Review Article The Role of mTOR Inhibitors in Liver Transplantation: Reviewing … · 2019. 7. 31. · maintenance immunosuppression in liver transplantation [ ], but their nephrotoxic

Review ArticleThe Role of mTOR Inhibitors in Liver Transplantation:Reviewing the Evidence

Goran B. Klintmalm1 and Björn Nashan2

1 Baylor Simmons Transplant Institute, Baylor University Medical Center, 3410 Worth Street, Suite 950,Dallas, TX 75246, USA

2Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Eppendorf,Martinistra𝛽e 52, 20246 Hamburg, Germany

Correspondence should be addressed to Goran B. Klintmalm; [email protected]

Received 30 May 2013; Revised 20 September 2013; Accepted 21 September 2013; Published 25 February 2014

Academic Editor: Andreas Zuckermann

Copyright © 2014 G. B. Klintmalm and B. Nashan. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Despite the success of liver transplantation, long-term complications remain, including de novomalignancies, metabolic syndrome,and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC).The currentmainstay of treatment, calcineurininhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need forbetter immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. Themammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressiveagents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTORinhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, andthe recurrence of HCC andHCV.The results of our review indicate that mTOR inhibitors are associated with efficacy comparable toCNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit sideeffects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-relatedallograft fibrosis, metabolic syndrome, and neurotoxicity.

1. Introduction

One-year survival rates for liver transplantation currentlystand at more than 80% in the US and Europe [1, 2]; however,the demand for liver transplants far outstrips the number ofavailable donor livers as increasing numbers of patients arereferred for transplantation. Moreover, the global incidenceof conditions that may ultimately require a liver transplant(hepatocellular carcinoma (HCC), nonalcohol fatty liverdisease, and cirrhosis) is predicted to increase [3–6], whichwould further drive demand for the procedure. This maybe balanced by a reduction in liver transplants requiredowing to hepatitis C virus (HCV) as a result of the use ofnew potent antivirals. The success of liver transplantation islimited by shortages of suitable donor organs, adverse eventsof immunosuppressive drugs, and recurrence of disease.

Although transplant surgery was an area of great interestin the 1960s and 70s, the mortality rate for liver transplanta-tion in 1978, using azathioprine and prednisone immunosup-pression, was approximately 75%. Cyclosporine, a calcineurininhibitor (CNI), changed the face of transplantation, andin a few years the survival rate of liver transplantation hadreached 80% [7]. The search for new and safer immuno-suppressants continued and in 1989, reports were publishedon the successful use of tacrolimus, another CNI, in livertransplantation [8]. CNIs have been the cornerstone ofmaintenance immunosuppression in liver transplantation[9], but their nephrotoxic effects are an important sourceof morbidity [10–13]. Several other factors are implicatedin the development of renal dysfunction following livertransplantation, including increased age, diabetes mellitus,hypertension, and preexisting kidney disease [14]. Data from

Hindawi Publishing CorporationJournal of TransplantationVolume 2014, Article ID 845438, 45 pageshttp://dx.doi.org/10.1155/2014/845438

2 Journal of Transplantation

the United Network for Organ Sharing demonstrate thatalmost 20% of liver transplant recipients have chronic renalfailure 5 years after transplantation [14]. High rates of renaldysfunction associated with the preexisting liver disease andwith the use of CNIs are compounded by the use of theModelfor End-Stage Liver Disease score for allocating transplantssince it favors liver transplantation in individuals with renaldysfunction.

In addition to renal dysfunction, long-term complica-tions associated with liver transplantation include the devel-opment of de novomalignancies and the recurrence of HCVand HCC. Recurrence of HCC occurs in approximately 20%of liver recipients [15] and is associated with poor prognosis[16]. In patients who receive a transplant due to HCV-relatedend-stage liver disease, graft reinfection is almost universaland a significant percentage of patients develop chronic hep-atitis in the graft [17–19]; 5-year survival rates after primaryliver transplantation are significantly reduced among HCV-positive patients compared to HCV-negative patients [19].A four-fold greater risk of developing de novo malignanciesposttransplant compared to the general population has alsobeen reported [20].

Another concern relates to adverse effects of the immuno-suppressants that are required to maintain the graft. Forexample, new-onset diabetes mellitus (NODM) has beenestimated to occur in 5–27%of liver transplant recipients [21–23] and is associated with a negative impact on patient andgraft survival [24]. CNIs, particularly tacrolimus, have beenshown to increase the risk of developing NODM [21, 25, 26]and are also associated with an increase in the incidence ofmalignancies are transplantation [20, 27, 28] and with casesof neurotoxicity [28–30]. In addition, metabolic syndrome,which refers to the combination of abdominal obesity, hyper-tension, hyperglycemia, and hyperlipidemia, is common afterliver transplantation and has been reported to affect 43–58% of liver transplant recipients [31]. Hypertension is alsoassociated with CNIs, particularly with cyclosporine [32].

Taken together, an unmet need clearly remains foridentifying alternative immunosuppressive regimens that (1)maintain antirejection efficacy with substantially reducedCNI exposure; (2) optimize renal function, both short- andlong-term, by minimizing CNI nephrotoxicity; (3) avoidor minimize CNI-associated adverse events; (4) reduce therecurrence of HCV and HCC; (5) reduce the occurrenceof de novo posttransplant malignancies. The mammaliantarget of rapamycin (mTOR) inhibitors could potentiallymeet these criteria, in part because they allow the use ofimmunosuppressive regimens that include reduced doses ofCNIs. The mTOR inhibitors also possess a mechanism ofaction that is different from other classes of immunosup-pressants: sirolimus and everolimus engage FKBP12 to createcomplexes that engage and inhibit the target of rapamycinbut cannot inhibit calcineurin (Figure 1). Inhibition of thetarget of rapamycin blocks signal 3 by preventing cytokinereceptors from activating the cell cycle [33]. In addition,mTOR inhibitors may promote tolerance through actions onregulatory T-cells and dendritic cells [34, 35].

Two mTOR inhibitors are currently approved for use intransplantation. Everolimus is approved by the FDA for renal

and liver transplantation and by the EMA for renal, heartand liver transplantation (Certican and Zortress, NovartisPharma AG; Basel, Switzerland) [36, 37]. Clinical experiencewith everolimus in liver transplantation is limited by the factthat it was only recently approved for liver transplantationand it was not approved for renal transplantation in the EUuntil 2003 and in the US until 2010. Sirolimus is approvedby the European Medicines Agency (EMA) and the US Foodand Drug Administration (FDA) for renal transplantation(Rapamune, Pfizer, NY, USA) [38, 39]. In the US, sirolimuswas approved for renal transplantation in 1999. Although notapproved for liver transplantation, it has still been used inseveral centres in liver transplant recipients.

Everolimus is a derivative of sirolimus, differing by oneextra hydroxyethyl group at position 40 [40]. In humanstudies, everolimus has a shorter half life (30 hours) comparedto the 62 hours of sirolimus and a quicker time to steady state(4 days versus 6 days) [36, 38]. Both everolimus and sirolimusare substrates in the p-glycoprotein and cytochrome P450-3A4 pathways [40, 41]. Therefore, the absorption and clear-ance of mTOR inhibitors may be influenced by drugs thataffect cytochrome P450-3A4 and/or p-glycoprotein, includ-ing common drugs such as fluconazole, azithromycin, andprotease inhibitors [36, 38, 39]. An important interactionof mTOR inhibitors is with cyclosporine, with simultaneousadministration leading to increases in blood levels of mTORinhibitor [42, 43], although this appears to be more pro-nounced with sirolimus than with everolimus, necessitatingthe administration of sirolimus 4 hours after cyclosporine[38, 39].

Initial enthusiasm for the use of mTOR inhibitors in livertransplantation was tempered when the FDA issued a blackbox warning for de novo sirolimus use in liver transplantationafter two studies reported hepatic artery thrombosis (HAT)[38, 44]. In 2009, the FDA issued a second black boxwarning, after a trial that compared conversion from CNIs tosirolimus versus continued CNI use showed that the numberof deaths (3.8% (15/393) versus 1.4% (3/214)) was higherin the conversion group, although this was not significant.In addition, the rates of premature study discontinuation,overall adverse events (specifically infections), and biopsy-proven acute liver graft rejection at 12 months were allsignificantly higher in the conversion group compared to thegroup continuing with CNIs [38]. Unfortunately, it was notuntil recently that the complete data that led to thesewarningswere published [45] allowing them to be properly scrutinized[46]. Notwithstanding the warnings, the Scientific Registryof Transplant Recipients (SRTR) indicates that between 1999and 2008 in the US, sirolimus and everolimus were used in8.8% and 0.2% of liver transplant recipients, respectively, asmaintenance therapy from the period of discharge to 1 yearafter transplantation [47]. Given the large amount of dataavailable on the use of mTOR inhibitors in liver transplanta-tion and the controversy surrounding the black boxwarnings,we have revisited the use of mTOR inhibitors in liver trans-plantation. To this end, we searched the literature from 2001to 2012 to determine whether the clinical evidence supportsa role for this class of immunosuppression with respect toefficacy, safety, and the ability to address unmet clinical needs.

Journal of Transplantation 3

Cell membrane

Interleukin-15Interleukin-2

Anti-CD25mAb

Anti-CD154mAb

Sirolimus,everolimus

CTLA-4-lg

Antigen

CalcineurinMAP kinases

IKK

NFAT AP-1 NF-𝜅B

Costimulation

Antigen-presenting cell

T cell

MHC/peptides

Signal 1

Signal 2

Signal 3

TCR/CD3

PI-3K

Nucleus mRNA

JAK3JAK3

PI-3K

PI-3K

Nucleotidesynthesis

G2Cellcycle

S

M

G1

mTORSynap

se

JAK3

Anti-CD3mAb

inhibitor

MPA

CD52(depletion)

Cellmembrane

Cyclosporine,tacrolimus

CD80, 86

CD154

CD25CD40

CD28

Anti-CD52mAb

CDK/cyclins

Azathioprine

Figure 1: Sites of action of immunosuppressive drugs (adapted from [33] with permission).

2. Methods

2.1. Identification of Published Clinical Data regarding the UseofmTOR Inhibitors in Liver Transplantation. We searched thebibliographic database, PubMed, for studies published fromJanuary 2001 to April 2012.The following search criteria wereused in the PubMed search: “everolimus liver transplanta-tion” OR “sirolimus liver transplantation” OR “everolimusliver transplant” OR “sirolimus liver transplant.” Prospec-tive or retrospective clinical studies and reviews of singletransplantation centers were considered. We only includedstudies that met the following criteria: (1) focus on adultliver transplant recipients receiving immunosuppressionwithmTOR inhibitors, (2) publication in English, and (3) a patientsample size of at least 𝑛 = 7 in the mTOR inhibitortreatment group. The studies identified were not subjectedto a systematic review but are summarized and discussedbased on the combined clinical experience of the authors. DrKlintmalm has been involved in the use of mTOR inhibitorsin over 1,500 patients at the Simmons Transplantation Insti-tute at Baylor University Medical Center, including 650 livertransplant recipients converted to an mTOR inhibitor, 525liver transplant recipients who received de novo therapy, andover 375 kidney transplant recipients. Professor Nashan hasbeen using mTOR inhibitors (both de novo and conversion)in liver and renal transplantation for the last 17 years and inthat time has been involved in numerous key clinical trials ofmTOR inhibitors for both indications.

2.2. Identification of Pertinent Studies Presented at RecentLiver Transplant Congresses. Weretrieved abstracts reporting

results from trials pertaining to liver transplantation andeverolimus or sirolimus that were presented at the followingcongresses: the American Transplant Congress, 2011; The62nd and 63rdAnnualMeetings of the AmericanAssociationfor the Study of Liver Diseases (AASLD), 2011 and 2012; 15thCongress of the European Society for Organ Transplantation,2011; 23rd International Congress of the TransplantationSociety, 2010; the 2011 Joint International Congress of theInternational Liver Transplantation Society (ILTS); the Euro-pean Liver and Intestine Transplant Association; the LiverIntensive Care Group of Europe.

2.3. Identification of Ongoing Clinical Trials on the Useof mTOR Inhibitors in Liver Transplantation. The onlinedatabase ClinicalTrials.gov was searched for ongoing clinicaltrials investigating mTOR inhibitors in liver transplantation.

2.4. Organization of Studies by Dosage Level and DosingStrategy. We divided the studies according to their statedmode of mTOR inhibitor administration, that is, de novo(given from the time of transplantation) or conversion(where liver transplant recipients were converted to anmTORinhibitor). In a small number of studies mTOR inhibitorswere not given de novo but at some point after transplantationwithout the previous immunosuppression being stated; theseare termedmaintenance.We further classified the conversionstudies according to whether sirolimus or everolimus wasstarted “early” or “late,” because evidence suggests that thetimepoint at which conversion takes place has an impacton renal function [10]. NODM and hypertension are alsoassociated with the use of CNIs (see Introduction 1), so


early conversion would also be expected to have a positiveimpact on these endpoints. We defined early conversion asadministration of anmTOR inhibitor at 3months or less aftertransplant and late conversion as conversion after 3 monthsafter transplant, in line with other studies [48–50]. All studieswere also classified according to a scoring system taking intoaccount mTOR inhibitor dosage level and the strength ofthe study design. Dosage level was included in the scoringsystem since serious adverse events appear to be associatedwith higher doses of sirolimus and everolimus [44, 45, 51, 52].We therefore based our dosage cut-off points on levels thatare associated with less serious adverse events [46, 52]. For denovo and maintenance studies, the following criteria scoredone point each: (a) inclusion of a control arm; (b) sirolimusor everolimus dose of ≤2mg/day; and (c) serum levels of≤10 ng/mL for sirolimus or ≤12 ng/mL for everolimus. Inthe case of conversion studies, the following criteria scoredone point each: (a) a predefined conversion timepoint of ≤3months after transplantation; (b) inclusion of a control arm;(c) specified dose of mTOR inhibitor (see above); and (d)specified serum level of mTOR inhibitor (see above). Thestudies were then classified as low (0-1 point), medium (2points), or high (≥3 points) quality.

3. Results

Our literature search retrieved 40 studies on sirolimus useand 16 studies on everolimus use (Tables 1(a)–1(d)). Weanalyzed these studies according to renal function, efficacy,safety, metabolic syndrome, HCC, neurological symptoms,HCV recurrence/fibrosis progression, and de novo tumors.

3.1. Efficacy of mTOR Inhibitors

3.1.1. Sirolimus. A retrospective study evaluating the use of denovo sirolimus versus CNIs found that patients who receivedsirolimus (𝑛 = 252) exhibited similar rates of patient and graftsurvival in comparison to liver transplant recipients receivingCNIs (𝑛 = 291). The percentage of patients who developedacute cellular rejection or those with BPAR was significantlylower in patients receiving sirolimus compared with thoseon CNIs (Table 2(a)) [53]. In a large retrospective studythat included de novo sirolimus use in liver transplantationcompared with a CNI control group there were no significantdifferences in rates of mortality or graft loss during the firstyear after liver transplant (Table 2(a)) [54].

In a high quality retrospective study assessing conversion(early versus late conversion), rejection rates in the sirolimusgroups (early conversion: 35%; late conversion: 38%) werecomparable to those in the CNI group (43%) [48]. In anotherretrospective study assessing conversion (medium quality),BPAR among patients converted at various times was 3.4%[67], while a medium quality review of a prospectivelymaintained database revealed an acute cellular rejection rateof 17.2% for those treated de novo with sirolimus versus 2.8%for those converted at various timepoints to sirolimus inresponse to rising serum creatinine concentrations [69].

Two single-arm prospective studies and one random-ized study (Table 2(a)) have shown that late conversion tosirolimus in liver transplant recipients is associated withgenerally low rates of acute rejection: 4.8% [83], 6.7% [82]and 7.7% [78]. In addition, a high quality retrospective studydemonstrated low rates of acute rejection: 5% among patientsconverted to sirolimus versus 4% for matched control groupmaintained on reduced-dose CNIs alone [72]. However, in alarge, prospective randomized trial in which liver transplantrecipients were converted late (more than 50% of patients ineach group entered the study at least 3 years posttransplan-tation) and abruptly (within 24 hours) from CNI treatmentto sirolimus, there were detrimental effects on efficacy andsafety, suggesting that an overlap period is necessary [45].The rate of BPAR (11.7% versus 6.1%) at 12 months afterrandomization (𝑃 = 0.02) and overall treatment failure (acutecellular rejection or discontinuation; 48.3% versus 26.7%;𝑃 < 0.001) was significantly higher in the sirolimus groupcompared to the control group who received CNI for upto 6 years. In addition, significantly more patients in thesirolimus group experienced ≥1 treatment-emergent adverseevent during the study compared to the CNI group (𝑃 =0.005) [45].

3.1.2. Everolimus. In a study in which de novo liver transplantrecipients were randomized to receive cyclosporine pluseverolimus (𝑛 = 89) at either 1, 2 or 4mg per day, BPAR rateswere 32.1%, 26.7%, and 25.8%, respectively, versus 40% forthe 30 patients receiving cyclosporine plus placebo, althoughthis difference was not significant [52]. There was evidenceof a dose relationship for treated acute rejection throughoutthe double-blind study period, with higher rates of acuterejection observed in patients on lower doses of everolimus(particularly the lowest dose of 1mg/day). In this study, therewere few deaths with patient survival reported as 83.3%,82.1%, 96.7%, and 87.1% in liver transplant recipients whoreceived placebo or everolimus at 1, 2, or 4mg per dayrespectively; no deaths were considered to be treatment-related [52]. Rejection rates at 1 year after transplantation ina prospective, randomized study in which patients receivedeither de novo everolimus or tacrolimus were 11% versus 3%,respectively [88]. In a high quality maintenance study inwhich liver transplant recipients were randomized at 1 monthafter transplant to either everolimus-facilitated eliminationof tacrolimus, everolimus-facilitated reduction of tacrolimus,or standard-dose tacrolimus, withdrawing tacrolimus didnot provide sufficient efficacy with a BPAR rate of 19.9%(although everolimus did allow substantial tacrolimus reduc-tion in de novo liver transplant recipients while resulting in asignificantly lower rate of BPAR at 1 year) [87].

In five early conversion studies (Table 2(b)), all of whichwere high quality, prospective, randomized trials, efficacywaseither similar to [50, 89, 91] or better than [87, 90] controlgroups. One of these investigated whether everolimus couldbe used to withdraw or reduce immunosuppression withtacrolimus in de novo liver transplant recipients [87]. Theresults of this study showed that withdrawing tacrolimus didnot provide sufficient efficacy with a BPAR rate of 19.9%.


Table1:(a)Sirolim

ustrials(den

ovoa

ndmaintenance

dosin

g)retrievedfro

mPu

bMed/con

gresssearch,(b)siro

limus

conversio

ntrialsretrievedfro

mPu

bMed/con

gresssearch,(c)everolim

ustrials(den

ovodo

sing)

retrievedfro

mPu

bMed/con

gresssearch,(d)e

verolim

usconversio

ntrialsretrievedfro

mPu

bMed/con

gresssearch.

(a)

Participants

Stud

ydesig

naDurationof

study

Sirolim

usdo

sing

Streng

thof

study

desig

nbased

ondefin

edcriteria

b

Den

ovodo

sing

Chinnakotla

etal.LiverTran

spl.

2009;15:1834–4

2[55]

𝑁=227recipients

(i)𝑛=121(SRL

)(ii)𝑛=106(TAC

)R/P

5years

2mgorally,

once

daily.Levels

maintained

at5–8n

g/mLforthe

first3mon

thsa

ndat

5ng/mLthereafte

rHigh

Asthanae

tal.Ca

nJ

Gastro

enterol.2011;25:28–34

[56]

𝑁=141recipients

(i)𝑛=88

(den

ovoSR

L)(ii)𝑛=53

(CNI)

R12

mon

ths

Maintainedat8–12ng

/mL

Medium

McK

enna

etal.A

mJT

ranspl.

2011;11:2379–87[57]

𝑁=455recipients

(HCV

-positive)

(i)𝑛=173(SRL

)(ii)𝑛=282(SRL

-free)

R/P

2years

2mgdaily

with

outa

loadingdo

sebeginn

ingon

thefi

rstp

ostoperativ

eday

Medium

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tal.Int

Immun

opharm

acol.2010;10:

990–

3[58]

𝑁=67

recipients

(HCV

-positive)

(i)𝑛=39

(SRL

)(ii)𝑛=28

(CNI)

P,C

12mon

ths

Trou

ghlevelswerem

aintainedbetween3

and8n

g/mL

Medium

Zhou

etal.TransplantP

roc.2008;

40:3548–553[59]

𝑁=73

recipients(H

CCexceedingMilancriteria

)(i)𝑛=27

(SRL

)(ii)𝑛=46

(TAC

)

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Given

1mon

thaft

ertransplant:initia

ldo

seof

3mg/m

2adjuste

dover

timeto

achieves

teady-sta

tetro

ughlevelsof

≈5–8n

g/mL

Medium

Asthanae

tal.Presentedat

AASLD2011(A

bstract184)[60]

𝑁=100recipients(recurrent

HCV

)(i)𝑛=40

(SRL

)(ii)𝑛=35

(TAC

)(iii)𝑛=24

(cyclosporine)

(iv)𝑛=36

lostto

follo

wup

P,C

Medianof

77.6

mon

ths

Not

stated

Low


(a)Con

tinued.

Participants

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ydesig

naDurationof

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Sirolim

usdo

sing

Streng

thof

study

desig

nbased

ondefin

edcriteria

b

Campsen

etal.J

Tran

splant.2011;

2011:913094[54]

𝑁=672recipients

(i)𝑛=328(C

NI+

MPS

attim

eof

discharge)

(ii)𝑛=135(C

NI+

MPS

attim

eof

discharge;SR

Laddedwith

inthefi

rst6

mon

thsa

ndcontinued

throug

hthefi

rstyear)

(iii)𝑛=15

(CNI+

MPS

attim

eof

discharge;SR

Lwas

added

with

inthefi

rst6

mon

thsa

nddiscon

tinuedbefore

thefi

rst

year)

(iv)𝑛=156(SRL

asprim

ary

immun

osup

pressio

n)(v)𝑛=38

(SRL

asprim

ary

immun

osup

pressio

nand

discon

tinuedbefore

thefi

rst

year)

R1y

ear

Not

stated

Low

Dun

kelbergetal.LiverTran

spl.

2003;9:463–8

[61]

𝑁=350recipients

(i)𝑛=170(SRL

)(ii)𝑛=180(historiccontrols)

R12

mon

ths

6mgon

day0,and2m

g/daythereafte

rno

targetlevelw

asspecified

Low

Jiménez-Rom

eroetal.

Hepatogastro

enterology.2011;58:

115–21

[62]

𝑁=16

recipientswho

developed

denovo

tumors

Allsw

itchedfro

mCN

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toSR

Lmon

otherapy

P,S

Meanof

15.7mon

ths

Loadingdo

se:4

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wed

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until

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seadjuste

dto

achievetargetb

lood

levelof

5–10ng

/mL

Low

Knetem

anetal.LiverTran

spl.

2004;10:1301–11[63]

𝑁=40

recipients(H

CC)

AllgivenSR

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4years

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dto

achievetargetlevels

of12–20n

g/mL

Low

Maram

attom

and

Wijd

icksNe

urology.2004;63:

1958–9

[64]

𝑁=202recipients

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mon

ths

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se:6

mg,thereafte

r:1–10mg/daywith

targetbloo

dlevelof

8–15ng

/mL

Low

Molinarietal.Tran

splIntl.2010;

23:155–6

8[53]

𝑁=543recipients

(i)𝑛=252(SRL

)(ii)𝑛=291(C

NI)

R5years

Orald

osea

djustedto

keep

theb

lood

levelsin

ther

ange

of10–15n

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ring

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rst3–6

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ndthen

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rangeo

f5–10n

g/mLaft

erwards

Low

Toso

etal.H

epatology.2010;51:

1237–4

3[65]

𝑁=2491

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Wiesner

etal.A

mJT

ransplant.

2002;2

(s3):464

(Abstract1294)

[44]

𝑁=163recipients

(i)𝑛=111(SRL

+Cs

A)

(ii)𝑛=52

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centratio

n-controlledTA

C(tr

ough

levels5–15ng

/mL)

+corticosteroids)

P,Ra

6mon

ths

Fixed-do

seof

5mg/day

Low

Zimmerman

etal.LiverTran

spl.

2008;14:633–8[15]

𝑁=97

recipients(cirr

hosis

+concom

itant

HCC

)(i)𝑛=45

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)(ii)𝑛=52

(stand

ardregimen

inclu

ding

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MF,and

corticosteroids)

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w

Com

binatio

nof

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andmaintenance

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g

Kazimietal.Tran

splantation.

2010;90(2S):697

(Abstract1950)

[66]

𝑁=114recipients

(i)𝑛=65

(SRL

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(CNI)

R1111±800days

Not

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Participants

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thof

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desig

nbased

oncriteria

b

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)

Rogersetal.C

linTran

splant.

2009;23:887–96

[48]

𝑁=82

recipients

(i)𝑛=42

(SRL

)(ii)𝑛=40

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mon

ths

TargetSR

Llevelsforthe

firstthree

mon

thsa

fterc

onversionwere8

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onths3

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5–6n

g/dL

after

mon

th12

High

Harpere

tal.Tran

splantation.

2011;91:128–32

[67]

𝑁=148recipients

Allconvertedto

SRL

RMedianof

1006

days

Con

versionfro

mCN

ItoSR

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rmed

with

anoverlap

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enna

etal.ILT

S.2011

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-17)

[68]

𝑁=1078

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(i)𝑛=202(SRL

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stated

Medium

8 Journal of Transplantation(b)Con

tinued.

Participants

Stud

ydesig

naDurationof

study

Sirolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

Schleicher

etal.TransplantP

roc.

2010;42:2572–5

[49]

𝑁=57

recipients

(i)𝑛=11

(earlyconversio

n,im

paire

dperio

perativ

erenal

functio

n;SR

L=7,EV

L=4)

(ii)𝑛=7(earlyconversio

n,no

rmalperio

perativ

erenal

functio

n;SR

L=6,EV

L=1)

(iii)𝑛=23

(lateconversio

n,im

paire

dperio

perativ

erenal

functio

n,SR

L=15,E

VL=8)

(iv)𝑛=16

(lateconversio

n,no

rmalperio

perativ

erenal

functio

n;SR

L=12,E

VL=4)

R12

mon

ths

Initialdo

seof

10mg/day.Doses

were

adjuste

dsuccessiv

elyto

maintaintro

ugh

levelsof

5–10ng

/mL

Medium

Sancheze

tal.Tran

splant

Proc.

2005;37:44

16–23[69]

𝑁=64

recipients

(i)𝑛=29

(denovoSR

L)(ii)𝑛=35

(con

versionSR

L)P,C

2years

Inrecipientswith

HCC

orautoim

mun

edisorders,SR

Ldo

sesu

sedweretypically

either

a5mgor

3mgloadingdo

sefollo

wed

by2m

geach

day

Afte

rcon

version,

SRLlevelswere

maintainedat10–15n

g/mLwhenused

with

in3mon

thso

ftransplantatio

nandat

5–10ng

/mLaft

er3mon

thsa

fter

transplantation

Medium

Forgacse

tal.Tran

splant

Proc.

2005;37:1912–4

[70]

𝑁=7recipients

Allconvertedto

SRL

RUpto

425days

Not

stated

Low

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)

Campb

elletal.Clin

Tran

splant.

2007;21:377–84

[71]

𝑁=179recipients

(i)𝑛=79

(SRL

conversio

n)(ii)𝑛=100(C

NIcon

trols)

RMedianof

359days

2mgdaily,dosea

djustedun

tiltarget

levelsof

5–8n

g/mLachieved

High

DuB

ayetal.LiverTran

spl.2008;

14:651–9

[72]

𝑁=114recipients(w

ithrenal

insufficiency)

(i)𝑛=57

(SRL

)(ii)𝑛=47

(low-doseC

NIs)

R12

mon

ths

Recipientson

CNIm

onotherapy

were

startedon

SRL1m

g/dayandtheC

NI

dose

was

halved.A

t1week,theC

NIw

assto

pped,and

theS

RLdo

sewas

adjuste

don

theb

asisof

thes

erum

levels.

For

recipientson

combinatio

ntherapy,the

CNIw

assto

pped,and

SRLwas

started

onthes

amed

ayat2m

g/daywhilethe

antim

etabolite

orste

roid

dosesw

ere

maintainedattheirc

urrent

levels.

Inbo

thgrou

pstheS

RLdo

sewas

adjuste

dto

maintaintro

ughlevelsof

5–15𝜇g/day

High


(b)Con

tinued.

Participants

Stud

ydesig

naDurationof

study

Sirolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

Herlenius

etal.TransplantP

roc.

2010;42:44

41–8

[73]

𝑁=25

recipients(w

ithchronic

kidn

eydisease)

(i)𝑛=12

(SRL

)(ii)𝑛=13

(MMF)

P,Ra

12mon

ths

Asin

gleb

olus

dose

of10mgSR

Lfollo

wed

bythreec

onsecutiv

edailydo

seso

f8mg.

Targettro

ughconcentrationof

10ng

/mL

Medium

Lam

etal.D

igDisSci.2004;49:

1029–35[74]

𝑁=28

recipients(w

ithrenal

insufficiency

after

transplantation)

Allconvertedto

SRL

P,S

Meanof328±57

days

SRLinitiated

at2m

g/day.Doses

adjuste

dto

achievetargetlevelof

4–10ng

/mL

Medium

Morardetal.LiverTran

spl.2007;

13:658–6

4[75]

𝑁=48

recipients

(i)𝑛=16

(SRL

)(ii)𝑛=19

(SRL

+MMF)

(iii)𝑛=7(SRL

+prednisone)

(iv)𝑛=2(SRL

+CN

I)(v)𝑛=4(SRL

+MMF+

prednisone)

RMedianof22.6±11

mon

ths

Loadingdo

se:6

mg(day

1)follo

wed

by2m

g/day(day

2–7).SRL

dose

adjuste

dto

maintaintro

ughlevelsof

5–10ng

/mL

Medium

Shenoy

etal.Transplantatio

n.2007;83:1389–92[76]

𝑁=40

recipients(w

ithrenal

dysfu

nctio

n)(i)𝑛=20

(SRL

)(ii)𝑛=20

(CNI)

P,Ra

12mon

ths

5mgloadingdo

se,followed

by3m

gSR

Lon

cedaily.L

evels

maintained6–

10ng

/mL

Medium

Uhlmannetal.E

xpClin

Tran

splant.2012;10:30–

8[77]𝑁=25

recipients

Allconvertedto

SRL

P,S

75.6mon

ths

SRLsta

rted

at1m

g/day,do

seadjuste

dto

maintaintro

ughlevelsat69

ng/m

LMedium

Watsonetal.LiverTran

spl.2007;

13:1694–

702[78]

𝑁=27

recipients

(i)𝑛=13

(SRL

)(ii)𝑛=14

(CNI)

P,Ra

12mon

ths

CNIw

asdiscon

tinuedthee

vening

before

conversio

n,andrecipientsweres

tarted

on2m

g/daySR

Lon

thefollowingday.

Targetrangeo

f5–15n

g/mL

Medium

Steinetal.P

resented

atthe

American

Transplant

Con

gress

2011(A

bstract8

17)[79]

𝑁=40

recipients(received

transplant

forH

CV)

(i)𝑛=18

(SRL

conversio

n)(ii)𝑛=22

(TAC

)

R5years

Not

stated

Low

Vivarelli

etal.TransplantP

roc.

2010;42:2579–8

4[80]

𝑁=78

recipients

(i)𝑛=38

(SRL

)(ii)𝑛=40

(SRL

+CN

I)R

510±366days

5mg/m

2for1stday,then

2mg/daily,

adjuste

dto

troug

hbloo

dlevel<

10ng

/mL

Low

DiB

enedetto

etal.Transplant

Proc.200

9;41:1297–9[81]

𝑁=31

recipients

Allconvertedto

SRL

RMeanof

27.5mon

ths

(range:2–71.2

mon

ths)

SRLataloading

dose

of0.1m

g/kg

onday

1ofthe

switch,then

0.05

mg/kg

forthe

next

fewdays.D

osea

djustedto

maintain

troug

hlevelsof

8–10ng

/mL

Low


(b)Con

tinued.

Participants

Stud

ydesig

naDurationof

study

Sirolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

Abdelm

alek

etal.A

mJ

Tran

splant.2012;12:694–705

[45]

𝑁=607recipients

(i)𝑛=393(SRL

conversio

n)(ii)𝑛=214(C

NIcon

tinuatio

n)P,Ra

Upto

6years

Loadingdo

seof

SRL:10–15m

g.Firstd

ose

given≥4h

after

thelastC

NId

ose;second

dosesg

iven

12hlater.Onstu

dydays

2–6,

SRLdo

seso

f3–5

mg/daywereg

iven.

Thereafter,SR

Ldo

sesm

aintainedto

achieveb

lood

levelsof

6–16ng

/mL

(chrom

atograph

ic)a

ndsubsequentlyto

8–16ng

/mL(chrom

atograph

ic)o

r10–20n

g/mL(im

mun

oassay)

Low

Bäckman

etal.C

linTran

splant.

2006;20:336–

9[82]

𝑁=15

recipients

Allconvertedto

SRL

P,S

6mon

ths

Loadingdo

seof

15mgSR

Lon

days

1and

2,then

8mg/dayandadjuste

dto

achieve

troug

hlevelsof

13–22and10–22n

g/mL

Low

Fairb

anks

etal.LiverTran

spl.

2003;9:1079–

85[83]

𝑁=21

recipients(develop

edrenald

ysfunctio

nwhileon

CNI

therapy)

Allconvertedto

SRL

P,S

Meanof66.8±38.9

weeks

Initially1-2

mg/dayandincreasedweekly

by1m

gto

achievetherapeuticlevels

(9–12n

g/mL)

Low

Naire

tal.LiverT

ranspl.2003;9:

126–

9[84]

𝑁=16

recipients

Allconvertedto

SRL

R6mon

ths

Loadingdo

seof

5mgon

day1,follo

wed

by2m

g/day.Atro

ughlevelof

5–10ng

/mLwas

maintained

Low

Neff

etal.TransplantP

roc.2003;

35:3029–

31[85]

𝑁=14

recipients

Allconvertedto

SRL

R90

days

Meansta

rtingdo

seof

SRL(10m

g/day)

adjuste

dto

maintaintro

ughlevelsof

8–12ng

/mLdu

ringfirstmon

thand

subsequently3–5n

g/mLforrecipientso

nmaintenance

combinatio

ntherapywith

SRL

Low

Wadeietal.Transplantatio

n.2012;93:1006–12[86]

𝑁=102recipients

Allconvertedto

SRL

RMedianof

3.1y

ears

CNId

oser

educed

by50%un

tiltarget

SRLlevelof8–12n

g/mLachieved

Low

Search

term

swere“sirolim

usliver

transplantation”

OR“siro

limus

liver

transplant.”

CNI:calcineurin

inhibitor;HCC

:hepatocellularc

arcino

ma;HCV

:hepatitisC

virus;ILTS

:2011Joint

InternationalC

ongresso

fthe

InternationalL

iver

TransplantationSo

ciety;MMF:mycop

heno

latem

ofetil;SR

L:sirolim

us;TAC

:tacrolim

us.

a Study

desig

n:C:

coho

rt;P

:prospectiv

e;R:

retro

spectiv

e;Ra

:rando

mized;S:single-arm.

b See

Section2ford

escriptio

nof

howcriteria

ared

efined.

Journal of Transplantation 11(c)

Participants

Stud

ydesig

naStud

ydu

ratio

nEv

erolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

DeS

imon

eetal.Am

JTransplant.

2012;12:3008–20[87]

𝑁=719recipients

(i)𝑛=245(EV

R+TA

C-RD

)(ii)𝑛

=231(EV

R+TA

C-WD)

(iii)𝑛=243(TAC

-SD)

P,Ra

12mon

ths

ForE

VR+TA

C-WD,E

VRinitiated

ata

dose

of1.0

mgb.i.d

.with

in24

hof

rand

omizationwith

thed

osea

djusted

from

day5on

ward,to

maintainC0

3–8n

g/mLun

tilmon

th4aft

ertransplantation,

after

which

thetarget

rang

eincreased

to6–

10ng

/mL

IntheE

VR+TA

C-RD

arm,EVRinitiated

andmon

itoredas

forE

VR+TA

C-WD,

butthe

initialtargetrangeo

f3–8

ng/m

Lmaintainedthroug

hout

thes

tudy

High

Grazietal.P

resented

atILTS

;2011(A

bstractP

-256)[88]

𝑁=64

recipients(H

CV-related

cirrho

sis)

(i)𝑛=28

(EVR+Bm

ab+

steroids)

(ii)𝑛=36

(TAC

+Bm

ab+

steroids)

P,Ra

1year

Not

stated

Low

Levy

etal.Liver

Transpl.2006;

12:164

0–8[52]

𝑁=119recipients

(i)𝑛=28

(EVR1.0

mg)

+CN

I(ii)𝑛=30

(EVR2.0m

g)+CN

I(iii)𝑛=31

(EVR4.0m

g)+CN

I(iv

)𝑛=30

(placebo

)+CN

I

P,Ra

36mon

ths

1,2or

4mg/day

Low

Search

term

swere“everolim

usliver

transplantation”

OR“everolim

usliver

transplant.”

Maintenance

therapyrefersto

immun

otherapy

forthe

lifetim

eofthe

graft

.Con

versiontherapyiswhere

liver

transplant

recipientswerew

ithdraw

nfro

mCN

Isandsw

itchedto

everolim

us.

Bmab:basiliximab;C

NI:calcineurin

inhibitor;EV

R:everolim

us;H

CV:hepatitisC

virus;SR

L:sirolim

us;TAC

:tacrolim

us.

a Study

desig

n:P:

prospective;R:

retro

spectiv

e;Ra

:rando

mized.

b See

Section2ford

escriptio

nof

howcriteria

ared

efined.

(d)

Participants

Stud

ydesig

naStud

ydu

ratio

nEv

erolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)

DeS

imon

eetal.Am

JTransplant.

2012;12:3008–20[87]

𝑁=719recipients

(i)𝑛=245(EVR+TA

C-RD

)(ii)𝑛=231(EV

R+TA

C-WD)

(iii)𝑛=243(TAC

-SD)

P,Ra

12mon

ths

ForE

VR+TA

C-WD,E

VRinitiated

ata

dose

of1.0

mgb.i.d

.with

in24

hof

rand

omizationwith

thed

osea

djusted

from

day5on

ward,to

maintainC0

3–8n

g/mLun

tilmon

th4aft

ertransplantation,

after

which

thetarget

rang

eincreased

to6–

10ng

/mL.

IntheE

VR+TA

C-RD

arm,EVRinitiated

andmon

itoredas

forE

VR+TA

C-WD,

butthe

initialtargetrangeo

f3–8

ng/m

Lmaintainedthroug

hout

thes

tudy

High


(d)Con

tinued.

Participants

Stud

ydesig

naStud

ydu

ratio

nEv

erolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

Fischere

tal.Am

JTransplant.

2012;12:1855–6

5[50]

𝑁=203recipientson

CNI

with

/out

corticosteroids

(i)𝑛=101(EVR)

(ii)𝑛=102(C

NIcon

tinuatio

n)

P,Ra

12mon

ths

EVRsta

rted

at1.5

mgb.i.d

.and

adjuste

dto

achievea

targettro

ughlevelof

5–12ng

/mL(8–12n

g/mLin

patie

ntso

ntre

atmentw

ithCs

A),whenCN

Iwas

taperedby

70%of

theinitia

lCNId

ose

High

Masettietal.A

mJT

ransplant.

2010;10:2252–6

2[89]

𝑁=78

recipients

(i)𝑛=52

(EVR)

(ii)𝑛=26

(CsA

)P,Ra

12mon

ths

Initialdo

se:2.0mg/day,tro

ughlevelof

6–10ng

/mL.WhenCs

Adiscon

tinued,

troug

hlevel:8–12ng

/mLun

tilendof

mon

th6and6–

10ng

/mLthereafte

r

High

Salib

aetal.AASLD2012

[90]

𝑁=719recipientsfro

mDe

Simon

eetal.Am

JTransplant.

2012

[40]

(i)𝑛=245(EVR+TA

C-RD

)(ii)𝑛=231(EVR+TA

C-WD)

(iii)𝑛=243(TAC

-SD)

P,Ra

24mon

ths

Samea

sDeS

imon

eetal.Am

JTran

splant.2012[40]

High

Schlitt

etal.A

ASLD2012

[91]

𝑁=81

recipientsfro

mFischere

tal.A

mJT

ransplant.2012

(i)𝑛=41

(EVRwith

/out

corticosteroids)

(ii)𝑛=40

(CNIw

ith/out

corticosteroids)

P,Ra

35mon

ths

Samea

sFisc

here

tal.Am

JTransplant.

2012

[43]

High

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)

Bilbao

etal.T

ransplantP

roc.

2009;41:2172–6

[92]

𝑁=25

recipients

Allconvertedto

EVR

RMeanof10±9

mon

ths

Inrefractory

rejection:

initialdo

se0.5m

g/12h.Trou

ghlevels5n

g/mL.Fo

rCN

I-relatedadversee

vents,EV

Rsta

rted

at0.5m

gon

ceor

twicea

day.Fo

rmalignancy,EV

Rintro

ducedat

0.5m

g/day,adjusting

troug

hlevelsto

<3n

g/mL

Medium

Casano

vase

tal.Tran

splant

Proc.

2011;43:2216–9

[93]

𝑁=35

recipients

Allconvertedto

EVR

P,S

Meanof

134mon

ths

Initialdo

se0.25

mg/12hforthe

first4

days.Targettroug

h3–5n

g/mL

Medium

Castr

oagudı́netal.LiverTran

spl.

2009;15:1792–7

[94]

𝑁=21

recipients(chron

icrenal

dysfu

nctio

n)Allconvertedto

EVR

P,S

Medianof

19.8

mon

ths

0.75

mgb.i.d

.,with

targettro

ughlevelsof

3–8n

g/mL

Medium


(d)Con

tinued.

Participants

Stud

ydesig

naStud

ydu

ratio

nEv

erolim

usdo

sing

Streng

thof

study

desig

nbased

oncriteria

b

DeS

imon

eetal.Tran

splInt.

2009;22:279–

86[95]

𝑁=40

recipients

P,S

12mon

ths

EVR1.5

mg/day.Trou

ghlevelof

3–8n

g/mL

Medium

DeS

imon

eetal.LiverT

ranspl.

2009;15:1262–9

[96]

𝑁=145recipients

(i)𝑛=72

(EVRtherapywith

CNIreductio

nor

discon

tinuatio

n)(ii)𝑛=73

(CNIcon

tinuatio

n)

P,Ra

12mon

ths

Initial:3

mg/day×2on

day1.Afte

rweek

2:EV

Rtro

ughlevelm

aintainedat

3–8n

g/mLdu

ringconcom

itant

CNI

administratio

nand6–

12ng

/mLifCN

Ielim

inated

Medium

Bilbao

etal.P

resented

atILTS

;2011(A

bstractP

-68)

[97]

𝑁=62

recipients

Allreceived

EVR

RMedianof

12mon

ths

EVRtro

ughlevelat∼

3ng/mL

Low

Salib

aetal.LiverT

ranspl.2011;

17:905–13[98]

𝑁=240maintenance

recipients

Allreceived

EVR

R12

mon

ths

Intro

ducedatmean2.4m

g/day.Th

emeantro

ughlevel=

7.3ng

/mLatmon

th1

and8.1n

g/mLatmon

th12

acrosstotal

popu

lation,

with

high

ervalues

inmon

otherapy

coho

rt(8.8ng

/mLat

mon

th12)

Low

Vallinetal.C

linTran

splant.2011;

25:660–9

[99]

𝑁=94

recipients

Allreceived

EVR

RMeanof12±7

mon

ths

Initialdo

se0.75–1.5mgb.i.d

.Troug

hadjuste

dto

3–8n

g/mL

Low

𝑃values

areincludedwhere

available.

Search

term

swere“everolim

usliver

transplantation”

OR“everolim

usliver

transplant.”

AASLD:A

nnualM

eetin

gsof

theA

merican

Associatio

nforthe

Stud

yof

LiverD

iseases;b.i.d.:twiced

aily;C

NI:calcineurin

inhibitor;Cs

A:cyclosporin

A;E

VR:

everolim

us;ILT

S:2011JointInternatio

nalC

ongress

oftheInternatio

nalL

iver

TransplantationSo

ciety;TA

C:tacrolim

us;TAC

-RD:reduced-dosetacrolim

us;TAC

-SD:stand

ard-do

setacrolim

us;TAC

-WD:tacrolim

uswith

draw

n.a Study

desig

n:P:

prospective;R:

retro

spectiv

e;Ra

:rando

mized;S:single-arm.

b See

Section2ford

escriptio

nof

howcriteria

ared

efined.


Table2:(a)E

fficacy

ofsirolim

us,(b)

efficacy

ofeverolim

us.

(a)

Patie

ntsurvivalrate(%

)Graftrejectionrate(%

)Ac

uter

ejectio

nrate(%

)BP

AR(%

)

Acutec

ellularrejectio

nrate

6mon

ths

1year

Crud

emortality

rate/10

00person

-mon

ths

Crud

egraft

failu

rerate/10

00person

-mon

ths

1year

(%)

ACR/1000

person

-mon

ths

Steroid-resistant

rejection/1000

person

-mon

ths

Den

ovodo

sing

Sancheze

tal.

Tran

splant

Proc.2005;

37:4416–

23[69]

17.2

Molinarietal.

Tran

splIntl.2010;23:

155–68

[53]

95versus

94(SRL

versus

CNI)

92versus

91(SRL

versus

CNI)

0versus

0(SRL

versus

CNI)

32.5versus

44.1(SRL

versus

CNI,

𝑃=0.03)

46.7versus

58.9(SRL

versus

CNI,

𝑃=0.003)

Campsen

etal.J

Tran

splant.2011;2011:

913094

[54]

∗Seefoo

tnotefor

grou

ps

2.39

(group

1),

1.96and3.88

(SRL

conversio

ngrou

ps2and3),

1.82and2.13

(SRL

denovo

grou

ps4and5).

AllNS

2.68

(group

1),

2.15

and3.88

(SRL

conversio

ngrou

ps2and3),

1.82and2.13

(SRL

denovo

grou

ps4and5).

AllNS

12.5(group

1),

13.4,12.9(SRL

conversio

ngrou

ps2,3,

𝑃=NSversus

control),

6.5,5.2

(SRL

denovo

grou

ps4,5;𝑃≤

0.0001,𝑃=

0.0007

versus

controls)

3.48

(group

1),

4.29,3.88(SRL

conversio

ngrou

ps2,3,

𝑃=0.03,𝑃=

NSversus

controls),1.58,

1.54(SRL

denovo

grou

ps4,

5;𝑃<

0.001,𝑃=0.04

versus

controls)

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)

DuB

ayetal.Liver

Tran

spl.2008;14:

651–9[72]

5versus

4(SRL

versus

control)

Shenoy

etal.

Tran

splantation.2007;

83:1389–

92[76]

5versus

5(SRL

versus

control)

Watsonetal.Liver

Tran

spl.2007;13:

1694–702

[78]

7.7versus

0(SRL

versus

CNI)

Journal of Transplantation 15(a)Con

tinued.

Patie

ntsurvivalrate(%


)Ac

uter

ejectio

nrate(%

)BP

AR(%

)

Acutec

ellularrejectio

nrate

6mon

ths

1year

Crud

emortality

rate/10

00person

-mon

ths

Crud

egraft

failu

rerate/10

00person

-mon

ths

1year

(%)

ACR/1000

person

-mon

ths

Steroid-resistant

rejection/1000

person

-mon

ths

Abdelm

alek

etal.A

mJT

ransplant.2012;12:

694–

705[45]

(Low

)

93.4versus

94.4(SRL

versus

CNI)

0versus

0(SRL

versus

CNI)

6.4versus

1.9(SRL

versus

CNI)

11.7versus

6.1

(SRL

versus

CNI,

𝑃=0.02)

Bäckman

etal.C

linTran

splant.200

6;20:

336–

9[82]

6.7

DiB

enedetto

etal.

Tran

splant

Proc.200

9;41:1297–9[81]

12.9

Fairb

anks

etal.Liver

Tran

spl.2003;9:

1079–85[83]

4.8

Naire

tal.Liver

Tran

spl.2003;9:

126–

9[84]

0

Con

versiontim

escompared

Rogersetal.Clin

Tran

splant.2009;23:

887–96

[48]

35,38,43

(early,

late

conversio

nSR

Land

CNI)

Varia

blec

onversiontim

es

Harpere

tal.

Tran

splantation.2011;

15;91:128–32

[67]

3.4

Sancheze

tal.

Tran

splant

Proc.2005;

37:4416–

23[69]

2.8

𝑃values

areincludedwhere

available.

ACR:

acutec

ellularrejectio

n;BP

AR:

biop

sy-provenacuter

ejectio

n;CN

I:calcineurin

inhibitor;NS:no

nsignificant;SR

L:sirolim

us.

∗Ke

yto

grou

ps:

(1)C

NI+

MPS

attim

eofd

ischarge.

(2)C

NI+

MPS

attim

eofd

ischarge;SR

Laddedwith

inthefi

rst6

mon

thsa

ndcontinuedthroug

hthefi

rstyear.

(3)C

NI+

MPS

attim

eofd

ischarge;SR

Lwas

addedwith

inthefi

rst6

mon

thsa

nddiscon

tinuedbefore

thefi

rstyear.

(4)S

RLas

prim

aryim

mun

osup

pressio

n.(5)S

RLas

prim

aryim

mun

osup

pressio

nanddiscon

tinuedbefore

thefi

rstyear.


(b)

Patie

ntsurvivalrate(%


)Ac

ute

rejectionrate

(%)

BPAR(%

)

6mon

ths

1year

Other

time

points

6mon

ths

1year

3years

6mon

ths

1year

Other

time

points

Den

ovo/maintenance

dosin

g

DeS

imon

eetal.Am

JTran

splant.2012;12:

3008–20[87]

96.3versus

97.5(EVR+

TAC-

RDversus

TAC-

SD,

𝑃=NS)

2.4versus

1.2(EVR+

TAC-

RDversus

TAC-

SD,

𝑃=NS)

4.1v

ersus10.7

(EVR+

TAC-

RDversus

TAC-

SD,

𝑃=0.005)

Grazietal.P

resented

atILTS

;2011(Ab

stract

P-256)

[88]

Levy

etal.Liver

Tran

spl.2006;12:

1640

–8[52]

(Low

)+CN

I

82.1,

96.7,

87.1

forE

VR1,2

and

4mg/day∗†

0,13.3and3.2

forE

VR1,2

and

4mg/day∗†

39.3,30.0and

29.0forE

VR

1,2and

4mg/day∗†

32.1,

26.7,

and

25.8forE

VR

1,2and,

4mg/day∗†

39.3,30.0,and

29.0forE

VR1,

2,and

4mg/day∗†at3

years

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)

Fischere

tal.Am

JTran

splant.2012;12:

1855–1865[50]

95.8versus

95.9(EVR

versus

CNI

controlat11

mon

ths,

𝑃=NS)

2.1v

ersus2

.0(EVRversus

CNIcon

trol

at11mon

ths)

17.7versus

15.3

(EVRversus

CNIcon

trolat11

mon

ths)

Schlitt

etal.A

ASLD

2012

[91]

95.7versus

90.0

(EVRversus

CNIcon

trolat

35mon

ths,

𝑃=NS)

24.4versus

15.8

(EVRversus

CNIcon

trolat

35mon

ths,

𝑃=NS)

Masettietal.A

mJ

Tran

splant.2010;10:

2252–6

2[89]

92.3versus

92.3(EVR

versus

CsA,

𝑃=NS)

90.4versus

88.5(EVR

versus

CsA,

𝑃=NS)

5.7at40–87

days

after

transplant

versus

7.7atdays

41–240

after

transplant

CsA

(𝑃=NS)

Journal of Transplantation 17(b)Con

tinued.

Patie

ntsurvivalrate(%


)Ac

ute

rejectionrate

(%)

BPAR(%

)

6mon

ths

1year

Other

time

points

6mon

ths

1year

3years

6mon

ths

1year

Other

time

points

DeS

imon

eetal.Am

JTran

splant.2012;12:

3008–3020[87]

96.5versus

96.3versus

97.5(TAC

elim

versus

EVR+

TAC-

RDversus

TAC-

SD)

2.2versus

2.4

versus

1.2(TAC

elim

versus

EVR+

TAC-

RDversus

TAC-

SD)

19.9versus

4.1

versus

10.7

(TAC

elim

versus

EVR+

TAC-

RDversus

TAC-

SD)

Salib

aetal.AASLD

2012

[90]

6.1v

ersus13.3;

delta

risk:−7.2

%(95%

CI:

−13.5%,−

0.9%

;𝑃=0.010.

EVR+

TAC-

RDversus

TAC-

SDat24

mon

ths)

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)

Casano

vase

tal.

Tran

splant

Proc.2011;

43:2216–

9[93]

94.3

Castr

oagudı́netal.

LiverT

ranspl.200

9;15:1792–7[94]

0

DeS

imon

eetal.

Tran

splInt.200

9;22:

279–

86[95]

100

015

DeS

imon

eetal.Liver

Tran

spl.2009;15:

1262–9

[96]

98.6versus

100(EVR

versus

CNI)

95.8versus

95.9(EVR

versus

CNI)

0versus

0(EVRversus

CNI)

1.4versus

1.4(EVRversus

CNI)

4.2versus

4.1

(EVRversus

CNI)

Salib

aetal.Liver

Tran

spl.2011;

17:

905–13

[98]

1.6

Vallinetal.C

linTran

splant.2011;25:

660–

9[99]

9

𝑃values

areincludedwhere

available;∗𝑃:not

significantfor

allefficacy-related

eventsversus

placebo;otherw

ise,w

here

notstated.

†Timepoint

refersto

timea

fterimmun

osup

pressio

nwas

initiated.

AASLD:Th

eLiverMeetin

g62n

dAnn

ualM

eetin

gofthe

American

Associatio

nforthe

Stud

yofLiverDise

ases;BPA

R:biop

sy-provenacuterejectio

n;Cs

A:cyclosporinA;C

NI:calcineurin

inhibitor;EV

R:everolim

us;

NS:no

nsignificant;TA

Celim;tacrolim

uselimination;

TAC-

RD:reduced

dose

tacrolim

us(C0:3–5n

g/mL);T

AC-SD:stand

ard-do

setacrolim

us(C0:6–

10ng

/mL).


However, everolimus did allow substantial tacrolimus reduc-tion in de novo liver transplant recipients while resulting in asignificantly lower rate of BPAR at 1 year (4.1% versus 10.7%:everolimus + reduced-dose tacrolimus versus standard-dosetacrolimus, 𝑃 = 0.005). The lower rate of BPAR wasmaintained at 24 months (6.1% versus 13.3%, 𝑃 = 0.010)[90]. In a second study, at 1 year there were similar rates ofpatient survival (95.8% versus 95.9%), graft loss (2.1% versus2.0%), and BPAR (17.7% versus 15.3%) in patients convertingto everolimus versus those remaining on CNI treatment [50].Similarly, in the extension phase of this study, at 35 monthstherewere similar rates of patient survival (EVR: 95.7%versusCNI: 90.0%, 𝑃 = 0.535), BPAR (24.4% versus 15.8%, 𝑃 =0.434), and efficacy failure (29.8% versus 28.2%, 𝑃 = 0.903)[91].

In four late-conversion studies (two prospective and tworetrospective; Table 2(b)), the incidence of BPAR up to 1 yearafter conversion was 1.6% [98], 2.8% [96], 9% [99] and 15%[95].

3.2. The Effect of mTOR Inhibitors on Renal Function

3.2.1. Sirolimus. In two large retrospective studies (one highquality and one low quality) in which patients receivedsirolimus as de novo therapy, there were reductions in theglomerular filtration rate (GFR) up to 1 year [54] or up to5 years after transplant [55]. In contrast, in a third de novo,retrospective (low quality) study, modest improvements inrenal function in patients receiving sirolimus were recordedat both 6 and 12months after transplant, with creatinine levelsdecreasing by 0.22 and 0.28 mg/dL, respectively, compared toincreases in creatinine of 0.61 and 0.35 mg/dL, respectively,in a control group receiving a standard immunosuppressionregimen [15] (Table 3(a)).

Four retrospective studies (two high quality and twomedium quality) reported renal function in liver transplantrecipients converted early to sirolimus from CNI treatment(Table 3(b)) [48, 49, 67, 68]. Two of these studies includeda control group. In the first retrospective study in which72 liver transplant recipients converted to sirolimus fromCNI treatment were stratified according to whether theyhad been converted


Table3:(a)E

ffecton

renalfun

ctionof

denovo

mTO

Rim

mun

osup

pressio

n(b)effecton

renalfun

ctionof

convertin

gto

sirolim

us(c)effecton

renalfun

ctionof

convertin

gto

everolim

us(d)

associationof

mTO

Rim

mun

osup

pressio

nwith

proteinu

ria.

(a)

mTO

Rinhibitor

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(m

g/dL

)afte

rcon

version

Change

inCr

Cl(m

L/min)

from

baselin

eat

postc

onversiontim

epoint

3mon

ths

6mon

ths

1year

2years

5years

6mon

ths

1year

6mon

ths

1year

Levy

etal.

Liver

Tran

spl.

2006;

12:

1640

–8[52]

EVR

EVR:

1,2,and

4mg/day

versus

placebo:

−18.7,−36.5,

and−33.2

versus−37

EVR:

1,2,and

4mg/dayversus

placebo:−20.2,

−43.0,and−36.9

versus−36.9

Chinnakotla

etal.

Liver

Tran

spl.

2009;

15:1834–

1842

[55]

SRL

−46

.5versus

−41.0(SRL

versus

TAC)

−39.5versus

−30.0(SRL

versus

TAC)

−43.5versus

−31.5(SRL

versus

TAC)

−38.5versus

−37.0(SRL

versus

TAC)

Campsen

etal.

JTran

splant.2

011;2011:

913094

[54]

SRL

−2.85

versus−9.6

6(C

NIv

ersusS

RL,

𝑃=0.0465)

−6.29

versus

−13.32

(CNI

versus

SRL,

𝑃=0.0320)

Zimmerman

etal.

Liver

Tran

spl.

2008;

14:633–8

[15]

SRL

−0.22

versus

+0.61(SR

Lversus

CNIs,

𝑃=0.0021)

−0.28

versus

+0.35(SRL

versus

CNIs,

𝑃<0.0001)

𝑃values

areincludedwhere

available.

CNI:calcineurin

inhibitor;Cr

Cl:creatininec

learance;E

VR:

everolim

us;G

FR:glomerular

filtrationrate;m

TOR:

mam

maliantargetof

rapamycin;SRL

:siro

limus;TAC

:tacrolim

us.

(b)

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇m/L)a

fterc

onversion

Change

in24

hCr

Cl(m

L/min)a

fterc

onversion

3mo

6mo

1year

2years

3years

1mo

3mo

6mo

1year

2years

3years

3mo

1year

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)

McK

enna

etal.

ILTS

.2011

(AbstractO

-17)

[68]


(b)Con

tinued.

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇m/L)a

fterc

onversion

Change

in24

hCr

Cl(m

L/min)a

fterc

onversion

3mo

6mo

1year

2years

3years

1mo

3mo

6mo

1year

2years

3years

3mo

1year

Rogersetal.C

linTran

splant.2009;

23:887–9

6[48]

+29.7

versus

+18.5

(early

versus

latec

on-

version,

𝑃<0.05)

+28.7

versus

+12.4

(early

versus

latec

on-

version,

𝑃<0.05)

+25.5versus

+14.7(early

versus

late

conversio

n,𝑃<0.05)

Harpere

tal.

Tran

splantation.

2011;91:128–32

[67]

+10.6versus

baselin

e(𝑃<0.05)

Schleicher

etal.

Tran

splant

Proc.

2010;42:2572–5

[49]

+15

versus

+9(early

versus

latec

on-

version,

𝑃=0.04)

+16

versus

+10(early

versus

latec

on-

version,

𝑃=0.05)

+22†

versus

+12†

(early

versus

late

conversio

n,𝑃=0.04)

−0.7‡

(early

conversio

nversus

baselin

e,𝑃=0.01)

−0.6‡

(late

conversio

nversus

baselin

e,𝑃=0.05)

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)

Campb

elletal.

Clin

Tran

splant.

2007;21:377–84

[71]

0‡(SRL

versus

CNI)

DiB

enedetto

etal.

Tran

splant

Proc.

2009;41:1297–9

[81]

DuB

ayetal.Liver

Tran

spl.2008;14:

651–9[72]

Journal of Transplantation 21(b)Con

tinued.

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇m/L)a

fterc

onversion

Change

in24

hCr

Cl(m

L/min)a

fterc

onversion

3mo

6mo

1year

2years

3years

1mo

3mo

6mo

1year

2years

3years

3mo

1year

Herlenius

etal.

Tran

splant

Proc.

2010;42:44

41–8

[73]

+12versus

baselin

e(𝑃=0.03)

Lam

etal.D

igDis

Sci.2004;49:

1029–35[74]

−0.32‡

versus

baselin

e(𝑃=0.029)

+0.12‡,

versus

baselin

e(𝑃=NS)

Sancheze

tal.

Tran

splant

Proc.

2005;37:44

16–23

[69]

+8.2,

𝑃=0.05

versus

case

control

+20.2,NS

versus

case

control

+16.1,NS

versus

case

control

−0.1

00

Shenoy

etal.

Tran

splantation.

2007;83:1389-92

[76]

+12versus

−4,NS

versus

CNI

Uhlmannetal.

ExpC

linTran

splant.2012;

10:30–

8[77]

+11.9

versus

baselin

e(𝑃<0.05)

−27

versus

baselin

e(𝑃<0.05)

Watsonetal.Liver

Tran

spl.2007;13:

1694–702

[78]

+7.7

versus

baselin

e(𝑃=0.001)

+6.1versus

baselin

e(𝑃=0.024)

Abdelm

alek

etal.

AmJT

ransplant.

2012;12:694–

705

[45]

−4.45

versus

−3.07

(SRL

versus

CNI,

𝑃=0.34)

Bäckman

etal.

Clin

Tran

splant.

2006;20:336–

9[82]

+6.4

(𝑃=NS

from

baselin

e)

Fairb

anks

etal.

LiverT

ranspl.2003;

9:1079–85[83]

+9∗versus

baselin

e(𝑃=0.01)

22 Journal of Transplantation(b)Con

tinued.

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇m/L)a

fterc

onversion

Change

in24

hCr

Cl(m

L/min)a

fterc

onversion

3mo

6mo

1year

2years

3years

1mo

3mo

6mo

1year

2years

3years

3mo

1year

Naire

tal.Liver

Tran

spl.2003;9:

126–

9[84]

−0.45‡

versus

baselin

e(𝑃=0.001)

Neff

etal.

Tran

splant

Proc.

2003;35:3029–31

[85]

+11.3

versus

baselin

e

Vivarelli

etal.

Tran

splant

Proc.

2010;42:2579–8

4[80]

+18

versus

baselin

e†

+19

versus

baselin

e†+19versus

baselin

e†

Wadeietal.

Tran

splantation.

2012;93:1006–12

[86]

+3.5†versus

baselin

e(𝑃=0.03)

−0.1v

ersus

baselin

e(𝑃=0.25)

𝑃values

areincludedwhere

available.

∗MedianeG

FR,m

eanof

67weeks;†mL/min;‡mg/dL

.CN

I:calcineurin

inhibitor;Cr

Cl:creatininec

learance;G

FR:glomerular

filtrationrate;m

o:mon

th;N

S:no

nsignificant;SR

L:sirolim

us.

(c)

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇mol/L)a

fterc

onversion

Change

inCr

Cl(m

L/min)

from

baselin

eatp

ostcon

version

timep

oint

6mon

ths

1year

Other

timep

oints

3mon

ths

6mon

ths

1year

6mon

ths

1year

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)

Fischere

tal.Am

JTran

splant.2012;

12:1855–65

[50]

11-mon

thdata(EVR

versus

CNI):

CG-G

FR:m

eanchange

from

baselin

e:+4.4±27.1

versus0.9±29.2

LSmeandifference±

SE:

−2.923±

3.920(𝑃=0.457 )

§

MDRD

-GFR

:mean

change

from

baselin

e:+2.0±23.2versus

−2.8±23.1LS

mean

difference±

SE:−7.778±

3.338(𝑃=0.021 )

§

Journal of Transplantation 23(c)Con

tinued.

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇mol/L)a

fterc

onversion

Change

inCr

Cl(m

L/min)

from

baselin

eatp

ostcon

version

timep

oint

6mon

ths

1year

Other

timep

oints

3mon

ths

6mon

ths

1year

6mon

ths

1year

Schlitt

etal.

AASLD2012

[91]

35mon

ths:

differenceineG

FRbetweenEV

Rand

CNI:

Cockcroft-Gault:

−10.5mL/min

(𝑃=0.096)

and

Nankivellform

ula:

−10.5mL/min

(𝑃=0.015)

Masettietal.A

mJ

Tran

splant.2010;

10:2252–62

[89]

+6.1versus−16.5

(EVRversus

CsA,

𝑃<0.001

comparis

onof

absolutevalues)

+5.9versus−14.8(EVR

versus

CsA,𝑃<0.001

comparis

onof

absolute

values)

DeS

imon

eetal.

AmJT

ransplant.

2012;12:3008–20

[87]

EVR+TA

C-RD

(adjusted

meandifferenceineG

FRchange

forE

VR+

TAC-

RDversus

TAC-

SD:

+8.50±2.12;𝑃<0.001)

Salib

aetal.

AASLD2012

[90]

24mon

ths:

EVR+TA

C-RD

versus

TAC-

SD:

meandifferencein

eGFR

change:

+6.66(97.5

%CI

:+1.9,+11.42;𝑃=

0.0018)

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)

Castr

oagudı́netal.

LiverT

ranspl.2009;

15:1792–7[94]

+3.99(N

Sversus

baselin

e)+7.65(𝑃=0.016versus

baselin

e)−0.09

(NS

versus

baselin

e)

−0.22‡

(𝑃<0.05

versus

baselin

e)

+5.18

(NSversus

baselin

e)+9

.82(𝑃=0.025

versus

baselin

e)

DeS

imon

eetal.

Tran

splInt.200

9;22:279–86[95]

+4.03

24 Journal of Transplantation(c)Con

tinued.

Change

inGFR

(mL/min/1.73

m2 )aft

erconversio

nCh

ange

inserum

creatin

inec

oncentratio

n(𝜇mol/L)a

fterc

onversion

Change

inCr

Cl(m

L/min)

from

baselin

eatp

ostcon

version

timep

oint

6mon

ths

1year

Other

timep

oints

3mon

ths

6mon

ths

1year

6mon

ths

1year

DeS

imon

eetal.

LiverT

ranspl.2009;

15:1262–9[96]

EVR:

+1.0;

controls:

+2.3

(NS)

Salib

aetal.Liver

Tran

spl.2011;

17:

905–13

[98]

+6.6chronicr

enal

failu

resubp

opulation

versus

baselin

e(𝑃=0.0002)

+4.2overallversus

baselin

e(𝑃=0.007)

+8.6chronicr

enalfailu

resubp

opulationversus

baselin

e(𝑃=0.02)

−11versus

baselin

e(𝑃=0.04)

−9versus

baselin

e(𝑃=NS)

−6versus

baselin

e(𝑃=NS)

𝑃values

areincludedwhere

available.

∗MedianeG

FR;†mL/min;‡mg/dL

.§ B

etween-grou

pdifference(calculated

asCN

Igroup

minus

everolim

usgrou

p)atmon

th11aft

erbaselin

e;results

basedon

ANCO

VAmod

el.CG

-GFR

:GFR

calculated

with

theC

ockcroft-Gaultform

ula;CN

I:calcineurin

inhibitor;Cr

Cl:creatininec

learance;C

sA:cyclosporin

A;EVR:

everolim

us;G

FR:glomerular

filtrationrate;LS:leastsqu

are;MDRD

:mod

ificatio

nof

dietin

renald

isease;MDRD

-GFR

:GFR

calculated

usingtheM

DRD

form

ula;NS:no

nsignificant;SE

:stand

arderror;TA

C-RD

:reduced-dosetacrolim

us(C0:3–5n

g/mL);TAC

-SD:stand

ard-do

setacrolim

us(C0:6–

10ng

/mL).

(d)

Proteinu

ria(afte

rcon

versionun

lessotherw

isesta

ted),%

recipients

Sirolim

usstu

dies

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)Harpere

tal.Tran

splantation.2011;91:128–32

[67]

Proteinu

ria:preconversio

n:45;6

mon

ths:72;3

years:63;5

years:58

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)DuB

ayetal.L

iverTran

spl.2008;14:651–9[72]

7versus

4(SRL

versus

CNI)

Herlenius

etal.T

ransplantP

roc.2010;42:44

41–8

[73]

8.3versus

7.7(SRL

versus

MMF)

Morardetal.L

iverTran

spl.2007;13:658–64

[75]

Album

inuria:36

Uhlmannetal.E

xpClin

Tran

splant.2012;10:30–

8[77]

Proteinu

riaincreasedat6mon

thsa

fterc

onversion(𝑃<0.05)

Wadeietal.Transplantatio

n.2012;93:1006–12[86]

81Ev

erolim

usstu

dies

Early

conversio

n(≤3mon

thsa

ftertransplantatio

n)DeS

imon

eetal.Am

JTransplant.2012;12:3008–20[87]

EVR+TA

C-RD

versus

TAC-

SD:2.9versus

0.4(RR:

6.89,95%

CI0.85,55.54)

Fischere

tal.Am

JTransplant.2012;12:1855–6

5[50]

EVRversus

CNI:9.9

versus

2.0

Lateconversio

n(>3mon

thsa

ftertransplantatio

n)Ca

stroagudı́netal.LiverTran

spl.2009;15:1792–7

[94]

38.1

Salib

aetal.LiverT

ranspl.2011;17:905–13[98]

5.4

Vallinetal.C

linTran

splant.2011;25:660–9

[99]

13versus

29(pre-v

ersusa

fterc

onversion,𝑃<0.05)

𝑃values

areincludedwhere

available.

CNI:calcineurin

inhibitor;EV

R:everolim

us;M

MF:mycop

heno

latem

ofetil;SR

L:sirolim

us;R

R:relativerisk

;95%

CI:95%

confi

denceinterval;T

AC:tacrolim

us;TAC

-RD:reduced-dosetacrolim

us(C

0:3–5n

g/mL);

TAC-

SD:stand

ard-do

setacrolim

us(C0:6–

10ng

/mL).


(𝑛 = 89) or placebo (𝑛 = 30) to liver transplant recipientsreceiving cyclosporine, there was no improvement in renalfunction, with liver transplant recipients receiving everolimusshowing a decrease in creatinine clearance at 6 months aftertransplant (Table 2(c)) [52].

Four high quality, prospective, randomized studiesshowed good results in liver transplant recipients convertedearly to everolimus from CNI treatment (Table 3(c)) [50,87, 89, 91]. One of these evaluated whether early CNIwithdrawal and initiation of everolimus monotherapy in denovo liver transplantation patients would lead to superiorrenal function, compared to the cyclosporine control, at 12months after transplantation [89]. At randomization, themean eGFR value calculated by the modification of diet inrenal disease (MDRD) formula was 81.7 ± 29.5mL/min/1.73m2 in the everolimus group and 74.7 ± 24.6mL/min/1.73m2in the cyclosporine group (𝑃 = 0.30). At 6 and 12 months,respectively, the mean eGFR values in the everolimus groupwere 87.8 ± 36.7 and 87.6 ± 26.1mL/min versus 58.2 ± 17.9 and59.9 ± 12.6mL/min in the cyclosporine group (𝑃 < 0.001 forboth the 6- and 12-month comparisons). In a per-protocolanalysis, the incidence of stage ≥3 chronic kidney disease(estimated GFR < 60mL/min) was significantly lower in theeverolimus group at 1 year after liver transplant (52.2% versus15.4%, in the cyclosporine group, respectively, 𝑃 = 0.005)[89]. More recently, results from an 11-month, multicenter,prospective, open-label trial were published in which livertransplant recipients with good renal function at 4 weeksafter transplant were randomized to either continue CNItreatment with/without corticosteroids (𝑛 = 102) or switchto everolimus with/without corticosteroids (𝑛 = 101) [50].There was a significant difference between treatments usingthe MDRD formula (−7.8mL/min in favor of everolimus,𝑃 = 0.021), although this was not significant whenusing the Cockcroft-Gault formula (−2.9mL/min in favor ofeverolimus, 𝑃 = 0.46) [50]. Results of the extension phase in81 patients demonstrated that everolimus maintained betterrenal function at 35 months (difference in eGFR betweeneverolimus and CNI arms: Cockcroft-Gault: −10.5mL/min,𝑃 = 0.096 and Nankivell formula: −10.5mL/min, 𝑃 = 0.015)[91].

In the fourth early-conversion prospective, randomized,high quality study (Table 3(b)) [87], 719 de novo livertransplant recipients were given a 30-day run-in periodwith tacrolimus-based immunosuppression (± mycophe-nolate) and then randomized to the following groups:everolimus (trough concentration, C0: 3–8 ng/mL) plusreduced-exposure tacrolimus (TAC-RD, C0: 3–5 ng/mL; 𝑛 =245); everolimus (C0: 6–10 ng/mL) with tacrolimus beingwithdrawn (TAC-WD, 𝑛 = 231) at 4 months or standard-exposure tacrolimus (TAC-SD, C0: 6–10 ng/mL, 𝑛 = 243).Enrolment in the TAC-WD arm was stopped prematurelydue to a higher incidence of biopsy-proven acute rejection(BPAR) around the time of tacrolimus elimination. However,renal function at 1 year post-randomization improved sig-nificantly with everolimus plus TAC-RD, with an adjustedmean difference in eGFR change of +8.5mL/min/1.73m2

(97.5% confidence interval (CI) 3.74, 13.27mL/min/1.73m2)

versus that observed in patients in the TAC-SD group (𝑃 <0.001). The recent publication of final results from this trialdemonstrates that significantly better renal function withTAC-RD was maintained at 24 months (mean difference ineGFR change: 6.66mL/min/1.73m2 (97.5% CI: 1.9, 11.42; 𝑃 =0.0018)) [90].

Of four late-conversion studies involving everolimus(Table 3(b)), two prospective, single-arm studies and oneretrospective study demonstrated a benefit [94, 95, 98].The other, a prospective, randomized, multicenter, mediumquality study that involved administering everolimus withCNI reduction or discontinuation to 72 liver transplantrecipients experiencing CNI-related renal impairment, failedto show a significant improvement in renal function frombaseline or when compared to renal function in 73 CNIcontrols [96, 100]. A number of confounding factors werenoted by the authors that may have potentially contributed tothe negative result, including low CNI exposure at baselinedue to previous efforts by the clinical team to improverenal function, and the fact that the extent of CNI dosereductions in the control group was higher than expected fora maintenance population.

Proteinuria was reported in four everolimus (two highquality and two low quality) studies identified in the literaturesearch (Table 3(d)), occurring with incidences of 2.9% [87],5.4% [98], 9.9% [50] and 29% [99]. One of these was aprospective randomized study that compared liver transplantrecipients who received CNIs with/without corticosteroids(𝑛 = 102) to those who were switched early to everolimuswith/without corticosteroids (𝑛 = 101). The incidence ofproteinuria at 11 months post-randomization was higher inthe everolimus group (9.9%) compared to the CNI group(2%), although six out of ten cases were mild with theremaining cases being moderate [50]. In another largeprospective randomized high quality trial, in which patientswere converted to everolimus early, proteinuria was observedin the everolimus plus reduced tacrolimus dose group duringa 12-month followup period, but the maximum mean valuesfor urinary protein to creatinine ratio were below 0.3 g/g, andpreexisting cases of proteinuria did not worsen [87].

3.3. Safety of mTOR Inhibitors

3.3.1. Hepatic Artery Thrombosis (HAT)

Sirolimus. Two multicenter randomized studies in de novoliver transplant recipients suggested that the use of sirolimusin combination with cyclosporine or tacrolimus was associ-ated with an increase in HAT [38, 44]. In subsequent studies(a mixture of quality and trial designs) that reviewed the useof sirolimus in liver transplant recipients, increased rates ofHAT have not been observed (Table 4(a)) [15, 45, 48, 53, 55,57, 61]. In fact, two of these studies recorded significantlylower incidences of HAT among patients receiving sirolimuscompared to controls [53, 57]. In these studies, sirolimus wasgiven at 2mg per day without a loading dose, and sirolimuslevels were targeted at

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Review Article The Role of mTOR Inhibitors in Liver Transplantation: Reviewing … · 2019. 7. 31. · maintenance immunosuppression in liver transplantation [ ], but their nephrotoxic