Transplantation Reviews xxx (2016) xxxxxx

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Transplantation Reviews
journal homepage: www.elsevier.com/locate/trre

Use of everolimus in liver transplantation: The French experience

Jrme Dumortier a, Sebastien Dharancy b, Yvon Calmus c, Christophe Duvoux d, Franois Durand e,
Ephrem Salam f, Faouzi Saliba g,
a
Unit de Transplantation Hpatique-Fdration des Spcialits Digestives, Hpital Edouard Herriot and Universit Claude Bernard Lyon 1, Lyon, France
b
Service des Maladies de l'Appareil Digestif et de la Nutrition, Hpital Claude Huriez Centre Hospitalier Universitaire, Lille, France
c
Unit Mdicale de Transplantation Hpatique, AP-HP Hpital Universitaire Piti Salptrire, Paris, France
d
Service d'Hpato-Gastroenterologie, Hpital Henri Mondor, Assistance Publique, Hpitaux de Paris, Crteil, France
e
Hepatology and Liver Intensive Care, INSERM U1149, Hospital Beaujon, Clichy, France
f
Chirurgie Digestive, Endocrinienne et Transplantation Hpatique, Hpital Trousseau, Tours, France
g
AP-HP Hpital Paul-Brousse Centre Hpato-Biliaire and INSERM, Unit 1193, Universit Paris-Sud, UMR S1193, Villejuif, France

a b s t r a c t

The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved for rejection prophylaxis after liver
transplantation. The current article pools the experience of French liver transplant surgeons and physicians in use
of everolimus and, particularly, practical guidance on dosing, appropriate concomitant immunosuppression and
management of adverse events. In terms of indication, introduction of everolimus from week 4 after liver
transplantation, with or without concomitant calcineurin inhibitor (CNI) therapy, offers a signicant renal
benet without loss of immunosuppressive efcacy. De novo treatment with everolimus, either selectively or
systematically, may play a role in the prevention and treatment of recurrence of hepatocellular cancer and
de novo malignancies. For maintenance patients, the most frequent indications for introducing everolimus are in
response to renal dysfunction, recurrent hepatocellular cancer, diabetes, hypertension, or neurotoxicity, or as a
preventative approach to avoid malignancies. Of these, the strongest evidence exists for a renoprotective effect.
However, the low rate of acute rejection following switch of maintenance patients from CNI-based
to everolimus-based therapy means that this can be considered even where robust data are not yet available.
Most adverse events associated with mTOR inhibitors can usually be managed successfully, often with
concentration-controlled dose reductions. Dosing algorithms are provided, with suggestions for target ranges in
specic settings, and treatment strategies for the most common side effects are proposed. Although further
research is required, everolimus has become an established part of the immunosuppressive arsenal for liver
transplant recipients over the last decade. Sharing experience from units which have embraced its use may help
other centers develop their own protocols.
2016 Elsevier Inc. All rights reserved.

1. Introduction
The mammalian target of rapamycin (mTOR) inhibitors, everolimus
(EVR) and sirolimus, inhibit intracellular pathways that prevent B- and
T-cell proliferation [1]. EVR (Certican; Novartis Pharma AG, Basel,
Switzerland) has recently been approved in the EU and the USA for pro-
phylaxis of organ rejection in patients receiving a liver transplant, in
combination with tacrolimus and steroids [2]. Sirolimus is not currently
licensed for use in liver transplantation. Both agents share a similar
structure, other than addition of an extra hydroxyethyl group in the
EVR molecule which gives rise to a shorter half-life [3] and more rapid
attainment of stable blood concentrations [4] compared to sirolimus.
An extensive series of clinical trials has explored the use of EVR
within various different immunosuppressive regimens for both
Corresponding author at: AP-HP Hpital Paul-Brousse Centre Hpato-Biliaire, Villejuif,
F-94800, France. Tel.: +33 1 45 59 64 12; fax: +33 145 59 38 57.
E-mail address: faouzi.saliba@pbr.aphp.fr (F. Saliba).
de novo and maintenance patients after all types of solid organ
transplantation [5]. Initially, the main emphasis for investigation was
in kidney [5,6] and heart [7,8] transplantation, but more recently
randomized trials [913] and investigator-led single-center reports
have substantially increased the evidence base in liver transplant
recipients [14]. To date, however, this experience has not prompted
publication of practical guidance on how EVR can be optimally
employed in the setting of liver transplantation.
This article summarizes the expert opinion of French liver transplant
surgeons and physicians who have been treating patients with EVR for
more than 10 years. Based on published data and personal experience,
it considers the appropriate selection of liver transplant patients for
EVR therapy and the practicalities of its use.
2. Methods
The authors met on three occasions to develop the manuscript:
(1) to identify topics for inclusion which were each then allocated to a

http://dx.doi.org/10.1016/j.trre.2015.12.003
0955-470X/ 2016 Elsevier Inc. All rights reserved.

Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
2 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx
single author to undertake a literature research and develop draft text
(2) to present and discuss draft outputs (3) to ne-tune the nal con-
tent, which was agreed by all authors. Each author conducted a litera-
ture review using some or all of the following key words, as
appropriate: mTOR inhibitors, liver transplantation combined with:
pharmacokinetics, EVR, sirolimus, tacrolimus, renal function, hepatocel-
lular carcinoma (HCC), hepatitis C, liver brosis, de novo cancer, neuro-
toxicity, dyslipidemia, surgery, pregnancy, fertility. Additional
references were identied from key review papers.
3. EVR in the de novo setting
3.1. Preservation of renal function
Impaired renal function is a well-established complication in pa-
tients with end-stage liver disease, and frequently progresses after
transplantation. A population-based cohort study estimated that 18.1%
of liver transplant recipients develop chronic renal failure (dened as
estimated GFR [eGFR] b 30 mL/min/1.73m 2) by ve years post-
transplant, and with an associated four-fold increase in mortality [15].
The causes of post-transplant chronic renal insufciency are multifacto-
rial, but long-term exposure to calcineurin inhibitor (CNI) therapy is an
important contributor. Renal-sparing strategies have included use of
monoclonal anti-CD25 antibody induction to delay CNI initiation
[16,17], addition of mycophenolate mofetil (MMF) [18,19] and, more re-
cently, introduction of mTOR inhibitor therapy to reduce CNI exposure
[9,10] or discontinue CNI entirely either early (b3 months post-
transplant) [11,13] or later [12]. EVR acts synergistically with CNIs
[20], allowing CNI exposure to be substantially reduced while maintain-
ing sufcient immunosuppressive activity [10,11,20].
In order to minimize CNI-related nephrotoxicity and preserve long-
term renal function, CNI exposure should be tapered as soon as possible
after transplantation, but this needs to be balanced with effective im-
munosuppression. In the two-year, multicenter, open-label, random-
ized H2304 study, patients received standard-exposure tacrolimus
with steroids for the rst month [9]. At week 4 post-transplant, patients
were randomized to (1) standard-exposure tacrolimus as the control
regimen (n = 243), (2) EVR with reduced-exposure tacrolimus (n =
245), and (3) EVR with tacrolimus elimination (n = 231). One-year
rates of biopsy-proven acute rejection (BPAR) were 10.7% in the control
group versus 4.1% for EVR with reduced-exposure tacrolimus (p =
0.005 in favor of the EVR cohort). All cases of BPAR in EVR-treated patients
were graded borderline or mild [9]. The between-group difference in the
rate of BPAR was sustained at two years (13.3% versus 6.1%, p = 0.010)
[9]. A recent review by Klintmalm et al. concluded that EVR-based immu-
nosuppression achieves similar rates of acute rejection, graft and patient
survival to conventional regimens comprising CNI and MMF [14].
Entirely CNI-free immunosuppression with EVR and mycophenolic
acid (MPA), however, may not provide adequate protection against rejec-
tion [21], and even early CNI withdrawal must be undertaken cautiously.
In the tacrolimus elimination arm of the H2304 study, randomization was
discontinued prematurely due to high rates of BPAR clustered around the
time of tacrolimus withdrawal. In that trial, CNI was withdrawn abruptly
after month 4 post-transplant. In contrast, the randomized PROTECT
study found that more gradual CNI elimination over an eight-week period
starting at week 4, coupled with basiliximab induction, found no loss of
efcacy after CNI discontinuation [11].
Early introduction of EVR, either with ongoing reduced-exposure
CNI or CNI withdrawal, has consistently shown a clinically relevant
renal benet versus a standard CNI regimen which appears to be
sustained to at least three years after liver transplantation (Table 1).
3.1.1. Practical implications
Renal function (eGFR) should be evaluated prior to liver transplant,
immediately post-transplant, at months 1, 3, 6 and 12 and subse-
quently twice a year
Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
The Modication of Diet in Renal Disease (MDRD) and the Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae
are most often used to estimate GFR measurement reliably.
24-h proteinuria or urinary protein/creatinine ratio should be measured
prior to introduction of EVR. (The H2304 study excluded patents with
urinary protein excretion 0.8 g/day at baseline, and all randomized
trials of early switch to EVR stipulated minimum levels of baseline
renal function, so outcomes are undocumented in these patients.)
In patients with moderate to severe renal impairment, and those
with proteinuria N0.8 g/day, consider consultation with a nephrologist
and perform renal biopsies when necessary.
Introduction of EVR should take place as early post-transplant as
possible. CNI withdrawal, if undertaken, should be carried out
gradually (e.g. over 8 weeks) and induction therapy may be helpful
to maintain immunosuppressive efcacy during early switch from
CNI treatment.
Induction is also likely to be useful if CNI initiation is delayed, or if
CNI levels are decreased rapidly, in EVR-treated patients.
3.2. Prevention of de novo or recurrent non-HCC malignancies
Post-transplant malignancy has become one of the main causes of
death after liver transplantation, irrespective of the primary indication
for transplant [24,25]. The overall standardized incidence ratio for risk
of malignancy compared to the general population has been reported
to range from 2.1 to 3.2 [2628] and is signicantly higher when pa-
tients are transplanted for alcoholic liver disease [29]. The mTOR inhib-
itor class can exert an antitumoral effect depending on the type of
cancer (especially its hypervascularized characteristics). At higher
doses, mTOR inhibitors can exert a direct antiproliferative effect on can-
cer cells, while the lower doses used in transplant recipients are associ-
ated with an antiangiogenic effect [30]. There is evidence for an anti-
neoplastic activity at clinically relevant doses (5 mg/day) [21,31]. In-
deed, EVR is indicated for the treatment of renal cell carcinoma, breast
cancer, neuroendocrine tumors and angiomyolipoma [3237]. Studies
in kidney transplantation have reported a lower incidence of de novo
post-transplant malignancies under mTOR inhibitor therapy [3840].
Data are more limited in liver transplant populations. One large retro-
spective single-center analysis of liver transplants performed during
1996 to 2013 compared the incidence of new-onset post-transplant ma-
lignancies in 243 patients who were given EVR for reasons other than
malignancy versus 1182 patients without any mTOR inhibitor treat-
ment [41]. After a median follow-up of 1740 days, the incidence of
new-onset malignancies was 0.2% in the EVR-treated group and 3.4%
in the patients without an mTOR inhibitor. EVR-free immunosuppres-
sion was found to be an independent predictor for risk of malignancy.
Conrmatory studies are lacking, however. Also, since increased CNI ex-
posure is associated with higher risk of solid cancers after liver trans-
plantation [41,42], it is not clear to what extent any reduction in
malignancies may be due to inhibition of the mTOR pathway, and
what contribution arises from reduced CNI exposure in the presence
of an mTOR inhibitor.
For patients receiving a liver transplant due to malignancies such as
hilar cholangiocarcinoma or liver metastases from neuroendocrine tu-
mors, it is unknown whether an mTOR inhibitor-based immunosup-
pressive regimen could inuence the rate of recurrence [43]. The
relative rarity of such cases, and the long follow-up required, are bar-
riers to reaching a denitive answer.
3.2.1. Practical implications
At present no rm conclusions can be drawn regarding prevention
of de novo or recurrent cancers using EVR therapy and this cannot
currently be regarded as a rm indication for EVR after liver
transplantation.
Data available from renal transplant registries are highly encouraging;
similar data from liver transplant populations are awaited.
 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx 3

Table 1
Renal outcomes under everolimus (EVR)-based immunosuppression in prospective trials of liver transplant recipients.

Study Reference Follow-up Treatment group N Mean (SD) eGFR, Mean difference for change p Value for
(months) mL/min/1.73m2 in eGFR from (EVR control) difference

Early EVR + reduced CNI

H2304 De Simone 2012 [9] 12 EVR + low TAC 245 80.9 (27.3) 8.5 (97.5% CI 3.7, 13.3) b0.001
TAC Control 243 70.3 (23.1
Saliba 2013 [10] 24 EVR + low TAC 245 74.7 (26.1) 6.7 (97.5% CI 1.9, 11.4) 0.002
TAC Control 243 67.8 (21.0)
Fischer 2015 [22] 36 EVR + low TAC 106a 78.7 (25.7) 8.5 b0.005
TAC Control 125a 63.5 (18.3)

Early EVR + CNI discontinuation

PROTECT Fischer 2012 [11] 12 Switch CNI to EVR by M4 101 80.3 (26.4) 7.8 (95% CI 0.1, 14.7) 0.021
CNI Control 102 72.1 (24.5)
Sterneck 2014 [23] 36 Switch CNI to EVR by M4 41a 77.5 (23.4) 9.4 (95% CI -0.4, 19.8) 0.053
CNI Control 40a 67.9 (21.8)
Single-center prospective Masetti 2010 [13] 12 EVR from day 10, 52 87.7 (26.1)b - -
CNI withdrawn after day 30
CsA control 26 59.9 (12.6)b

Maintenance patients: Conversion from CNI to EVR

RESCUE De Simone 2009 [12] 6 Switch from CNI to EVR 72 52.8 (12.2)c -1.1 (95% CI -3.9, 1.9)c
CNI control 73 52.7 (10.4)c 0.463
12 Switch from CNI to EVR 72 53.8 (12.8)c -
CNI control 73 52.5 (12.7)c

CI, condence interval; CNI, calcineurin inhibitor; eGFR, estimated glomerular ltration rate (Modication of Diet in Renal Disease formula); EVR, everolimus; SD, standard deviation; TAC,
tacrolimus.
a
Study extension population.
b
p b 0.001 for between-group difference in observed eGFR at month 12.
c
Creatinine clearance (Cockcroft-Gault formula).

The exception is neuroendocrine tumors, for which evidence from facilitate CNI reduction or elimination. An increase in rejection with
non-transplant populations suggests that EVR can be an effective the requirement for intensication of immunosuppression would,
treatment option [35]. however, be counterproductive due to the enhanced risk of tumor
recurrence.
3.3. Recurrence of HCC Two options can be considered:

HCC is now a leading indication for liver transplantation but because

post-transplant tumor recurrence is almost invariably fatal within two
years, patients are selected according to dened risk factors such as
those specied in the well-established Milan criteria [44]. Selection
criteria are based on the morphological characteristics of the carcinoma
and, to a lesser extent, on biomarker levels (e.g. alpha-fetoprotein)
which reect tumor biological behavior. The criteria are not compre-
hensive and do not take into account the type and intensity of the im-
munosuppressive regimen. There is growing evidence to suggest, for
example, that the risk of HCC recurrence increases with cumulative
CNI exposure [45,46] and use of ATG induction [47].
Interest is growing in a role for EVR in preventing post-transplant
HCC recurrence [48]. The mTOR pathway is activated in 3040%
of HCC cases [49] and preclinical data suggest that clinical exposure
levels are adequate to exert antitumor activity in HCC [31], with anti-
proliferative effects on HCC cell lines sustained even with concomitant
tacrolimus administration [50]. It would be appealing to initiate EVR
selectively in cases where there is pathological proof of mTOR pathway
activation, but this remains impractical at present.
Clinically, data relating to an effect of mTOR inhibition are largely re-
stricted to retrospective and non-randomized prospective analyses [48].
These suggest a benet for HCC recurrence rates versus standard CNI
therapy [48,5155]. In some cases the patient population was extremely
selected [51,56,57], but EVR has also been shown to offer advantages for
HCC recurrence and post-recurrence survival for patients transplanted
outside the Milan criteria [58]. A randomized controlled trial using
EVR in this setting is ongoing (NCT01888432).
3.3.1. Practical implications
Reducing the risk of post-transplant HCC recurrence should include
avoidance of anti-thymocyte globulin induction, with early CNI mini-
mization or even withdrawal. mTOR inhibition can be helpful to
(i) Detection on explant pathology and prognosis is poor (poor dif-
ferentiated tumor, microvascular invasion, outside Milan criteria;
the current trend in France), i.e. the risk of recurrence was under-
stated pre-transplant.
(ii) Systematic introduction of EVR to support CNI minimization/
withdrawal in all cases of liver transplant for HCC, irrespective
of explant pathology. Such an approach is supported by the US ex-
perience in which HCC recurrence was reduced under sirolimus
therapy for patients transplanted within Milan criteria [59].
For either CNI reduction strategy, start EVR by the end of month 1,
then when EVR trough level reaches 38 ng/mL reduce CNI dose
by half then gradually taper CNI (target trough levels of tacrolimus:
35 ng/mL) for 612 months.
Consider progressing to EVR monotherapy after year 1 depending on
the risk/benet ratio for tumor recurrence, and targeting EVR trough
levels of 610 ng/mL if CNI is withdrawn. EVR exposure below
6 ng/mL may be considered in low-risk maintenance patients receiving
MPA therapy.
Addition of MPA therapy may be helpful to prevent rejection in
patients switched from CNI to EVR during the rst year post-
transplant.
A few centers have attempted very early introduction of EVR post-
transplant but few data are available on the safety of this strategy.
3.4. Hepatitis C virus (HCV) recurrence
Prospective trials investigating the role of mTOR inhibitors after liver
transplant for HCV-related disease are lacking, and the available evi-
dence is inconclusive. However, an analysis from the HCV-positive

Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
4 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx
subpopulations in three controlled studies showed a trend to less
brosis progression in patients receiving EVR with reduced CNI versus
standard immunosuppression [60]. A non-randomized study cohort in
de novo liver transplant patients reported reduced HCV replication in
sirolimus-treated patients with previous HCV infection [61], but no
effect on viral load was observed in the H2304 study [9]. Three
published trials of mTOR inhibition in de novo patients have observed
delayed brosis in HCV-positive recipients [6163].
However, introduction of new direct-acting antiviral (DAA) therapies such
as sofosbuvir, simeprevir, sofosbuvir + daclatasvir, sofosbuvir + ledipasvir
and ombitasvir/paritaprevir/ritonavir + dasabuvir has largely obviated
any inuence of the immunosuppressive regimen. Of note, unlike
sofosbuvir which is mainly metabolized by the kidney, the coadminis-
tration of these drugs with EVR has not been studied but as with CNIs,
they may increase EVR concentrations either due to CYP3A4 and/or P-
glycoprotein inhibition [64]. If used, therapeutic drug monitoring
of EVR should be performed when DAA therapy is started and stopped,
together with careful monitoring of DAA-related side effects
and toxicities.
3.4.1. Practical implications
EVR-based immunosuppression is an appropriate option in HCV-
positive liver transplant patients and may delay brosis progression,
but any such an effect is less relevant if DAA therapy is routinely
administered to HCV-positive recipients.
A summary of drugdrug interactions between DAA products
and immunosuppressive agents (including everolimus) is shown
in Table 2.
4. EVR in the maintenance setting
The literature contains reports of EVR introduction at various time
points after liver transplantation, for a range of indications [6571].
The authors' most frequent reasons for starting EVR in maintenance
patients are in response to renal dysfunction, recurrent HCC, diabetes,
hypertension, or neurotoxicity, or for the prevention or management
of malignancies. In the absence of data, the authors do not recommend
EVR to treat either acute or chronic rejection.
One prospective study [12] and retrospective series [65,6971] have
reported a low acute rejection rate after switch from CNI, as might be
expected in maintenance patients. Rates of adverse events and discon-
tinuations were acceptable.
4.1. Patients with deteriorating renal function
In a 12-month trial of 145 liver transplant patients with CNI-
related renal impairment (baseline creatinine clearance in the range
2060 mL/min), De Simone et al. found no renal benet in the group
randomized to EVR with CNI discontinuation (80%) or reduction (20%)
versus a CNI-continuation control arm [12]. Results were complicated
by the fact that 77% of controls also received CNI dose reductions; addi-
tionally, the mean time post-transplant was more than three years.
Table 2
Drugdrug interactions between direct-acting antiviral (DAA) therapies against HCV infection and immunosuppressive agents [64]. More details are available at www.hep-
druginteractions.org [64].
Simeprevir Daclatasvir Sofosbuvir
Azathioprine
Cyclosporine +++
Everolimus + +
Mycophenolic acid
Sirolimus + +
Tacrolimus + +
, No clinically signicant interaction expected.
+, Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.
+++, These drugs should not be co-administered.
Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
Other, non-comparative studies have described a signicant improve-
ment in renal function following switch from CNI to EVR which appears
to be sustained to at least one year after conversion [65,72]. Overall, the
available data indicate that maintenance patients can be switched from
CNI to EVR in response to renal deterioration without an increase in
rejection risk [12,65,72] but that late CNI withdrawal is less effective
in ameliorating loss of renal function [73].
4.1.1. Practical implications
In maintenance liver transplant patients who have developed CNI-
related renal impairment, introduce EVR and taper CNI exposure.
Withdraw CNI in patients who are more than 1 year post-transplant
unless there is a high risk of rejection (e.g. previous rejection
episodes, autoimmune disease).
Maintain EVR trough levels toward the upper end of a 38 ng/mL
target range if CNI is discontinued, and consider introduction of
MMF to maintain immunosuppressive efcacy in the absence of CNI.
4.2. CNI-induced neurotoxicity
Post-operative neurological complications such as confusion, sei-
zures and tremor occur in approximately 1015% of liver transplant pa-
tients [74,75], with rare (b1%) severe neurological complications such
as cerebral hemorrhage, ischemic stroke, and posterior reversible
encephalopathy syndrome (PRES) [75,76]. CNI therapy is known to be
associated with neurotoxic adverse events such as tremor, confusion
and seizures, which usually resolve or improve signicantly with dose
reduction. Switch from CNI to mTOR inhibitor therapy is undertaken
due to neurotoxicity in approximately 15% of cases [77]. CNI agents
are also the principal cause of PRES, and most cases improve if the
patient is converted to an mTOR inhibitor at an early stage [77].
4.2.1. Practical implications
CNI-induced PRES mandates emergency discontinuation of CNI
therapy. Switching to an mTOR inhibitor is generally considered
the best option to prevent further progression while providing
effective immunosuppression.
4.3. Management of post-transplant malignancy
4.3.1. HCC recurrence
Management of HCC recurrence is based on the premise that
treatment of an advanced oncological disease with an extremely poor
prognosis is a greater clinical priority than prevention of rejection.
Three options can be considered, irrespective of the surgical possibilities
for tumor resection:
(i) Introduce EVR with immediate CNI withdrawal.
(ii) Introduce EVR if mTOR pathway activation is detected on
biopsies of tumor tissue. However, this approach is not routinely
available.
Sofosbuvir + ledipasvir 3D (ritonavir-boosted paritaprevir + ombitasvir + dasabuvir)
+ +
+ +++
+
+
+
 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx
(iii) Combine EVR with sorafenib on the grounds that pre-clinical
studies and case reports have suggested a synergistic effect
between the two therapies [78,79], although a cautious approach
is required due to safety concerns.
4.3.1.1. Practical implications.
Start EVR at 1 mg b.i.d., targeting trough levels of 812 ng/mL
according to patient tolerability, and discontinue CNI as soon as possible.
If the patient is receiving MMF, assess if this should be continued
based on local practices.
Consider combination therapy with sorafenib, although poor
tolerability of sorafenib when combined with EVR may necessitate
a sorafenib starting dose of 200 mg b.i.d. adjusted according to
therapeutic drug monitoring.
4.3.2. other solid tumors
Small studies have examined switching liver transplant recipients
with de novo solid tumors from a CNI to sirolimus or EVR [69,8082].
Converting to sirolimus with rituximab was associated with improved
long-term disease-free survival after treatment of lymphoproliferative
disorders in one report [83]. In a small retrospective study, Gomez-
Camarero et al. showed that patients presenting de novo malignancies
after liver transplantation survived longer when switched to EVR [81].
In a single-center study of 83 patients transplanted for alcoholic liver
disease, 38 patients started EVR therapy with CNI discontinuation in
the majority of cases (64.1%) [69]. One- and ve-year survival was
77.4% and 35.2% in the EVR cohort compared to 47.2% and 19.4% in the
control group (p = 0.003) [69].
Converting from CNIs to mTOR inhibitors is part of the routine
treatment of post-liver transplant Kaposi sarcoma [84].
There are no clinical studies suggesting a signicant protective effect
of mTOR inhibition against recurrence of pre-existing malignancies
after liver transplantation. Nevertheless, EVR may be considered a
therapeutic option for some malignant tumors such as kidney and
breast cancers, because EVR is approved in these settings.
4.3.2.1. Practical implications.
Conversion to EVR (target 510 ng/mL) could be considered in
patients with a poor metastatic prognosis, to increase short-term
survival. Concomitant MMF is an option according to local practice,
but is contraindicated in patients with severe chemotherapy-
induced anemia.
CNI should be tapered and discontinued within a few months of
starting EVR. CNI discontinuation can be considered depending on
the severity and prognosis of the cancer and the risk of rejection.
The authors have anecdotal occasional negative experiences com-
bining EVR with certain chemotherapies (e.g. gemcitabine combined
with oxaliplatin, bevacizumab)
Caution should be taken in EVR-treated patients given radiation
therapy because of the enhanced risk of tissue burning or injury.
4.3.3. Skin cancer
Ducroux et al. recently reported a 13.5% prevalence of skin cancers in
371 liver transplant patients over a median follow-up of 8.2 years [85],
comparable to that observed after kidney transplantation. A random-
ized trial in kidney transplant patients has shown that switch from
CNI therapy to sirolimus signicantly reduced the risk of cutaneous
squamous cell carcinoma recurrence [86]. Similar data are not available
for a liver transplant population.
4.3.3.1. Practical implications.
Switch from CNI to an mTOR inhibitor in liver transplant patients
with previous squamous cell carcinoma, and possibly other forms
of non-melanoma skin cancer, is of potential interest.
More data are required in the liver transplant population and for
other types of skin cancer.
Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
5
5. Management of EVR-related adverse events
Class-related adverse events and clinical complications associated
with mTOR inhibitors are well documented in the literature [68] and
can usually be managed successfully [87]. These include inhibition of
wound healing, peripheral edema, mouth ulceration, dermatological
side effects such as acne, hypercholesterolemia, proteinuria and, rarely,
interstitial pneumonitis. Some adverse effects are less frequent and less
severe if appropriate starting doses are used and if therapeutic blood
levels are carefully controlled [68]. Many side effects are dose depen-
dent and frequently the rst response is to check EVR exposure and con-
sider a dose reduction. Suggestions for management are outlined in
Table 3, and specic adverse events are discussed below.
5.1. Wound healing complications
In a rat model, EVR has been shown to signicantly inhibit the cell
proliferation and new collagen deposition that is required for normal
wound repair [95]. Clinically, the effect appears to be dose dependent.
In a pooled analysis of three prospective studies in kidney transplanta-
tion, wound healing complications were more frequent when EVR
trough levels of 610 ng/mL were targeted versus a MMF-treated con-
trol group, but comparable to controls when the target trough level
was 38 ng/mL [96].
Surgically, liver transplantation is more complex than kidney en-
graftment, with more frequent complications. Wound healing events
after liver transplantation can include thrombosis of the hepatic artery
or portal vein, incisional hernias, biliary stulas, or delayed cutaneous
wound repair.
In the H2304 study, introduction of EVR with reduced tacrolimus at
four weeks post-transplant was associated with a similar 12-month rate
of wound healing complications to the tacrolimus control arm (11.0%
versus 8.3%) based on a target EVR range of 38 ng/mL [9]. Randomized
trial data relating to EVR therapy from the day of transplant are not
available. There are published cases of liver transplant patients under-
going major abdominal or thoracic surgical procedures while receiving
an unchanged dose of an mTOR inhibitor [97] but this has not been ex-
amined rigorously.
5.1.1. Practical implications
Delay EVR introduction until complete surgical healing if the patient
has surgical complications, infections or a general condition that
may negatively affect wound healing, such as prolonged hyperventi-
lation post-surgery.
In rare cases, particularly with T-tube external biliary drainage,
consider delaying EVR until months 3 and 4.
It may be advisable to avoid early EVR in malnourished patients with
low body mass index (BMI) (e.g. b 20 kg/m2) and in obese patients
(BMI N 35 kg/m 2). Ensure correct wound healing (including signs
of wound budding) before starting EVR in these patients, since low
or high BMI can increase risk of healing complications.
Consider interrupting EVR 45 days before major elective surgery
with a compensatory increase of CNI dosing (to allow for EVR clear-
ance based on a half-life of 28 h), reintroducing EVR approximately
one month after the procedure.
5.2. Dyslipidemia
Hyperlipidemia is common in organ transplant recipients, and is ex-
acerbated by CNI agents and mTOR inhibitors [91,98]. The dyslipidemic
inuence of mTOR inhibitor therapy has diminished using contempo-
rary dosing protocols which avoid a loading dose and deliver lower,
concentration-controlled exposure compared to early trials, but an ef-
fect persists [91]. Liver transplant recipients, unlike heart transplant pa-
tients, do not routinely receive statins and total cholesterol levels are
frequently toward the upper end of normal. Most lipid-related adverse
6 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx

Table 3
Incidence and management of everolimus (EVR)-related adverse events.

Adverse event Incidence in liver transplantation Management

Wound healing complications
Peripheral edema
Mouth ulcers
Dermatological disorders
Hematological disorders
Hyperlipidemia
Proteinuria
Interstitial pneumonitis
2.215% (may be less prevalent with EVR vs. sirolimus)
717.6% [9,13,65,68,89]
Up to 20% of de novo patients [68]
19% in maintenance patients [65]
Acne, rash and eczema reported in 1420% [9,65,68]
Anemia (13%), leukopenia (9%),
thrombocytopenia (6%)
(may be more frequent under sirolimus) [65,87]
743% [14,91]
5.518% in maintenance patients
converted to EVR [65,68]
0.40.5% of solid organ tx patients overall [94]
Withdraw EVR 45 days before major or parietal surgery and reintroduce
after 30 days (or after complete healing) [88]
Consider the possible contribution of concomitant drugs
Evaluate response to diuretics
Consider EVR reduction (particularly if trough concentration is high)
or EVR withdrawal if serious periorbital or angioedema
Warn patients of this side effect
Rule out viral/fungal infection
Topical analgesic
Topical steroids
Betamethasone can be prescribed as a preventive treatment,
to be used as soon as mucosal lesions appear
Consider EVR dose reduction
Rule out infection
May resolve spontaneously within a few weeks
Topical treatment e.g. emollients
Consider reintroducing low-dose steroids [90]
Refer to a dermatologist if required
Consider EVR reduction (particularly if trough concentration is high)
or EVR withdrawal
Rule out other causes (mycophenolic acid, ganciclovir/valganciclovir or other drugs,
vitamin or iron deciency, viral infections)
Evaluate reduction or withdrawal of MMF
Erythropoiesis stimulation/iron therapy
GM-CSF treatment
Thrombopoietin receptor agonists
Suggest lifestyle changes
Initiate lipid-lowering therapy with statins and/or omega-3 fatty acids
Do not switch to mTOR inhibitor therapy if 24 h proteinuria is 0.8 g/L [50]
Perform renal biopsy if necessary [92]
Consider reduction or withdrawal of EVR if possible
Initiate treatment with an angiotensin-converting enzyme inhibitor or
angiotensin II receptor blocker [93]
Evaluate reduction of EVR exposure or withdrawal if symptoms persist
Initiate steroid treatment if infection and cancer are ruled out
Refer to lung specialist
Consider thoracic scan as a reference examination

CNI, calcineurin inhibitor; EVR, everolimus; GM-CSF, granulocyte-macrophage colony-stimulating factor; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin; tx,
transplantation.

events under EVR are mild and can be managed successfully [87], and 6. Dosing and monitoring of EVR
are not generally regarded as a barrier to EVR therapy.
6.1. De novo liver transplant patients (Fig. 1a)
5.2.1. Practical implications
6.1.1. Initiation of EVR and target trough concentration
Monitor lipid prole and manage dyslipidemia closely with combi-
Liver transplantation is associated with a relatively high
nations of diet modication, appropriate statin therapy, ezetimibe,
rate of post-transplant healing complications and surgical re-
sh oils, brates or extended release niacin and physical activity.
interventions, such as laparotomy. The product license therefore
recommends that EVR be initiated approximately four weeks after
liver transplantation at a starting dose of 1.0 mg twice daily, targeting
5.3. Pregnancy and male fertility
a trough concentration 38 ng/mL, in combination with tacrolimus
and steroids.
Retrospective studies, mostly from the early high-dose era of
In practice, the authors usually start EVR at either 0.75 mg or
sirolimus therapy, have suggested a potential negative effect of mTOR
1.0 mg twice daily, increasing the dose progressively as required,
inhibitors on male gonadal function [99]. If male patients with a low
usually to a maximum of 2 mg b.i.d. The ideal target trough level
sperm count under sirolimus wish to reproduce, they may be successful
should be 56 ng/mL, particularly during the early post-
under sirolimus or can be switched to another drug for a period. Tissue
transplant period (i.e. the rst four months) but certainly levels
banks may not accept sperm from donors with viral hepatitis. The role
should not fall below 3 ng/mL. Dose adjustments are required ac-
of mTOR inhibitors in pregnancy is poorly documented, being limited
cording to trough level, individual response, tolerability, and
to single case reports that have not described signicant fetal effects
changes in co-medications [68] but should be made only after measur-
[100]. The authors are cautiously optimistic about breast-feeding
ing trough levels 45 days after reaching steady state. Trough level
under mTOR inhibitor therapy, but more data are required. Given the
should be monitored after any dose change and then at regular consul-
small number of cases and the variety of immunosuppressive regimens,
tation visits.
only broad-based registry participation will provide the evidence need-
In patients with renal impairment at time of transplant, inter-
ed to support more condent recommendations.
leukin 2 (IL-2) receptor antagonist induction therapy with
basiliximab should be followed by triple therapy comprising
5.3.1. Practical implications MPA, low-dose steroids and tacrolimus delayed until days 35 (targeting
EVR should be stopped if pregnancy is planned (at least six weeks 610 ng/mL during the rst month). EVR can then be initiated from
before conception) or occurs. week 4.

Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx 7

A Liver Tx

Renal impairment
TAC MPA + steroids CsA MPA + steroids
at time of transplant

Basiliximab induction
Delayed CNI (day 3-5)
MPA + low-dose steroids

EVR 1.0mg bid EVR <1.0mg bid

Week 4 Discontinue MPA overnight Discontinue MPA overnight
Continue steroids Continue steroids

Measure EVR trough Measure EVR trough

level after 4-5 days level after 4-5 days

Measure EVR trough When EVR trough is When EVR trough is

level 4-5 days after 3-8ng/mL, progressively 3-8ng/mL, rapidly reduce
any dose change reduce TAC to 3-5ng/mL CsA to 50-100ng/mL

Target EVR trough Target EVR trough

Month 3 level 5-6ng/mL* level 5-6ng/mL*
(minimum 3ng/mL**) (minimum 3ng/mL**)

* Particularly to month 4 post-transplant

** Increase dose if <3ng/mL and measure trough level 4-5 days later

B Maintenance patients
(>6 months post-transplant)

Reduced CNI EVR monotherapy

(only >1 year post-transplant)

CNI MPA + steroids CNI MPA + steroids

EVR 0.75 bid EVR 1.0 mg bid

Day 0 Discontinue MPA overnight Discontinue MPA overnight
Continue steroids Continue steroids

Increase dose if EVR Measure EVR trough

Day 7 trough level <3ng/mL level after 4-5 days

Measure EVR trough When EVR trough is

level every 4-5 days to When EVR trough is
3-8ng/mL, progressively 6-12ng/mL, taper &
day 21 and after reduce CNI (e.g. discontinue CNI
any dose change TAC 3-5ng/mL)

Target EVR Target EVR trough

trough level >3ng/mL* level 6-12ng/mL**

* Increase dose if <3ng/mL and measure trough level 4-5 days later
** Increase dose if <6ng/mL and measure trough level 4-5 days later

Fig. 1. Suggested approach to everolimus (EVR) dosing in (a) de novo and (b) maintenance liver transplant patients.

Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
8 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx

Table 4
Areas for future research relating to everolimus therapy in liver transplantation.

Topic Rationale Study data required in Ongoing study/studies

liver transplantation

Earlier introduction of EVR
(before week 4 post-transplant)
Prevention of HCC recurrence
and survival after tx for HCC
Prevention of malignancy/survival
benet for de novo post-tx cancer
Prevention of skin cancer
recurrence after liver tx
De novo DSA
Dyslipidemia
Randomized trials to date have not Prospective, randomized data HEPHAISTOS
started CNI reduction/withdrawal b30 days (NCT01551212) [103]
Limited data to date suggest benet [48] Prospective data H2307 (everolimus)
e.g. casecontrolled (NCT01888432)
cohort studies SILVER study (sirolimus)
(NCT003558662)
Only retrospective data available to Prospective data from larger SIMCER study (EVR)
date in liver transplantation [69] studies e.g. cohort or (NCT01625377)
case-control studies extension phase
(CERTITUDE)
Switch from CNI to mTOR inhibitor Prospective data -
inhibits SCC recurrence after kidney tx [86] e.g. case-controlled cohort studies
Switch from CNI to EVR with low-dose Prospective data evaluating
MPA steroids at M3 associated with rate of de novo DSA under
under-immunosuppression and increased EVR + MPA (CNI-free) vs. EVR
DSA in kidney transplantation [104] with reduced CNI
EVR therapy is associated with increased Long-term data on SIMCER study (EVR)
lipid levels but antiproliferative effects may be cardioprotective cardiovascular event rate (NCT01625377)
extension phase (CERTITUDE)

CNI, calcineurin inhibitor; DSA, donor-specic antibodies; EVR, everolimus; HCC, hepatocellular carcinoma; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; SCC, squamous
cell carcinoma; tx, transplantation.

6.1.2. Switch from MPA
MPA can be safely discontinued abruptly (overnight) when EVR
is introduced with concomitant CNI, as demonstrated in the H2304
trial [9].
6.1.3. Concomitant MPA therapy
Randomized trials to date have not included MPA therapy in
everolimus-based CNI-free treatment regimens [1113]. The ongoing
SIMCER study, however, randomizes de novo liver transplant patients
at one month post-transplant to either switch from tacrolimus to everoli-
mus while continuing MPA therapy (steroids) or to remain on tacrolimus
with MPA (steroids), all with basiliximab induction (NCT01625377). The
primary endpoint is change in eGFR from randomization to month 6
post-transplant, and results are awaited with interest.
6.1.4. Concomitant CNI therapy
CNI dose should be progressively reduced only after EVR trough
level reaches the range 38 ng/mL. The nal tacrolimus target range is
35 ng/mL [9]. EVR exposure is increased in patients receiving concom-
itant cyclosporine A (CsA) compared to tacrolimus [101,102]. In CsA-
treated patients, the authors start EVR at a dose less than 1 mg/day
twice daily and rapidly reduce the CsA dose (targeting 50100 ng/mL)
after EVR trough level reaches 38 ng/mL.
6.1.5. EVR monotherapy
EVR monotherapy is not generally recommended during the rst
12 months after liver transplantation, due to an increased rejection
risk [9], although earlier monotherapy may be appropriate in certain
cases e.g. onset of malignancy. CNI withdrawal, if undertaken, should
be carried out gradually (e.g. over eight weeks) and induction therapy
may be helpful to maintain immunosuppressive efcacy, as in the
PROTECT study protocol [11].
6.2. Maintenance liver transplant patients (Fig. 1b)
6.2.1. EVR initiation and target trough concentration
In the RESCUE trial, EVR was started in patients who had undergone
liver transplantation at least 12 months previously at an initial dose of
0.75 mg b.i.d., adjusted after two weeks to target a trough concentration
of 38 ng/mL in CNI-treated patients and 612 ng/mL if CNI therapy was
eliminated [12]. To improve tolerance, the authors usually start EVR at a
dose of between 0.25 and 0.75 mg b.i.d., slowly increasing the dose over
approximately three weeks to achieve the same targets and continuing
monitoring at routine consultation visits.
For patients in whom EVR is introduced in response to renal deteri-
oration, the RESCUE study showed a signicant inverse relationship be-
tween baseline renal function and the renal benet from switch to EVR
[12], so EVR should be considered as early as possible.
6.2.2. Switch from MPA
As in the de novo setting, MPA can be stopped abruptly when EVR is
introduced in maintenance patients.
6.2.3. EVR monotherapy
The authors consider that EVR monotherapy is an option after the
rst post-transplant year in selected patients, with very low rates of re-
jection reported [12,65]. In the absence of concomitant CNI or MPA, the
target EVR range should be 610 ng/mL.
7. Future prospects
Certain questions remain unanswered about EVR therapy in liver
transplantation and novel indications for its use that require explora-
tion. Several clinical studies are underway which may shed light on
these questions (Table 4).
There is a particular need for further research into the potential ef-
fects of EVR therapy on recurrence of HCC, and recurrence or de novo de-
velopment of skin and non-skin cancers after liver transplantation
potentially one of the most interesting aspects of EVR-based immuno-
suppression. Experience from kidney transplantation cannot necessarily
be extrapolated.
Certain safety aspects, notably the risk of de novo donor-specic
antibody (DSA) production after CNI withdrawal, and the balance
of conventional cardiovascular risk factors versus potentially
cardioprotective effects associated with mTOR inhibition [88], also
merit additional investigation. Further studies and clinical experience
may also help to improve rates of EVR discontinuation, as familiarity
with adverse events and their management grows [68], and ideally
may help to identify patients at risk for events such as proteinuria in
order to target EVR use more accurately.
Lastly, there is growing interest in dening possible biomarkers
which could identify patients in whom EVR is likely to be most

Please cite this article as: Dumortier J, et al, Use of everolimus in liver transplantation: The French experience, Transplant Rev (2016), http://
dx.doi.org/10.1016/j.trre.2015.12.003
 J. Dumortier et al. / Transplantation Reviews xxx (2016) xxxxxx
benecial, for example regarding prevention of HCC recurrence [105]
and minimizing intolerance, although this is still at a very early stage.
Although further research is required, EVR has become an
established part of the immunosuppressive arsenal for liver transplant
recipients over the last decade. Centers which have embraced its use
have learned strategies for EVR initiation and dosing, and optimal con-
comitant regimens, while managing side effects to minimize intolerance.
The experience summarized here may help other centers develop their
own strategies for incorporating EVR into local liver transplant care.
Conict of Interest
The authors have the following conicts of interest to declare in
relation to Novartis in the last three years:
Jerme Dumortier has received a grant, research support and
speaker's fees from Novartis and is a member of a Novartis advisory
committee.
Sebastian Dharancy has received a grant and speaker's fees from
Novartis, Gilead, BMS and is a member of advisory committees for
Novartis, Chiesi and Gambro advisory committee.
Yvon Calmus has participated in advisory boards for Novartis and
been an investigator for clinical studies funded by Novartis.
Christophe Duvoux has participated in advisory boards for Novartis.
Franois Durand has been a consultant for Novartis, Astellas, Gilead
and BMS and has received grants from Astellas and Gilead.
Ephrem Salame has participated at advisory boards for Astellas,
Novartis, Chiesi, Gilead, Sano and Roche.
Faouzi Saliba has received speaker fees and/or research funding
from, and/or has participated at advisory boards for, Novartis, Astellas,
Roche, Genzyme, Merck Sharp & Dohme, Gilead, Janssen, Gambro and
Vital Therapies.
Acknowledgements
The authors would like to thank Pr Georges-Philippe Pageaux of
Saint Eloi University Hospital, University of Montpellier I, Montpellier,
France, for his review of the manuscript. Medical writing support for
the authors was funded by Novartis Pharma SAS.
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