following the introduction of a number of promising classes of cART with lower drug interactive potential.²⁸ Raltegravir, an integrase inhibitor and maraviroc, a CCR5-antagonist, were both introduced in 2007. Current HIV treatment guidelines recommend on treatment options for first line therapy in treatment naive patients. In addition to protease inhibitor (PI)-based regimens and an efavirenz based regimen the option exists to utilize the combination of raltegravir and tenofovir/emtricitabine.²⁸ This combination would be preferred in the HIV-infected SOT population given the lack of drug interactions. A summary of the pharmacokinetic and pharmacodynamic interactions between all currently available classes of cART and immunosuppressants is provided in Table 2. Tables 3 and 4 summarize the results of the pharmacokinetic and pharmacodynamic studies on the combination of cART and immunosuppressants.

Table 2.

Potential Pharmacokinetic and Pharmacodynamic Interactions Between cART and Immunosuppressants

	Glucocorticoids		Calcineurininhibitors		Antimetabolites		mTor inhibitors
	PK	PD	PK	PD	PK	PD	PK	PD
NRTIs	N.E.	U.K.	0	N.E.	0	HIV ±	N.E.	U.K.
NNRTIs	[GCs] ↓	U.K.	[CNI] ↓	U.K.	0	U.K.	[mTor] ↓	U.K.
Protease inhibitors	[GCs] ↑	U.K.	[CNI]↑↑ ↑	HIV ±	0	N.E.	[mTor]↑↑	U.K.
Integrase inhibitors	N.E.	U.K.	0	U.K.	N.E.	U.K.	0	U.K.
CCR5-antagonists	N.E.	U.K.	N.E.	Tx +	N.E.	U.K.	N.E.	HIV +
Fusion inhibitors	N.E.	U.K	N.E.	N.E.	N.E.	U.K	N.E.	HIV +

cART, combination antiretroviral therapy; GCs, glucocorticoids; CNI, calcineurin inhibitor; mTor, mTor inhibitor; Tx +, positive effect on transplant outcome; HIV +, positive effect on antiviral activity; HIV ±, negative and positive effects on antiviral activity have been reported; 0, no interaction found in clinical studies; N.E, not expected based on theoretical considerations and U.K., unknown. An upwards arrow indicates an increase in concentration and a downwards arrow indicates a decrease in concentration. The number of arrows respesent the magnitude of the pharmacokinetic interaction.

Table 3.

Summary of Data on Pharmacokinetic Interactions Between Antiretroviral and Immunosuppressive Agents

Drug–drug IA	Study	Study design	n	Reported antiretroviral regimen	Change in pharmacokinetic parameters or drug levels	Need for dose adjustment	Clinical toxicity	Other comments
NNRTI
EFV/NVP+CsA/TAC	Frassetto et al. (2007)	Observational study of HIV infected KT or OLT	31	EFV or NVP	No PK values reported	Change in dose of CsA from 189 to 275 mg twice daily at week 2 and from 147 to 279 mg twice daily at week 12 for EFV	None reported	Subjects on NVP required CsA and TAC at doses and intervals close to non–HIV–infected transplant subjects on the same IS. Though levels with EFV averaged about 50–60% lower on a dose-adjusted basis.
NVP+CsA	Gruber et al. (2008)	Case series of HIV infected KT	2	NNRTI	Not reported	75 and 150 mg twice daily	None reported	Striving to reduce acute rejetion rates next to adding an anti-interleukin (IL)-2 receptor antibody for induction and TDM of MPA, trough levels of CsA were increased significantly
EFV+TAC	Tan et al (2004)	Observational study of HIV infected KT	2	3TC, AZT, EFV	Not reported	None	None reported	Biopsy proven TAC renal toxicity and elevated serum creatinine were reported
EFV+TAC	Teicher et al. (2007)	Observational study of HIV/HVC coinfected OLT	4	EFV+NRTIs	Rise in mean oral clearance from 277 to 530 mL/h	Minimal adjustment was required	None reported	Patients taking efavirenz required a small change in the daily TAC dose, which was close to the intrapatient variability
NFV/EFV+MPA	Millan et al. (2005)	Observational study of chronically HIV-1–infected patients	7	ABC+NFV/EFV	None	No	None	MPA curves were taken within each patient before and after the recontinuations of HAART
PI
SQV+CsA	Brinkman et al. (1998)	Case report of an HIV-infected KT	1	SQV, 2 NRTI's	CsA: levels were 300% higher	Yes, 50% dose reduction	Fatigue, headache, GI-discomfort	SQV AUC 500% higher compared to controls
NFV+TAC	Sheikh et al. (1999)	Case report of an HVC/HIV-coinfected KT	1	NFV+2 NRTI's	TAC: trough level over 120 ng/mL	Yes, 95% dose reduction	Confusion, lethargy, liver toxicity were reported
NFV+TAC	Schvarc et al. (2000)	Case report of an HVC/HIV-coinfected OLT	1	3TC/AZT/NFV	Levels over 30 ng/mL	0.5 mg once a week; 1/70 of normal dose	None reported	ARVs were all withheld for 6 days due to high Tac concentrations
NFV+SRL	Jain et al. (2002)	Case report of one HIV infected OLT	1	3TC/AZT/NFV	A ninefold increase in trough levels	2 mg/day	None reported	NFV dose reduction to one fifth of normal dose was ineffective to avoid SRL overexposure
NFV+TAC	Teicher et al. (2007)	Observational study of HIV/HVC coinfected OLT	2	NFV+NTRIs	Drop in mean oral clearance from 2137 and 257 to 42.9 and 29.2 mL/h, respectively	Dose reduction of 99%	None reported	Two patients receiving NFV required a 75–93% decrease in the daily dose of TAC
NFV+TAC	Pea et al. (2008)	Case series of HIV-infected OLT	4	TDF/3TC or FTC/NFV (and later fosAMP)	Drop in levels after switching from NFV to fosAMP	0.29 mg/day with NFV 0.48 mg/day on fosAMP	None reported	Drop in levels was probably caused by the different modulation of Pgp mediated excretion of TAC by NFV and fosAMP
PI+CsA/SRL	Guaraldi et al. (2009)	Pilot PK study of HIV-infected OLT	4	2 NRTIs+PI	High levels were reported	Median fold decrease in dose were 2.9 and 4.0 for CsA and SRL, respectively	Acute renal failure was reported in 3 patients	Unboosted PIs had fewer pharmacokinetic interactions and were more manageable and easier to use compared to boosted PIs in the post-OLTx period
SQV/r+CsA	Gregoor et al. (1999)	Case report of one HIV infected KT	1	SQV/r/AZT	Levels over 1000 ng/mL	N.A.	Decrease in renal function	Rise of serum creatinine from 84 to 228 nmol/mL due to high CsA levels; all ARV's were stopped for 10 days to lower CsA. level.
AMP/r+MPA	Coull et al. (2001)	Observational study of chronically HIV-1–infected patients	7	ABC/DDI/EFV/AMP/r	AUC:50% compared to transplantation population	Unclear	None	50% of expected based on model of transplantation population. No effect of EFV was noticed.
LPV/r+MPA	Margolis et al. (2002)	Observational study of chronically HIV-1–infected patients	5	ABC/DDI/(EFV)/LPV/r	AUC: in line with results of Coull et al. (2001)	Unclear	None
LPV/r+TAC	Jain et al. (2003)	Case series of two OLT and one combined OLT and KT HIV/HVC coinfected patients	3	AZT/3TC/D4T/LPV/r	Levels over 70 ng/mL in one patient	0.5–1 mg/week	Altered mental status, jaundice, rise in bilirubin	Multiple peaks of TAC were noted after a single administration
PI(/r)+TAC	Neff et al. (2003)	Case series of HIV(/HBV/HCV)-coinfected OLT	13	PI(/r)+coadministration of NRTIs and NNRTIs	Levels over 30 ng/mL for 3 weeks in one patient	Reduction to 1–3 mg/week	Renal toxicity in one patient	In one case patient's PI was stopped by the local physician resulting in a drastic reduction in TAC levels resulting in acute rejection
LPV/r+TAC	Schonder et al. (2003)	Case report of an HVC/HIV-coinfected OLT	1	3TC/AZT/LPV/r	Levels over 70 ng/mL	0.5 mg once a week; 140-fold dose reduction	Decrease in renal function, insomnia depression, diarrhea	Rise of serum creatinine from 9 to 32 mg/dL due to high CsA levels; all ARVs were stopped for 10 days to lower CsA level.
LPV/r+CsA	Vogel et al. (2004)	Case series of HIV/HVC-coinfected OLT	3	TDF/3TC/LPV/r or ABC/3TC/LPV/r	Levels over 900 ng/mL in one patient	Dose reduction to 5–20% of standard dose was required	None reported	CsA concentration vs. time curves showed a rather flat absorption/ elimination kinetic profile
LPV/r+TAC	Tan et al. (2004)	Case series of HIV-infected KT	1	3TC/ABC/EFV/LOP/r	Not reported	0.1 mg/4 days	Elevated serum creatinine	Patient experienced 2 episodes of biopsy proven TAC renal toxicity
SQV/r+CsA	Hardy et al. (2004)	Case report of one HIV-infected KT	1	3TC/D4T/SQV/r	Levels over 175 ng/mL	0.5 mg once a week; 140-fold dose reduction	None reported
PI/r+TAC	Guaraldi et al. (2006)	Case series of HIV-infected OLT	2	3TC/TDF/T20/AMP/r (pat 1) and 3TC/TDF/FosAMP/r pat 2)	Levels over and 500 and 1000 ng/mL, respectively	A 12- and 3.5-fold dose reduction, respectively	None reported
PI/r+CsA	Frassetto et al. (2007)	Observational study of HIV-infected KT or OLT	21	PI/r+NRTI (and 8 of 21 patients were on a NNRTI)	No PK values reported	Dose reduction to 25 mg every 33 h	None reported	CsA dosing interval was significantly prolonged when an NNRTI was used simultaneously
LPV/r+TAC	Teicher et al. (2007)	Observational study of HIV/HVC-co-infected OLT	5	LPV/r+NTRIs	Drop in mean oral clearance from 492 to 5.0 mL/h	Dose reduction of 99%	None reported
RVT-boostedPI
PI(/r)+CsA	Gruber et al. (2008)	Case series of HIV-infected KT	5	2 NRTIs+PI(/r)	Not reported	Ranging from 25 mg/2 days to 175 mg/3 days	None reported	Striving to reduce acute rejetion rates next to adding an anti-interleukin (IL)-2 receptor antibody for induction and TDM of MPA, trough levels of CsA were increased significantly
DRV/r+TAC	Mertz et al. (2009)	Case report of an HIV-infected simultaneous kidney–pancreas transplantation	1	TDF/RAL/ETV/DRV/r	Levels over 100 ng/mL	Dose reduction to 3.5% of normal dose	None	During combination of DRV/r and TAC creatinine increased nearly 100%. DRV/r was replaced by T20 in order to lower TAC levels.
LPV/r+SRL	Dinavahi et al. (2009)	Case report of an HIV-infected KT	1	3TC/ABC/EFV/LOP/r	Not reported	1 mg/week	None reported	Patient was switched to SRL from CsA, because of suspected CNI-related nephrotoxicity
PI/r+CsA or SRL	Guaraldi et al. (2009)	This is a single-center, open-label pilot PK study of HIV-infected OLT	8	2 NNRTIs+PI	High levels were reported	Median fold decrease in dose were 7.5	Acute renal failure was reported in 4 patients	Unboosted PIs had fewer IS PK interactions and were more manageable and easier to use compared to boosted PIs in the post-OLTx period
PI/r+TAC	Bickel et al. (2010)	Case series of HIV/HVC and one HIV/HBV-coinfected OLT	2	TDF/3TC/LPV/SQV/r (pat 1) ABC/TDF/AZT/LPV/r (pat 2) 3TC/TDF/SQV/LPV/r (pat 3)	Patient 3 had levels over 140 ng/mL	Ranging from 0.03 to 0.08 mg daily	None reported	TAC pills of dosages raging from 0.01 to 0.08 mg were prepared by a pharmacist facilitating daily dosing of TAC
LPV/r+TAC (ER)	Morelle et al. (2010)	Case report of one HIV infected KT	1	3TC/TDF/NPV/LPV/r	Levels over 30 ng/mL for 15 days with administration of TAC	0.5 mg once a week; 140-fold dose reduction	Tremor, high creatinine levels
ATZ/r+TAC	Cousins et al. (2011)	Case report of an HIV-infected KT	1	ATZ/r	Levels as high as 160 ng/mL were reported	1.5 mg twice daily TAC resulted in high levels	Drowsy and drop in hemoglobin level with a raised bilirubin	ATZ/r was switched to RAL and afterwards TAC levels were therapeutic within 5 days after a break of 13 days
DRV/r+TAC	Ahktar et al. (2011)	Case report of an HIV-infected SKTP	1	RAL/ETV/DRV/r	Therapeutic	1 mg/week	None reported	Pretransplantation curves of TAC were drawn to predict posttransplantation exposure
PI/r+TAC	van Maarseveen et al. (2012)	Case series of HIV-infected KT	6	2 NNRTIs/NRTI+LPV/r or ATZ/r	40-fold lower oral clearance compared to an HIV negative population	Adviced loading dose of 1–2 mg directly after KT	Not applicable	Pretransplantation curves of TAC were drawn to predict posttransplantation exposure
Newer ARVs
RAL+SRL	Moreno et al. (2008)	Case report of an HIV-infected patient with renal impairment after OLT	1	RAL/3TC/ABC+SRL	None	None	None reported	The coadministration of RAL and SRL was safe and effective against HIV, with an improvement in CD4 count, and led to a rapid improvement in renal function after switching from D4T and CsA to RAL and SRL
T20+CNI	Teicher et al. (2009)	Observational study of OLT recipients with HIV coinfection treated with T20 or LPV/r in combination with 2 NRTI drugs	11	T20+NRTI's	None	None	None reported	Immunosuppressant doses were not modified by the reintroduction of T20, and there were no changes in mean trough concentrations over the 3 periods
RAL+CNI	Tricot et al. (2009)	Observational study in HCV/HIV-coinfected KT and OLT	13	RAL+2 NRTI's	None	None	None reported
RAL+TAC	Miro et al. (2010)	Case report of an HIV-infected simultaneous kidney pancreas transplantation	1	3TC/ABV/RAL	None	None	None reported	No influence of RAL detected on TAC levels
RAL+TAC	Bickel et al. (2010)	Case series of an HIV/HVB-coinfected OLT and an HIV-infected patient with Crohn's disease	2	RAL/3TC/AZT and RAL/TDF/FTC	None	None	None reported

ARVs, antiretroviral drugs, NRTIs, nucleoside reverse transcriptase inhibitors; NNRTIs, nonnucleoside reverse transcriptase inhibitors; AVRs, antiretrovirals; 3TC, lamivudine; ABC, abacavir; AZT, zidovudine; D4T, stavudine; DDI, didanosine; FTC, emtricitabine; TDF, tenofovir; DLV, delavirdine; EFV, efavirenz; ETV, etravirine; NVP, nevirapine; ATZ, atazanavir; DRV, darunavir; IDV, indinavir; NFV, nelfinavir; RTV, ritonavir; fosAMP, fosamprenavir; MVC, maraviroc; T20, enfuvirtide; RAL, raltegravir, AZA, azathioprine; MPA, mycophenolate acid; CsA, cyclosporin; TAC, tacrolimus; SRL, sirolimus; Pgp, P-glycoprotein.

Table 4.

Summary of Data on Pharmacodynamic Interactions Between Antiretroviral and Immunosuppressive agents

Drug combination	Study (ref)	Study population/design	Impact on antiviral activity or transplant outcome	Other comments
MVC+CsA	Li et al.⁷¹	Study in nonhuman primates to examine the effect and mechanism of MVC alone or in combination with cyclosporine (CsA) to prolong cardiac allograft survivals	Recipients treated with MVC plus CsA showed significantly prolonged survival of heart allografts (>240 d, p<0.001)	Grafts from the MVC/CsA group had elevated numbers of alternatively activated macrophages (AAMs) and the expression of peroxisome proliferator-activated receptor g (PPARg). Blockade of PPARg abrogated the prolonged allograft survival (median survival time, 45 d) and the upregulated AAMs in MVC/CsA-treated recipients.
MVC+CsA	Li et al.⁷²	Eighty fully MHC-mismatched murine cardiac allograft models were randomized to treatment with anti-CCR5 mAb and CsA, anti-CCR5 mAb alone, only CsA, and a control group with PBS	Recipient treatment with both anti-CCR5 mAb and CsA significantly prolonged heart allograft survival compared with PBS treatment (p<0.01), CsA treatment (p<0.01), and anti-CCR5 mAb alone treatment (p<0.05)	Treatment with anti-CCR5 mAb plus CsA significantly inhibited the progression of cardiac allograft vasculopathy
CCR5-antagonist+mTOR	Heredia et al.⁷³	In vitro	mTOR enhanced vicriviroc antiviral activity against both B and non-B clade isolates, potently suppressing clade G viruses with reported reduced sensitivities to vicriviroc and maraviroc	No signs of cell toxicity were found in vitro
T20+mTOR	Heredia et al.⁷⁰	In vitro	mTOR may potentiate the antiviral activity of T20 against R5 strains of HIV-1	R5 strains of HIV-1, which are generally present throughout the course of infection and are less sensitive to T-20 inhibition than are X4 strains
ABC/NFV/EFV+MPA	Millan et al.³¹	Randomized open-label study including 17 chronically HIV-1–infected patients with MPA (n=9) or without (n=8)	Viral load at day 150 was >200 copies/mL in all control patients and in 3 of 9 patients receiving mycophenolate mofetil	—
ABC/DDI/(EFV)/LPV/r+MPA	Margolis et al.³⁰	Cohort of 5 chronically HIV-1–infected patients	Three of five subjects had VL declines of >0.5 log₁₀ copies/mL immediately after adding MPA; a fourth subject had a sustained decline of >0.5 log₁₀ copies/mL after week 8. Declines of >0.5 log₁₀ copies/mL were lost in two patients at 6 and 8 weeks, and persisted in two patients at 36 and 60 weeks of follow-up, respectively.	—
D4T/3TC/NFV/SQV+CsA	Rizzardi et al.²²	Nine adults with primary HIV-1 infection were treated with CsA along with cART	Viral replication was suppressed to a comparable extent in the CsA and antiretrovirals cohort and in 29 control patients whose primary infection was treated with antiretrovirals alone	At week 48, the proportion of IFN-γ–secreting CD4+ and CD4+CCR7– T cells was significantly higher in the CsA and cART cohort than in the cART cohort
Antiretroviral therapy+CsA	Calabrese et al.²¹	Twenty-eight patients with confirmed HIV infection were stratified for the presence or absence of stable concomitant antiviral therapy	The low dose of CsA used in this study did not suppress immune activation or increase circulating CD4 cell counts	CsA-treated patients experienced a small but significant rise in plasma HIV RNA levels
ABC/DDI/EFV/AMP/r+MPA	Coull et al.²⁹	Cohort of 7 chronically HIV-1–infected patients	Median HIV RNA was 5.26 log₁₀ copies/mL at entry, 4.53 log₁₀ copies/mL at 4 weeks, and 5.13 log₁₀ copies/mL at 16 weeks	—

3TC, lamivudine; ABC, abacavir; D4T, stavudine; DDI, didanosine; EFV, efavirenz; NFV, nelfinavir; RTV of /r, ritonavir; AMP, amprenavir; MVC, maraviroc; T20, enfuvirtide; MPA, mycophenolic acid; CsA, cyclosporin; mTOR, mammalian target of rapamune; TAC, tacrolimus; SRL, sirolimus; cART, combination antiretroviral therapy.

Nucleoside Reverse Transcriptase Inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) are predominantly cleared renally and more importantly are neither inducers nor inhibitors of liver enzymes or transporters. Therefore, pharmacokinetic effects of NRTIs on immunosuppressants or vice versa are not to be expected and have not been detected in clinical studies.^29
–31 On the other hand, pharmacodynamically mycophenolic acid enhances the in vitro activity of abacavir and other NRTIs against sensitive and NRTI-resistant HIV. The mechanism is believed to be via depletion of intracellular deoxyguanosine triphosphate through inhibition of its synthesizing enzyme inosine monophosphate dehydrogenase by mycophenolic acid. This synergistic effect has also been blamed for the increased risk of mitochondrial toxicity in patients receiving the combination of mycophenolic acid with NRTIs such as lamivudine, didanosine, or abacavir.³² In contrast, the combination of mycophenolic acid and zidovudine or stavudine was found to be antagonistic, which is likely to be caused by inhibition of thymidine kinase.³⁰ Based on their in vitro findings, Margolis et al.³⁰ performed an in vivo study in which mycophenolic acid 500 mg twice daily was added as a single agent to the antiretroviral regimens of 5 patients failing maximal available therapy. Therapy included abacavir, and in most cases didanosine and tenofovir. After an initial viral load (VL) decline of 0.5 log₁₀ in 4 patients, the drop in VL persisted in 2 patients after 60 weeks of follow-up. CD4⁺ count did not differ significantly from baseline.³⁰ Sankatsing et al.³³ studied the antiretroviral effects of mycophenolic acid in a group of 19 HIV-1–infected patients starting a triple antiretroviral drug regimen. Patients were randomized to a group with or without mycophenolic acid. The addition of mycophenolic acid in treatment-naive patients did not significantly increase the plasma HIV-1 RNA decay rate or the decay rate of the latently infected cellular reservoir. Taking a closer look at the effect of mycophenolic acid on intracellular pools of deoxycytidine triphosphate and deoxyguanosine triphosphate, and on intracellular concentrations of the triphosphate of lamivudine, Sankatsing et al.²⁶ found no consistent or significant effects of mycophenolic acid. In conclusion, evaluation of the in vivo synergistic effects in clinical studies showed no consistent synergistic or toxic effects of mycophenolic acid and NRTIs and mycophenolic acid was generally well tolerated when coadministered with NRTIs. However, it is important to keep in mind that the synergistic effects of mycophenolic acid and some NRTIs may place patients at higher risk of complications such as lactic acidosis and mitochondrial toxicity.

Non-Nucleoside Reverse Transciptase Inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are known inducers of CYP enzymes and consist of efavirenz (EFV), nevirapine (NVP), and the recently approved etravirine (ETV). Concomittant administration of NNRTIs could lead to low levels of CNIs and mTOR inhibitors, which are primarily metabolized by CYP3A. It is, however, questionable whether this interaction leads to clinically relevant changes in immunosuppressants pharmacokinetics. Four reports of in total 15 patients on the combination of EFV or NVP with tacrolimus or cyclosporine reported no or minimal dosage adjustments.^34

–37 On the other hand, the largest study on the NNRTI-CNI interaction in a series of 31 kidney and liver transplant recipients performed by Frassetto et al reported that patients on NVP required a daily dose of cyclosporine close to non-HIV-infected transplant recipients, whereas subjects on EFV indeed needed allmost twice the dose of cyclosporine to achieve therapeutic trough levels.³⁸ Trough levels with EFV averaged approximately 50–60% lower on a dose-adjusted basis necessitating a 1.5- to 2-fold increased dose of CNIs thereby preventing loss of immunosuppressive effect of CNIs. The same effects were recorded for mTOR inhibitors.³⁸ Albeit there are no data available yet on the pharmacokinetic interactions of ETV on immunosuppressants kinetics, the same effects as with EFV could be anticipated.³⁹ Next to ETV, rilpivirine is currently investigated phase 3 clinical study and has shown promise as a once-daily medication with good bioavailability, safety, and tolerability at chosen doses of 25 and 75 mg. Like other NNRTIs, rilpivirine is a substrate and inducer of CYP3A. However, based on in vivo data, only mild induction of CYP3A was reported at 300 mg once daily and a clinically relevant affect on CYP3A is not considered likely.⁴⁰

Since coadministration of NNRTIs with CNIs or mTOR inhibitors seem quite manageable and could be considered to be within intrapatient variability, the combination does not need to be avoided. Nevertheless, close therapeutic drug monitoring is warranted when NNRTIs are started or stopped in patients using CNIs or mTOR inhibitors concomittantly to assure therapeutic exposure of these two classes of immunosuppressants in individual patients. Finally, both EFV and NVP show a relative high rate of drug-induced transaminitis in compared to other antiretroviral medications, especially in HCV coinfected patients.⁴¹ This may result in synergistic hepatotoxicity with CNIs.

Protease Inhibitors

PIs are a potent class of cART that currently include fosamprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, and darunavir. All PI preparations are primarily metabolized by CYP enzymes. Nowadays most PIs are prescribed together with ritonavir (RTV) to utilize its pharmacologic boosting effects on concurrently administered PIs.²⁸ PIs are known strong inhibitors of CYP3A enzymes and P-gp, but RTV is by far the most powerful CYP3A and Pgp inhibitor currently available requiring dramatic dosage adjustments of numerous CYP3A and Pgp substrates.³⁸ Glucocortoid clearance, for example, has been reported to be significantly reduced in patients on RTV-boosted PIs resulting in higher serum concentrations and side effects like Cushing syndrome²⁷ Since glucocortoid levels are not routinely monitored, dosages are mostly adjusted based on patient (in)tolerance and biochemical parameters.

Far more complex to manage are the interactions between PIs and CNIs or mTor inhibitors. Clinical studies have shown that dramatically lower daily doses and prolonged dosing intervals for CNIs are necessary in HIV-infected patients using unboosted PIs.^{36,38,42

–50} Moreover, in patients on RTV-boosted PIs even higher drastic dosage reductions up to 120-fold are necessary to achieve therapeutic through levels of tacrolimus, cyclosporine, and sirolimus.^{7,35,37,38,42,45,47,51

–64} Initiation of a posttransplant CNI dosing strategy similar to that used in a non-HIV positive patient can immediate lead to extremely high persistent CNI inhibitor levels and concurrent (nephro)toxicity [59]. CNI half life is prolonged 5- to 20-fold because of the systemic inhibition of CYP 3A and Pgp, resulting in dosing regimens of 0.5–1 mg once weekly for tacrolimus and 25 mg every 1–2 days for cyclosporine in kidney and liver transplant recipients.^36,38 Interestingly, the inhibitory effect seems to be independent of the type of transplantation and also comparable between pretransplantation and posttransplantation transplant recipients offering the opportunity to perform pretransplantation pharmacokinetic curves of CNIs in kidney recipients to predict exposition directly posttransplantation.⁶³ However, for patients awaiting liver transplantation, pretransplantation pharmacokinetic assesment of CNIs is clearly not appropiate, because of the hepatic route of elimination. The unique dosing regimens of CNIs that are necessary in patients on RTV-boosted regimens, lead to a number of serious clinical and pharmacokinetic dilemmas. With every patient, it is essential to have explicit communication between the transplant team, infectious disease team, and patient and family to achieve optimal therapeutic benefit of all medications. It is critical that the clinicians and patient are aware of the implications of the drug interactions between cART and immunosuppressants, and that timing of doses and immunosuppressant levels drawn, as well as doses amounts and frequencies are properly communicated and documented. In case of the withdrawal of PIs the inhibiting effect on CYP3A and Pgp promptly cease causing tacrolimus levels to drop below therapeutic target levels rapidly.^65,66 In one case, a patient's PI was accidentally stopped by the local physician resulting in a drastic reduction in tacrolimus levels precipitating acute rejection.⁵⁸ On the other hand, there are many reports of nephro- and neurotoxicity as a result of overexposure to CNIs because the CNI dose was not reduced beforehand.^{35,45,48,53,57,59} In these cases of extremely high CNI levels the quickest and most effective way of preventing serious toxicity is by withholding PIs for 2–3 days. Furthermore, patient compliance to CNIs is endangered by complicated dosing schedules, which may require intake of 0.5 mg tacrolimus every 5–8 days. Recently, Bickel et al.⁴² were successful by utilizing tailored “microdosing.” In this study tacrolimus pills in strength ranging from 0.01 to 0.08 mg were prepared by pharmacist in order to facilitate daily dosing of tacrolimus. This innovative approach deserves further exploration and may be of benefit in the future.

Additionally, the profound changes in CNI and mTOR inhibitor pharmacokinetics necessitate reviewing recommendations on therapeutic drug monitoring in patients simultaneously on PIs. CNI dosing is ideally based upon a 12-h area under the curve (AUC_0–12). Nevertheless, in clinical practice dosing is usually based on trough levels, assuming good correlation between AUC and trough level. Target AUCs for tacrolimus of 210 ng h/mL 1 month and 125 ng–h/mL 1 year after transplantation have been reported in HIV-negative kidney transplant recipients.⁶⁷ These target AUCs correspond with trough levels of approximately 12.5 and 7.5 ng/mL, respectively. However, pharmacokinetic curves of tacrolimus in patients on PIs, do not show the usual peak and trough pattern, but rather resemble a flat line. As a result the AUC_0–12 will be approximately 44% lower.⁶³ Similar pharmacokinetic effects have been described for cyclosporine in patients on RTV-boosted PIs.⁶¹ The hypothesis of targeting higher CNI trough levels in these patients is first of all indirectly supported by the results of Stock et al.,⁵ who found that higher tacrolimus trough levels were associated with a decreased risk of a first acute allograft rejection episode. Mean tacrolimus trough levels in that study in which half of the population was on a PI-based cART, were 9.1 ng/mL at 1 month and 7.2 ng/mL at 1 year posttransplantation, respectively. However, no significant correlation could be detected between the use of PIs, tacrolimus trough levels, and rejection. There is similar pharmacokinetic data supporting the need for higher tacrolimus levels in patients receiving tacrolimus as a continuous infusion. Nakamura et al.⁶⁸ reported that the target steady state concentration of tacrolimus after intravenous administration should be 1.4 times higher than the blood trough level after oral administration in order to reach equal exposure. Since administration of tacrolimus in RTV-patients takes place approximately every 7 days, the pharmacokinetic curve of tacrolimus in these patients resembles the pharmacokinetic curve of a continuous infusion.

While there are data to support therapeutic drug level monitoring time points beyond trough levels, such as 2-hour measurements for cyclosporine, limited data have been published on defining appropriate time-point measurements for CNIs in the presence of PIs. A single-center study assessed 141 pharmacokinetics curves of cyclosporine or tacrolimus in 26 kidney and 24 liver transplant recipients on PIs alone, NNRTIs alone, or PIs in combination with NNRTIs.³⁸ CNI levels were measured at time points 0 (predose trough), 1, 2, 3, and 4 h postdose. In the cyclosporine group, 19 patients were on PI alone and 5 were on PI with NNRTI versus 5 on NNRTI alone. For cyclosporine, 4-h postdose levels correlated better with AUC (R ² range for all 4-h measurements times=0.74–0.98) than predose trough (R ² range for all predose measurement times=0.38–0.95) or 2 h postdose concentrations (R ² range for all 2 measurement times=0.19–0.89). In the tacrolimus group, 4 patients were in the PI alone group and 2 patients were in the PI with NNRTI group, but sample size was too small to calculate correlations. For the tacrolimus and PI alone group, at week 2 all R ² values ranged between 0.97 and 0.99 for all times. In contrast, at week 12, 4-h postdose level had highest correlation with AUC (R ²=0.92 versus 0.22 at trough concentration).⁶⁹

Further studies on defining optimal time points for CNI and mTOR inhibitors level monitoring should be performed to better understand the change in pharmacokinetics of each class of immunosuppressive drugs respectively. Moreover, development of validated CNI and mTOR inhibitor therapeutic drug monitoring strategies in patients on PI-based therapies are necessary to decrease rejection rates in HIV-infected SOT recipients.

Antiretrovirals of Newer Classes

New antiretroviral agents that do not affect CYP3A or Pgp such as raltegravir, maraviroc, and enfuvirtide have recently been introduced and offer the advantage of low pharmacokinetic interactive potential with immunosuppressants in SOT recipients.

Fusion Inhibitors

The only currently available fusion ihnibitor is enfuvirtide (T20). It does not utilize the CYP pathway for metabolism nor inhibit or induce CYP3A enzyme activity and has shown in vitro pharmacodynamic synergy with mTOR inhibitors regarding its antiviral activity.^60,70 T20 has been administered to liver transplant recipients with HIV-HCV coinfection in combination with 2 NRTI drugs.⁶⁰ Immunosuppressant doses and levels were not modified during this study after the reintroduction of T20, showing absence of a clinically relevant pharmacokinetic interaction. Nonetheless, broad application of T20 is expected to remain limited as a result of its subcutaneous route of administration.

CCR5-Antagonists

CCR5-antagonists hold great potential for the treatment of HIV-infected transplant recipients with regards to both allograft rejection and viral control. Two studies performed by Li et al.^71,72 demonstrated that the combination of maraviroc, a CCR5-antagonist and cyclosporine resulted in significantly longer allograft survival compared to cyclosporine monotherapy in a murine and nonhuman primate cardiac allograft model, respectively. Mechanistically this effect could be attributed to elevated numbers of alternatively activated macrophages and the expression of peroxisome proliferator-activated receptor g. Furthermore, the combination of CCR5-antagonists with mTOR inhibitors reduced CCR5 density thereby enhancing the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1.⁷³ We anxiously await the first results of an ongoing trial investigating the effect of MVC added to standard prophylaxis with tacrolimus and methotrexate in HIV-negative patients undergoing nonmyeloablative allogeneic stem-cell transplantation.⁷⁴ Currently, there are no clinical reports of MVC in HIV-infected transplant recipients. Combining CCR5-antagonists with CNIs and mTOR inhibitors may improve both transplant outcomes and viral control in patients with CCR5 positive HIV, but cannot be applied in all HIV-infected patients because the use of MVC is limited to HIV strains using CCR5 coreceptor. Since MVC is a substrate of CYP3A, but not an inhibitor or inducer, it is not expected to have any relevant pharmacokinetic interactions with immunosuppressants⁷⁵ In contrast, it is yet to be determined whether the initiation of MVC in these immunocompromised patients will be limited by high rates of opportunistic infections.

Integrase Inhibitors

Raltegravir (RAL), an integrase inhibitor, is a welcome addition to the antiretroviral drug armamentarium of SOT candidates due to its good tolerability, low potential for interactions with immunosuppressants (Table 2), lack of overlapping toxicities, and good clinical efficacy.^76,77 RAL is not a substrate of CYP enzymes as its main pathway of metabolism is via UGT-mediated glucuronidation. It does not inhibit or induce CYP3A metabolism and has no effect on Pgp. Furthermore, early reports of positive outcomes with use of this agent in HIV-infected transplant recipients are promising.^13,42,77,78 The largest series was described by Tricot et al.,⁷⁷ in which 13 liver or kidney recipients were included. RAL was initiated either at the time of transplantation or posttransplant in patients experiencing persistently elevated CNI trough levels while on PIs. The median RAL trough concentration was well above the in vitro IC95 for wild-type HIV-1 strains. Target trough levels of CNIs were promptly obtained with standard doses of tacrolimus or cyclosporine. No episode of acute rejection was recorded and RAL tolerability was excellent. After a median follow-up of 9 months, all patients were alive with satisfactory graft function and HIV infection remained controlled.⁷⁷ Although RAL-based regimens offer an excellent alternative for HIV-infected transplant recipients, and has been shown to possess beneficial effects on the renal function in SOT recipients,⁷⁹ its use is complicated by a low genetic barrier to resistance.²⁸

A second integrase inhibitor, elvitegravir, which is currently in phase 3 trials and also possesses a high barrier to resistance, which will probably be marketed as a once-daily drug in the near future.⁸⁰ Nevertheless, since it is pharmacologically boosted by cobicistat, a potent mechanism-based inhibitor of CYP enzymes, the elvitegravir/cobicistat combination will likely not be a preferred regimen in patients receiving CNIs or mTOR inhibitors.

Finally, a third integrase inhibitor, dolutegravir, is currently in phase 3 clinical trials. It is suggested that dolutegravir will have a higher barrier to resistance compared to RAL in integrase inhibitor naive patients and its dosing will be limited to once daily in patients without previous RAL resistance. Similar to healthy volunteer data, dolutegravir participants in the phase 2b trial also experienced an increase in serum creatinine. However, this is not thought to represent nephrotoxicity, but rather inhibition of tubular secretion of creatinine via the organic cation transporter OCT2 (similar to the interaction seen with cimetidine or trimethoprim).⁸¹ Dolutegravir may play an important role in the treatment of HIV positive SOT recipients in the near future.⁸²

Conclusion

In conclusion, extremely complex management of CNIs and mTOR inhibitors has been recognized in patients on a PI-based cART and to a lesser extent on NNRTI based regimens. Therefore, caution and frequent drug level monitoring are necessary when these drugs are (re)introduced or withdrawn in HIV-infected transplant recipients. Furthermore, the pharmacokinetics of glucocorticoids, CNIs and mTOR inhibitors are significantly affected by PIs. Yet, avoiding use of these pivotal immunosuppressants would be detrimental to the prevention and treatment of allograft rejection. Until new immunosuppressants are available that could avoid these potent drug interactions, replacing PIs with integrase inhibitors or CCR5 antagonists should seriously be considered to avoid a pharmacologic minefield. Although there is little clinical experience with integrase inhibitors and CCR5 antagonists compared to PIs and long-term viral control will need to be demonstrated in HIV-infected transplant patients, they offer a number of advantages over PIs, such as lack of drug interactions and minimal overlapping toxicities. However, there are still patients whose HIV resistance profiles will not allow them to switch to a non-PI-based regimen. Therefore, it will still be important to establish an optimal immunosuppressive regimen, define ideal drug level measurement time points and establish therapeutic indices in HIV-infected transplant recipients on PIs.

Footnotes

Acknowledgments

The authors thank Prof. Dr. David Burger from the department of clinical pharmacy at Radboud University Nijmegen Medical Center, The Netherlands, for commenting on an earlier version of the manuscript.

Author Disclosure Statement

No competing financial interests exist.

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