Antiviral effects of mTOR-inhibitors: Focus on Everolimusicnu.ir/uploads/manual/2016/ppt/2/A/1200.pdf · Antiviral effects of mTOR-inhibitors: Focus on Everolimus Prof. Lionel ROSTAING,

Antiviral effects

of mTOR-inhibitors:

Focus on Everolimus

Prof. Lionel ROSTAING, MD, PhD

Clinique Universitaire de Néphrologie

CHU Grenoble, France

[email protected]

2nd ICNU meeting Tehran August 2nd 2016-1-

Place of mTOR inhibitors

• To avoid-CNI-associated nephrotoxicity

• To preserve renal function

• To prevent viral infections, e.g. CMV, BKV

• To decrease the rate of de novo cancers

• To improve cardiovascular outcomes

-2-

Commonly reactivated viruses in solid organ

transplant recipients

Virus Occurrence

VZV (HHV3) VZV infection: 2–10% of adult kidney and liver transplant recipients

EBV (HHV4) EBV-associated PTLD incidence: 1–6% in kidney or liver transplant patients

CMV (HHV5) CMV infection: >50% solid-organ transplant recipients within the first 3 months posttransplant

without antiviral prophylaxis

Common in kidney, liver and heart transplants

HHV6 Replication rate: 31–55%

Similar effect as CMV

HHV8 Incidence of Kaposi’s sarcoma: 1.24% in liver and 0.45% in kidney transplant recipients

HCV Accounts for 30% liver transplants

Recurrence is universal

HBV Geographic location–dependent

Recurrence rate <5% with the use of oral antiviral therapies

BKV BK viruria: ~30% immunosuppressed kidney transplant recipients

HPV Posttransplant incidence: 24–53% in solid organ transplant recipients

Parvovirus Parvovirus B19-mediated anemia reported to occur in 38% kidney transplant recipients with

anemia resistant to erythropoietin

Brennan DC, et al. Rev Med Virol. 2013;23:97–125.-3-

Cytomegalovirus

-4-

CMV infection is a major problem post-kidney

transplant

• CMV infection occurs in >50% of

transplant recipients and can result

in graft failure and rejection1,2

• CMV has many effects, both direct

and indirect, including acute and

chronic allograft dysfunction/CAN3,4

• CMV infection and CMV disease

are strongly associated with acute

rejection in renal transplant

recipients5

Transplant population6 Risk of CMV

disease, %

Heart–lung 39

Liver or pancreas 29

Heart 25

Kidney 8

CMV, cytomegalovirus; CAN, chronic allograft nephropathy

-5-

CMV infection has multiple detrimental effects in

solid organ transplant patients

CMV

infection

Indirect

effects

Direct

effects

CMV

syndrome

Organ-invasive

disease

CAN / IFTA4 CVD3 and

diabetes5

Acute / chronic

rejection1–3

Opportunistic

infections1–3 Malignancy1–3

1. Preiksaitis JK, et al. Am J Transplant 2005;5:218–227;

2. Fishman JA, Rubin RH. N Engl J Med 1998;338:1741–1751;

3. Valenzuela M, et al. Transplant Proc 2009;41:2673–2675;

4. Lautenschlager I, et al. Monogr Virol Basel, Karger 2003;24:10–22;

5. Leung Ki EL, et al. Clin Transplant 2008;22:245–249

-6-

CMV infection is associated with reduced

long-term survival in renal transplant patients

Prospective analysis of long-term survival of 471 kidney transplant recipients

transplanted between 1994–1997

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0Probability

of long-term

patient

survival

1000 2000 3000

Time post-transplant (days)

Low mortality risk, CMV–

Low mortality risk, CMV+

High mortality riska, CMV–

High mortality riska, CMV+

0

Sagedal S, et al. Clin Transplant 2007;21:309–313

-7-

Late-onset CMV infection remains a significant

problem despite prophylaxis

29%

(51 / 176)

Prophylaxisa

Statistical analysisb demonstrated a significant association between delayed onset tissue-invasive CMV disease and allograft loss or death

0

5

10

15

20

25

30

35

3630241812630

Retrospective analysis of a cohort of 176 kidney transplant recipients

at high-risk for CMV disease (donor +ve; recipient -ve)

Cumulative

incidence

(%)

Time since transplantation (months)

Arthurs SK et al. Clin Infect Dis 2008;46:840–846

-8-

Incidence of viremia, CMV syndrome, and peak

CMV load in D+R- kidney transplant recipients

Pro

po

rtio

n o

f p

ati

en

ts, %

CMV-viremia (n=158) and CMV-syndrome

(n=18) by Donor/Recipient serostatus

Peak viral loads (n=158) in D+R-, D+R+

and D-R+ groups at risk of CMV

infections

D+R-(n=28) D+R+(n=83) D-R+(n=47)

Pe

ak

vir

al lo

ad

(g

en

om

es

/ml) 106

105

104

103

102

P<0.0001

P<0.0001

Atabani SF, et al. AJT. 2012;12:2457–2464.-9-

CMV infection can lead to CAN / IFTA

CMV infection ofendothelial cells

proinflammatory cytokine production

Inflammation

Growth factor productionT-cell activation adhesion molecules

CMV-stimulatedimmune response

CAN / IFTA

Tubular atrophy, transplant vasculopathy, interstitial fibrosis, glomerulopathy

FibrosisPlaque formation

Inflammation of surrounding tissueInflux of inflammatory cells

Intimal thickening

Up-regulation of donor-specific

cytotoxic T-cells

Lautenschlager I, et al. Monogr Virol Basel, Karger 2003;24:10–22.

-10-

CMV infection: mTOR-Is vs. Antimetabolite

(in addition to CNIs)

Risk of cytomegalovirus (CMV) infection within the first year after

transplantation, stratified by antimetabolite comparator.

Webster AC et al. Transplantation 2006

-51%

-11-

Is cytomegalovirus prophylaxis dispensable in patients

receiving an mTOR inhibitor-based immunosuppression?

a systematic review and meta-analysis. (1)

Andrassy J, et al. Transplantation. 2012;;94:1208-1217

Flowchart of the selection of articles.

-12-




Andrassy J, et al. Transplantation. 2012;;94:1208-1217

Forest plot indicating the odds ratio of the occurrence of CMV on mTOR-Is

versus CNIs

CNI

-13-




CNI

Forest plot indicating the odds ratio of the occurrence of CMV on a

combination of mTOR-Is and CNIs versus CNIs

Andrassy J, et al. Transplantation. 2012;;94:1208-1217-14-

Spanish cohort (Sept. 2003 Feb. 2005) including 1,470 KTx patients: assessment of

predictive factors for CMV disease (n = 99; 6.7%) of whom 37 had tissue invasion.

Odds Ratio p

Donor age > 60 years 2.3 (1.5 – 3.7) <0.001

Cyclosporin (Yes) 1.7 (1.1 – 2.9) 0.03

Sirolimus (Yes) 0.27 (0.1 – 0.78) 0.016

Kidney-pancreas transplant (yes)

3.7 (1.5 – 9.1) 0.005

CMV D+/R- 7.3 (4.4 – 12) < 0.001

OKT3 or rATG (Yes) 2.14 (1.1 – 4.4) 0.04

Acute rejection (Yes) 2.7 (1.6 – 4.4) < 0.001

Renal dysfunction (Yes) 1.8 (1.1 – 2.9) 0.01

San Juan R et al. CID 2008;47:875-882

Predictive factors for CMV disease after kidney

transplantation

-15-

Everolimus-based calcineurin-inhibitor sparing

regimens for kidney transplant recipients:

a systematic review and meta-analysis (1).

Su L, et al. Int Urol Nephrol 2014;46:2035-2044

Meta-analysis in order to compare with regards to CMV infection the

efficacy of EVR-based CNI-sparing and standard CNI regimens in

KTs patients

7 studies that included 2,067 patients ;

6/7 studies included CsA as the CNI

-16-

Everolimus-based calcineurin-inhibitor sparing

regimens for kidney transplant recipients:

a systematic review and meta-analysis (2)

Su L, et al. Int Urol Nephrol 2014;46:2035-2044

Incidence of CMV infections was evaluated in six studies. Everolimus with CNI sparing did not contribute to any

more infections with an RR = 1.05 (95 % CI [0.97, 1.13]; P = 0.2; heterogeneity, I 2 = 0 %). Incidence of CMV infection

was lower in CNI sparing group (RR 0.47; 95 % CI [0.32, 0.70]; P = 0.0002; heterogeneity, I 2 = 61 %;

-17-

http://link.springer.com/search?dc.title=Everolimus&facet-content-type=ReferenceWorkEntry&sortOrder=relevance

Brennan DC et al. AJT 2011;11:2453-2462

Kaplan–Meier plot for any CMV event, comparison between everolimus 1.5 mg/day, everolimus 3.0

mg/day and MPA for KTx patients according to CMV prophylaxis.

CMV prophylaxis

No CMV prophylaxis P=0.006

P<0.0001

Studies B201, B251, and A2309; n=2004CsA +steroids + either MPA or EVR

CMV incidence between Everolimus vs.

Mycophenolate in de novo KTx:

pooled analysis of 3 clinical trials (1)

-18-

Brennan DC et al. AJT 2011;11:2453-2462

Kaplan–Meier plot for CMV viremia, comparison between everolimus 1.5 mg/day, everolimus 3.0

mg/day and MPA for KTx patients according to CMV prophylaxis.

CMV prophylaxisNo CMV prophylaxis

P=0.0002

P=0.08

CMV incidence between Everolimus vs.

Mycophenolate in de novo KTx:

pooled analysis of 3 clinical trials (2)

-19-

*All patients were administered basiliximab within 2 hours pre-transplantation and 4 days thereafter. Oral steroids administered according to local practice throughout the trial; CsA, cyclosporine;

Month 24

From Day 5 onwards; CsA (microemulsion) dose adjustments were made based on CsA C0-h; EVR: everolimus; MPA, mycophenolic acid (Myfortic, enteric-coated mycophenolate sodium); RD-CsA, reduced exposure CsA; ST-CsA, standard exposure CsA; C0-h, blood level at time zero or “trough”

Day 5 Month 4

Time (months)

post-transplantation Month 2 Month 6

EVR 1.5 mg/day (C0-h 3–8 ng/mL) + reduced-dose CsA (RD-CsA), N=277

<24 h

Transplant

surgery

Basiliximab*

±steroids*

CsA C0-h 100–

200 ng/mL

CsA C0-h

75–150 ng/mL

CsA C0-h

50–100 ng/mL

CsA C0-h

25–50 ng/mL

EVR 3.0 mg/day (C0-h=6–12 ng/mL) + RD-CsA, N=279

CsA C0-h

100–200 ng/mL

CsA C0-h

75–150 ng/mL

CsA C0-h

50–100 ng/mL

CsA C0-h

25–50 ng/mL

MPA 1440 g/day + Std-CsA, N=277

CsA C0-h

200–300 ng/mLCsA C0-h 100–250 ng/mL

Randomization

First dose of

study drug

(Day 1)

Month 12

Primary analysis

Combination of ciclosporine low-dose and

everolimus (Study RAD001A 2309)

Tedesco Silva H Jr et al. AJT 2010-20-

Lower incidences of BKV and CMV infections with both

EVR regimens vs. MPA (Safety population, Month 12)

0

10

20

30

40

50

60

70

80

Any

infection

Bacterial Fungal Viral BK virus CMV

Pe

rce

nt

inc

ide

nc

e o

f in

fec

tio

ns

, n

EVR 1.5 mg EVR 3.0 mg MPA 1440 mg

175 175

186

71 69 69

12 14 14

2720

57

2 311

3 1

23

Tedesco Silva H Jr et al. AJT 2010

Prospective assessment over the 1st year post-KTx

of CMV DNAemia, BKV DNAemia and BKV viruria

-21-

Reduced Incidence of Cytomegalovirus Infection in

Kidney Transplant Recipients Receiving Everolimus

and Reduced Tacrolimus Doses (1)

Tedesco Silva H et al. AJT 2015;15:2655-2664-22-

Mean tacrolimus whole blood concentrations.

Mean everolimus blood (whole) and mean

mycophenolate acid (plasma) concentrations.





Cumulative incidence of CMV infection/disease during the 12 months of follow up.





Impact of Everolimus and Low-dose Ciclosporin

on Cytomegalovirus Replication and Disease in

Pediatric Renal Transplantation (1)

Höcker B et al. AJT 2015 doi:10,111/ajt.13649-25-




Höcker B et al. AJT 2015 doi:10,111/ajt.13649-26-




Höcker B et al. AJT 2015 doi:10,111/ajt.13649

Risk factors in pediatric renal transplant recipients (n = 301)

for developing CMV replication (n = 41)

-27-

BK virus

-28-

Decoy cells

in urinec,3

Infected tubular

epithelial cellsb,3

BK-PyVANa,3

BK-PyVAN

1–10%1,2

BKV viraemia

~10–20%2

BKV viruria

30–50%2

BKV

seropositive

80–90%2,3

BKV replication is common in the renal

transplant population

1. Egli A et al. J Infect Dis2009;199:837–846;

2. Hirsch HH et al. N Engl J Med 2002;347:488–496;

3. Nickeleit V et al. N Engl J Med 2000;342:1309–1315.-29-

The influence of immunosuppressive agents on BK

virus risk following kidney transplantation, and

implications for choice of regimen (3)

Suwelack B et al. Transplantation Rev. 2012;26:201-211

Relative risk (month 24 posttransplant) OPTN data (2003–2006)

Variable Adjusted hazards ratio 95% CI

Induction therapy

Thymoglobulin vs IL-2 receptor antagonist induction 1.42 1.24–1.73

IL-2 receptor antagonist vs no induction 1.03 0.89–1.20

CNI therapy

No CNI vs tacrolimus 0.78 0.58–1.05

CsA vs tacrolimus 0.53 0.45–0.63

CNI therapy

No antimetabolite vs MMF 0.73 0.61–0.87

Azathioprine vs MMF 0.42 0.17–1.01

Corticosteroids

Yes vs no 1.16 1.02–1.31

mTOR inhibitors

Yes vs no 0.69 0.54–0.89

Relative risk of treatment of BKV infection within the first 12 or 24 months after kidney transplantation

reported in analyses of data from transplants recorded by the Scientific Renal Transplant Registry during

2004–2006 and the OPTN during 2003–2006, according to type of induction or maintenance

immunosuppression at the time of initial hospital

-30-

Retrospective analysis of Scientific Registry of Transplant Recipients database

from 34,937 solitary renal transplant recipients 2004–2006 using the term

‘Treatment for BK (polyoma) virus’

Time post-transplant (months)

0 12 24 36

1.00

0.95

0.90

0.85

0.80

0.75

0.70

Log-rank

P<0.001

BKV treatment within 6 months

No BKV treatment within 6 months

Significant difference

in overall graft

survival at 3 years

• 90% for patients

without treatment

for BKV

• 79% for patients

with treatment for

BKV (P<0.001)

Registry data confirm BKV replication is

associated with graft lossO

vera

ll g

raft

su

rviv

al

Schold JD et al. Transpl Int. 2009;22:626–634

-31-

The highest rates of BKV viremia and viruria

observed at 6 months after kidney transplantation

BKV viremia and viruria after kidney transplantation (n=682)

Viruria

Viremia

0 1 2 3 6 12

% o

f p

ati

en

ts

Month

Patients (n, urine) 378 582 584 592 558 462

Patients (n, plasma) 609 607 600 598 564 487

Hirsch HH, et al. Am J Transplant. 2013;13:136–145.

-32-

Infectious complications after ABO-i kidney

transplantation (1)

Habicht A, et al. NDT 2011;26:4124-4131

Incidence of infectious complications in ABOi and ABOc recipients One or more episodes of viral

infections, including CMV, HSV, VZV and BKV infections occured significantly more often in ABOi

recipients as compared to ABOc recipients (P=0.038).

-33-



transplantation (2)

-34-



transplantation (3)

-35-

BKV infection after ABO-i or HLA-i kidney

transplantation

• Retrospective analysis from 1998 to 2010 (62 ABO-incompatible and 221 HLA-

incompatible kidney transplantaion). Focus on patients in whom BKVAN was diagnosed by

biopsy (per protocol or for cause).

• Risk for BKVAN was greater among ABO-i than HLA-i patients (17.7% versus 5.9%;

P=0.008).

Of BKVAN cases, 42% were subclinical, diagnosed by protocol biopsy.

ABO-i and age were independent predictors for BKVAN on logistic regression.

C4d deposition without histologic features of glomerulitis and capillaritis (graft accommodation-like

phenotype) on 1-year biopsies of ABO-incompatible patients with and without BKVAN was 40%

and 75.8%, respectively (P=0.04).

Death-censored graft survival (91%) and serum creatinine level among surviving kidneys (1.8

mg/dL) were identical in ABO- and HLA-incompatible patients with BKVAN (median, 1399 and

1017 days after transplantation, respectively).

Sharif A, et al. CJASN 2012;7:1320-7.-36-

Incidence and outcomes of BK virus allograft

nephropathy among ABO-and HLA-Incompatible

kidney transplant recipients (2)

Sharif A et al. CJASN 2012;7:1320-1327

Incidence of BK virus allograft nephropathy in incompatible kidney transplant recipients (diagnosed by protocol

and for-cause biopsies). Cumulative incidence was 17.7% for ABO-incompatible kidney recipients and 5.9% for HLA-

incompatible kidney recipients; the difference was statistically significant (P=0.008).

Median time to BKVAN 134 days

Median time to BKVAN 183 days

Overall 3% of BKVAN between 1997 to 2008

-37-

http://cjasn.asnjournals.org/content/7/8/1320/F1.large.jpg

http://cjasn.asnjournals.org/content/7/8/1320/F1.large.jpg

Incidence and outcomes of BK virus allograft

nephropathy among ABO-and HLA-Incompatible

kidney transplant recipients (6)

Variable Odds Ratio P Value

ABO incompatibility 2.32 0.04

Age (median ≥ 46 yr) 3.27 0.01

Independent predictors for development of BK nephropathy by multivariable logistic

regression analysis

Sharif A et al. CJASN 2012;7:1320-1327

-38-

Moscarelli L et al. Clin Transplant. 2013;27:546-554

Patient selection and disposition

Everolimus leads to a lower risk of BKV viremia than

mycophenolic acid in de novo renal transplantation

patients: a single-center experience (1)

58 238

-39-

40

HR for BK viremia :

1.71, 95% CI:1.08-2.69; p=0.02

Kaplan–Meier plot of polyomavirus viremia-free patients in the two groups.

Moscarelli L et al. Clin Transplant. 2013;27:546-554

EVR

MPA

Everolimus leads to a lower risk of BKV viremia than

mycophenolic acid in de novo renal transplantation

patients: a single-center experience (2)

-40-

*All patients were administered basiliximab within 2 hours pre-transplantation and 4 days thereafter.

Oral steroids administered according to local practice throughout the trial; CsA, cyclosporine;

Month 24

From Day 5 onwards; CsA (microemulsion) dose adjustments were made based on CsA C0-h; EVR: everolimus; MPA, mycophenolic acid (Myfortic, enteric-coated mycophenolate sodium); RD-CsA, reduced exposure CsA; ST-CsA, standard exposure CsA; C0-h, blood level at time zero or “trough”

Day 5 Month 4Time (months)post-transplantation Month 2 Month 6

EVR 1.5 mg/day (C0-h 3–8 ng/mL) + reduced-dose CsA (RD-CsA), N=277

<24 h

Transplant surgery

Basiliximab*±

steroids*

CsA C0-h 100–200 ng/mL

CsA C0-h75–150 ng/mL



EVR 3.0 mg/day (C0-h=6–12 ng/mL) + RD-CsA, N=279





MPA 1440 g/day + Std-CsA, N=277


CsA C0-h 100–250 ng/mL

Randomization First dose of study drug

(Day 1)

Month 12Primary analysis

Combination of ciclosporine low-dose and

everolimus (Study RAD001A 2309)

Tedesco Silva H Jr et al. AJT 2010-41-

Lower incidences of BKV and CMV infections with both

EVR regimens vs. MPA (Safety population, Month 12)

0

10

20

30

40

50

60

70

80

Any

infection

Bacterial Fungal Viral BK virus CMV

Pe

rce

nt

inc

ide

nc

e o

f in

fec

tio

ns

, n

EVR 1.5 mg EVR 3.0 mg MPA 1440 mg

175 175

186

71 69 69

12 14 14

2720

57

2 311

3 1

23

Tedesco Silva H Jr et al. AJT 2010

Prospective assessment over the 1st year post-KTx

of CMV DNAemia, BKV DNAemia and BKV viruria

-42-

Everolimus-based immunosuppression therapy

for BK virus nephropathy (1)

Polanco N, et al. Transplant Proc 2015;47:57-61

• Prospective single-center case series study.

• 15 cases of BKV-nephropathy (2007 2010)

Modification of IS : withdrawn of MMF and conversion

from tacrolimus to EVR

-43-




sCr Before

BKN

sCr at

Diagnosis

of BKN

Proteinuria

(g/d)

Decoy

Cells

PCR-BK

Virus in

Plasma

Viral Load

of BK

Virus on

Diagnosis

Histology

Pattern

Simultane

ous Acute

Rejection

1 1.2 2.1 0.08 -- + 15,936 A No

2 1.28 2.3 0.06 Positive + 250,053 B Yes

3 1 1.7 0.03 -- + 1,036,782 -- --

4 1 1.8 0.29 Positive + 209,347 B Yes

5 1 1.5 0.28 -- + 64,713 -- --

6 1.65 1.9 0.3 -- + 10,715 -- --

7 1.3 2.17 0.3 Positive + 632,875 -- --

8 1.36 1.92 0.28 -- + 10,836 A Yes

9 1.2 1.79 0.27 Negative + 84,369 A Yes

Pattern A: Viral cytopathic changes in a normal renal parenchyma. Interstitial fibrosis and tubular atrophy and inflammation: insignificant or absent.

Pattern B: Combination of viral cytopathic changes and areas of interstitial fibrosis and tubular atrophy and focal/multifocal inflammation.

Abbreviations: BKN, BK virus nephropathy; sCr, serum creatinine.

Analytic and Histology Data of the Nine Patients at the Time of Diagnosis of BKN

-44-




Evolution of the serum creatinine (sCr) mean. BKN, BK virus nephropathy;

mTOR-i, mammalian target of rapamycin inhibitors.

-45-




Evolution of renal function of patients with conversion to mammalian target of rapamycin

inhibitors (group 1) and those in whom no conversion was made (group 2).

-46-

Factors influencing viral clearing and renal function

during polyomavirus BK-associated nephropathy

after renal transplantation (1)

Schwarz A, et al. Transplantation 2012;94:396-402

• 2008 2010 : 46 out of 859 KTx patients (51%) were diagnosed

with BKV-associated nephropathy

Intervention :

Reduction in MMF and CNI by 30 to 50% (n=53)

Or

Conversion from CNI to mTOR-Is at first instance (n=7) or in a

second instance in patients resulted in prolonged reduction in

BKV viral reduction (n=16)

-47-

Factors influencing viral clearing and renal function

during polyomavirus BK-associated nephropathy

after renal transplantation (2)

Schwarz A, et al. Transplantation 2012;94:396-402

Survival analysis (Cox

regression models) on viral load

reduction, defining reduction of

viral load by 1 log as an event;

the number of weeks needed to

reduce BK virus (BKV)

quantitative polymerase chain

reaction (qPCR) by 1 log was

used as the time variable; the

censored patients (those who

did not meet the event, n=2) are

marked with a vertical bar.

Kaplan-Meier curve of variable

immunosuppression.

-48-

Thank you for your attention.

-49-

Documents

Antiviral effects of mTOR-inhibitors: Focus on Everolimusicnu.ir/uploads/manual/2016/ppt/2/A/1200.pdf · Antiviral effects of mTOR-inhibitors: Focus on Everolimus Prof. Lionel ROSTAING,