© 2013 Direct One Communications, Inc. All rights reserved. 1 Current Perspectives on Personalizing Immunosuppression in Liver Transplantation Amit K

© 2013 Direct One Communications, Inc. All rights reserved. 1

Current Perspectives on Personalizing Immunosuppression in Liver Transplantation

Amit K. Mathur, MD, MS

University of Michigan Hospital and Health System, Ann Arbor, Michigan

A REPORT FROM THE 2013 AMERICAN TRANSPLANT CONGRESS


History of Immunosuppression

Immunosuppressants suppress the host response to incompatible graft antigens and retain the body’s normal programmed response to foreign antigens.1

Sir Roy Calne and his group at Cambridge University2,3 conducted the initial cyclosporine studies in solid organ transplant patients.

In the 1980s, several clinical studies investigated tacrolimus as an alternative to cyclosporine in liver transplant recipients. 4–6

Cyclosporine and tacrolimus represented a great advance in clinical liver transplantation and were studied using various protocol designs.


History of Immunosuppression

Rejection rates were much lower with cyclosporine and tacrolimus than those observed with traditional immunosuppressants.2,4–7

Problematic study designs involving cyclosporine and tacrolimus failed to demonstrate an actual survival benefit after liver transplantation.

Rates of secondary complications, such as renal failure, were exceptionally low with both drugs.

Study patients may have been subject to selection bias and were not particularly representative of the population being transplanted.


Tacrolimus vs Cyclosporine

In 1994, the US Multicenter FK506 Liver Study Group8 reported on 478 adults and 51 children given tacrolimus or cyclosporine for a first liver transplant.

Patient and graft survival rates 1 year later were statistically the same.

Compared with cyclosporine, tacrolimus resulted in:

» Significantly fewer acute rejection episodes

» Lower rates of corticosteroid-resistant rejection

» Fewer refractory rejection episodes



In this trial, tacrolimus led to higher rates of adverse events, including nephrotoxicity and neurotoxicity, and resulted in treatment conversion or study withdrawal.

» 37 patients in the tacrolimus arm (14%) and 13 in the cyclosporine arm (5%) discontinued the study because of adverse events (P < 0.001).

Nevertheless, based in large part on the results of this study, tacrolimus rapidly supplanted cyclosporine for long-term immunosuppression following liver transplantation, at least in the United States.



A 5-year follow-up study of the US trial showed comparable patient and graft survival rates for tacrolimus and cyclosporine.9

Half-life patient survival was significantly longer with tacrolimus.

Survival of hepatitis C virus (HCV)-positive patients was significantly better with tacrolimus.

Both groups had a low incidence of late acute rejection, late corticosteroid-refractory rejection, and death or graft loss related to rejection at 5 years after transplantation and an acceptable safety profile.



A European trial comparing cyclosporine with tacrolimus in 545 primary liver transplant patients confirmed similar graft and patient survival at 1 year.10 Tacrolimus was associated with fewer episodes

of acute, refractory, and chronic graft rejection.

Despite a higher frequency of adverse events, tacrolimus therapy was superior to cyclosporine in lowering rejection rates and permitting a reduction in concomitant corticosteroid dosing.



A clinical trial in the UK and Ireland randomized 606 patients undergoing a first orthotopic liver transplant to receive either cyclosporine or tacrolimus.11 At 1 year post transplant, patients in the tacrolimus

arm had lower rates of death, retransplantation, and treatment failure due to immunologic causes.

The superior efficacy of tacrolimus over cyclosporine for de novo liver transplantation was clear.



At 3-year follow-up, the benefits of tacrolimus over cyclosporine in the UK and Ireland trial were confirmed.12

» 62% of tacrolimus patients and 42% of cyclosporine patients were alive with their original graft and still on their allocated study medication at 3 years (P < 0.001).

» No difference between tacrolimus and cyclosporine was seen in HCV-positive patients.

» The greater nephrotoxicity of tacrolimus in this trial may have been due to the high drug plasma levels achieved.

Analysis of 10-year data from the Scientific Registry of Transplant Recipients13 led to adoption of tacrolimus-based protocols.


Current Immunosuppression

Prolonged maintenance immunosuppression in liver-transplant patients is tremendously diverse. » More than 30% of liver transplant patients reportedly

use tacrolimus monotherapy.

» Nearly 10% of patients remain on regimens that include tacrolimus, antimetabolites, and corticosteroids.

» Calcineurin-inhibitor (CNI) therapy is related to widely recognized side effects, particularly renal failure.

With stable liver-graft function, limited risk of kidney failure is the priority. » Kidney dysfunction is a significant source of morbidity

and mortality after liver transplantation and accounts for a significant increase in long-term graft loss.14


ReSPeCT Study15

The ReSPeCT study15 sought to determine the renal benefits of delayed initiation of tacrolimus with induction of daclizumab-based immunosuppressive therapy in liver transplant recipients.

Delaying tacrolimus resulted in less nephrotoxicity, with no significant changes in efficacy or tolerability.

The lower renal failure rate with daclizumab may have been related to difficulty in achieving goal tacrolimus trough levels using low doses.

Biopsy-proven acute rejection rates were lower with daclizumab after 1 year.


Minimizing Complications

Over the past decade, fewer patients have begun CNI monotherapy after receiving a liver transplant.

Relative increases in acute rejection episodes have resulted.

CNI-based therapy plus mycophenolate-based antimetabolite therapy has grown significantly.» From 8% to 10% of liver transplant recipients are

maintained completely off CNI-based therapies and on treatments based on mammalian target of rapamycin (mTOR) therapies (sirolimus, everolimus).

» Only 10%–15% of patients experience an acute rejection, which does not significantly affect the rate of graft failure.


Minimizing Complications

After liver transplant, significant predictors of post-transplant mortality include:

Renal failure (a nearly fourfold risk of post-transplant mortality when compared with the absence of renal failure)

Graft loss requiring a repeat transplant

HCV infection

Recurrent hepatocellular carcinoma (HCC)


HCV Infection

Mortality in liver transplant recipients with HCV infections primarily is related to disease recurrence.

One third of patients with HCV infection die of recurrent disease after a liver transplant.

Immunosuppressant therapy for liver transplant recipients infected with HCV should be tailored by reducing or avoiding corticosteroid pulse therapy for suspected rejection, since such use of therapies may lead to HCV proliferation and graft injury.


HCV Infection and Protease Inhibitors

Patients with recalcitrant HCV infections who are candidates for post-transplant protease inhibitors need to have their immunosuppresive regimen adjusted to accommodate changes in CNI metabolism.

Telaprevir therapy increases serum levels of CNIs, particularly those of tacrolimus (up to 100-fold).

Most transplant centers are converting HCV-infected patients to cyclosporine before starting anti-infective treatment.

However, side effects are still abundant.


HCV Infection and mTOR Inhibitors

Recurrent HCV infection and graft dysfunction related to progressive fibrosis may resolve with immunosuppressant therapy.

The rapamycin pathway plays a central role in the pathophysiology of fibrosis in hepatic stellate cells.16,17

» Sirolimus may be useful to correct this phenomenon but should not be used immediately after liver transplant due to its risk profile.19

McKenna et al18 reported less fibrosis among patients converted to sirolimus from CNIs than among those treated with tacrolimus for up to 2 years after liver transplant.


Kidney Failure and CNIs

Clinicians involved in liver transplant must limit the risk of renal failure due to CNI use.

Post-transplant renal failure often manifests within the first year after surgery.20

CNI avoidance offers clear benefits on the risk of post-transplant renal dysfunction.

The question remains: Can CNI avoidance be accomplished safely in liver transplant recipients by switching to mTOR inhibitors without negatively affecting graft function?


Switching from CNIs to mTOR Inhibitors

Patients with an impaired glomerular filtration rate (40–90 mL/min) at least 6 months after liver transplant who were converted from tacrolimus to sirolimus showed no tangible renal benefit from the conversion 1 year later.21

Sirolimus-treated patients experienced higher rates of acute rejection and major side effects compared with patients who continued on tacrolimus.





In other studies,22,23 the combination of everolimus with reduced-dose tacrolimus following liver transplantation improved the glomerular filtration rate 2 years after surgery, when compared with a standard tacrolimus-based regimen, without increasing the risk of acute rejection or major side effects.

This improvement in renal function also was identified retrospectively among liver transplant recipients converted from CNI therapy to everolimus for maintenance immunosuppression.24


HCC and mTOR Inhibitors

Interest has grown in using mTOR inhibitors for immunosuppression in patients who have received liver transplants for HCC because of these drugs’ antineoplastic activity.

The possibility that mTOR inhibitors might reduce the risk of recurrence of HCC in this patient population has never been tested prospectively.

An ongoing clinical trial is evaluating the recurrence of HCC as a specific endpoint.25

The safety, efficacy, and usefulness of this drug class for immunosuppression in lver transplant recipients have not been fully explored.


Tolerance to Immunosuppressive Therapy

Clinical tolerance represents the ultimate tailoring of immunosuppressive therapy. » Operational tolerance, or maintenance of graft function

without immunosuppression, has been difficult to achieve.

» Up to 20% of liver-transplant recipients could be operationally tolerant.26

» Withdrawal of immunosuppression carries the risk of acute rejection, which reportedly is as high as 50%.

Gene analysis may help to identify predictors of clinical tolerance. » Most clinically tolerant patients were younger.

» The presence of these clinical factors and biomarkers failed to predict tolerance prospectively.


Operational Tolerance

Dominant issues surrounding operational tolerance involve long-term monitoring of graft function.

There is a trend toward more graft fibrosis over time, particularly in presence of donor-specific antibody and complement deposition on allograft biopsy.

Timing of fibrotic onset has been inconsistent and has not had any major clinical effect on patients.

No patients in highly selected populations, such as recipients of living-donor liver transplants from parental donors, have returned to immunosuppression.


Minimizing or Withdrawing Therapy

For most liver-transplant recipients, operational tolerance is not likely over the next several years.

Results of several studies by the Immune Tolerance Network and others clearly showed the promise of minimizing or withdrawing immunosuppressants.

The challenge of monitoring graft function and identifying predictors of failure remains, particularly when attempting to identify good candidates for complete weaning from therapy.


References1. Busuttil RW, Klintmalm GK, eds. Transplantation of the Liver. 2nd ed. Philadelphia, PA: Elsevier

Saunders; 2005.

2. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2:1033–1036.

3. Calne RY. “It can’t be done.” Nat Med. 2012;18:1493–1495.

4. McCauley J, Fung J, Jain A, Todo S, Starzl TE. The effects of FK 506 on renal function after liver transplantation. Transplant Proc. 1990;22:17–20.

5. Todo S, Fung JJ, Demetris AJ, Jain A, Venkataramanan R, Starzl TE. Early trials with FK 506 as primary treatment in liver transplantation. Transplant Proc. 1990;22:13–16.

6. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2:1000–1004.

7. Fung JJ, Todo S, Jain A, et al. Conversion from cyclosporine to FK 506 in liver allograft recipients with cyclosporine-related complications. Transplant Proc. 1990;22:6–12.

8. The U.S. Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med. 1994;331:1110–1115.

9. Wiesner RH. A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation. 1998;66:493–499.

10. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet. 1994;344:423–428.

11. O’Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A. Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet. 2002;360:1119–1125.


References12. O’Grady JG, Hardy P, Burroughs AK, Elbourne D; UK and Ireland Liver Transplant Study Group.

Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: poststudy surveillance to 3 years. Am J Transplant. 2007;7:137–141.

13. Shapiro R, Young JB, Milford EL, Trotter JF, Bustami RT, Leichtman AB. Immunosuppression: evolution in practice and trends, 1993–2003. Am J Transplant. 2005;5:874–886.

14. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931–940.

15. Neuberger JM, Mamelok RD, Neuhaus P, et al. Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the “ReSpECT” study. Am J Transplant. 2009;9:327–336.

16. Akselband Y, Harding MW, Nelson PA. Rapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc. 1991;23:2833–2836.

17. Biecker E, De Gottardi A, Neef M, et al. Long-term treatment of bile duct-ligated rats with rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms. J Pharmacol Exp Ther. 2005;313:952–961.

18. McKenna GJ, Trotter JF, Klintmalm E, et al. Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression. Am J Transplant. 2011;11:2379–2387.

19. Rapamune [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; July 2011.

20. Sharma P, Schaubel DE, Guidinger MK, Goodrich NP, Ojo AO, Merion RM. Impact of MELD-based allocation on end-stage renal disease after liver transplantation. Am J Transplant. 2011;11:2372–2378.

21. Abdelmalek MF, Humar A, Stickel F, et al. Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial. Am J Transplant. 2012;12:694–705.

22. Saliba F, De Simone P, Nevens F, et al. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013;13:1734–1745.


References23. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves

renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant. 2012;12:3008–3020.

24. Saliba F, Dharancy S, Lorho R, et al. Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis. Liver Transpl. 2011;17:905–913.

25. Schnitzbauer AA, Zuelke C, Graeb C, et al. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer. 2010;10:190.

26. Feng S, Ekong UD, Lobritto SJ, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012;307:283–293.

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© 2013 Direct One Communications, Inc. All rights reserved. 1 Current Perspectives on Personalizing Immunosuppression in Liver Transplantation Amit K