The first studies of mammalian target of rapamycin (mTOR) inhibitors in solid organ transplantation were performed in kidney, and later heart, transplant recipients. Later, as the potential advantages of this class in supporting calcineurin inhibitor (CNI) sparing became apparent, trial programs and clinical use expanded to liver transplantation. Currently mTOR inhibitors are prescribed in approximately 4% of liver transplant patients from the time of transplant, with approximately 6% receiving mTOR maintenance treatment at 1 year posttransplant.1 The possible role for mTOR inhibitors in particular subpopulations and specific clinical situations after liver transplantation is currently the subject of debate but consensus is starting to emerge.2-4
Several scenarios could favor inclusion of an mTOR inhibitor in the immunosuppressive regimen. First, progressive kidney dysfunction and ultimately renal failure is a well-recognized complication after liver transplantation,5 and use of an mTOR inhibition to minimize CNI exposure is a well-documented strategy for reducing CNI-related nephrotoxicity. Second, in maintenance patients who prove intolerant to CNI therapy, mTOR inhibitors can facilitate CNI reduction or discontinuation to alleviate symptoms without loss of immunosuppressive efficacy.6 Third, it has been investigated whether mTOR inhibition may help to delay hepatocellular carcinoma (HCC) recurrence.7 Lastly, and more speculatively, there are limited but intriguing data suggesting that switch to an mTOR inhibitor may contribute to management of posttransplant malignancies.
Of the 2 commercially available mTOR inhibitors, only everolimus has licensed in liver transplantation, by both the European Medicines Agency and the Food and Drug Adminstration. It is approved for prophylaxis of rejection, in combination with tacrolimus, although in practice, it is also given in combination with cyclosporine (CsA) or in a CNI-free regimen. Everolimus does not demonstrate toxicity in combination with CNIs,8 as has been reported for sirolimus9 and in combination with CsA or tacrolimus has shown favorable effects on renal function after liver transplantation.6 Randomized trials have assessed outcomes in everolimus-treated patients within various regimens, most often starting everolimus therapy early posttransplant. Sirolimus has a smaller evidence base in liver transplant patients and remains unapproved in this setting. It has recently become clear, moreover, that structural variations in the sirolimus and everolimus molecules give rise to various differences in distribution, affinities to active drug transporters and metabolizing enzymes, and in interactions with proteins—notably the mTOR inhibitor complex 2.9 In particular, sirolimus enhances the unfavorable effects of CNIs on kidney cell metabolism while everolimus does not.9 The 2 agents cannot therefore be considered interchangeable.
There have recently been a number of key studies published in this evolving area of transplant medicine. This article seeks to clarify the current status of knowledge and to suggest where and how mTOR inhibtors can most usefully be included in the immunosuppressive armamentarium for liver transplant recipients.
mTOR Inhibitors With Reduced CNI Therapy in De Novo Liver Transplant Recipients
The pivotal H2304 study6 led to licensing of everolimus for use with reduced-exposure tacrolimus in liver transplantation. This multicenter study randomized 719 liver transplant patients to 1 of 3 groups: everolimus with reduced-exposure tacrolimus, everolimus with tacrolimus withdrawal, or a standard tacrolimus-based regimen. Everolimus was started on day 30 posttransplant. At 1 year posttransplant, renal function was significantly higher in the everolimus/reduced tacrolimus group versus the standard tacrolimus group: mean estimated glomerular filtration rate (eGFR) was 80.9 mL/min per 1.73 m2 versus 70.3 mL/min per 1.73 m2 (P < 0.001), a difference that remained significant after adjustment for baseline values. When renal function was assessed at 210 and 311 years posttransplant, the patients randomized to everolimus-based CNI-free therapy continued to show significantly better renal function (Figure 1). Patients who remained on everolimus showed the most marked improvement in eGFR versus controls,10,12 but discontinuation of everolimus was more frequent than discontinuation of tacrolimus (25.7% vs 14.1% by year 1).12 Strikingly, the rate of treated biopsy-proven acute rejection (BPAR) was significantly lower with everolimus/reduced tacrolimus than with the standard tacrolimus regimen at 1 year posttransplant,10 although the difference became nonsignificant thereafter10,11 (Figure 1). Even more notably, among the 206 patients in the everolimus/reduced tacrolimus arm who had a mean everolimus trough concentration within target range (3-8 ng/mL), only 2.9% experienced treated BPAR during the first year posttransplant.13 The same patients were also the least likely to have low eGFR (defined as <30 mL/min per 1.73 m2) (8.3%).13
Although confirmatory trials with everolimus or sirolimus have not yet been completed, this well-conducted study demonstrates that immunosuppression with everolimus and reduced tacrolimus early after liver transplantation offers a long-term improvement in renal function versus conventional therapy, with a low rate of BPAR, although discontinuation rates are high. Further evidence will be provided from the ongoing HEPHAISTOS trial (NCT01551212), in which a large cohort of de novo liver transplant patients have been randomized to everolimus with reduced tacrolimus, or to standard tacrolimus with mycophenolic acid (MPA), by the end of the first week posttransplant.14 The primary endpoint of HEPHAISTOS is eGFR at month 12, with a series of secondary efficacy and safety endpoints.
mTOR Inhibitors and CNI-free Therapy in De Novo Liver Transplant Recipients
Introduction of an mTOR inhibitor early after liver transplantation, with immediate or gradual CNI withdrawal, has been studied in a series of randomized trials (Table 1).12,15,16,18,19 Results have consistently shown a substantial improvement in renal function compared with standard CNI therapy comprising either tacrolimus,12,15,19 CsA18 or either agent,16 as confirmed in a recent meta-analysis.20 The difference in mean eGFR at month 12 posttransplant has ranged from 8 to 27 mL/min per 1.732 (Figure 2A), and statistical analyses have confirmed a substantial and significant benefit for mTOR inhibition with CNI-free therapy in terms of the change in eGFR from baseline.10,15,16,19 Follow-up data to 3 years posttransplant from 2 randomized studies has shown that the renal advantage of an mTOR inhibitor with CNI-free therapy is sustained.11,21
It should be borne in mind that trials that have assessed the renal impact of mTOR inhibition have all used estimated value of GFR, generally based on the Modification of Diet in Renal Disease formula, and that eGFR values can differ significantly from measured GFR in liver transplant patients.22
Preclinical data from a mouse model of kidney or heart transplantation during the development of everolimus demonstrated that even at high dose ranges the drug did not provide the same intensity of immunosuppression as CsA.23 Consistent with this, evidence regarding the risk for BPAR after early CNI withdrawal in liver transplant patients receiving an mTOR inhibitor, however, is less clear-cut than for combined therapy with reduced-exposure CNI (Figure 2B) (Table 1). One meta-analysis of 3 randomized trials reported an increase of 71% in the risk for treated BPAR after mTOR initiation with CNI elimination in the first 6 months after liver transplantation,20 consistent with a larger meta-analysis from 2016 in which 10 trials of either de novo or maintenance patients were included.24 The method of switching, and use of induction therapy and choice of concomitant immunosuppression, however, appears to be critical. The large PROTECT trial found no difference in BPAR at month 12,16 whereas the Spare-The-Nephron15 and SIMCER19 trials found BPAR to be significantly more frequent under mTOR inhibition than standard CNI therapy, although the difference was largely accounted for by mild episodes of BPAR. Recruitment to the everolimus/tacrolimus elimination arm of the H2304 study was discontinued prematurely due to high rates of acute rejection.11 Variations in study protocols—particularly the use of induction therapy and concomitant MPA—would seem the most likely explanation for these discrepancies between study results. In the H2304 CNI-free arm, neither induction therapy nor maintenance MPA were given, and patients appear to have been underimmunosuppressed. In contrast, the trials which have included MPA in the mTOR inhibitor regimens18,19 have shown a lower rate of BPAR than those with mTOR inhibitor monotherapy. The more gradual rate of CNI withdrawal used in the PROTECT trial (over eight weeks)16 may also be preferable to the 1-month withdrawal period specified in the H2304 study.12
Experience from these trials indicates that mTOR inhibitors can successfully support gradual CNI withdrawal before month 6 after liver transplantation and achieve a highly relevant improvement in renal function, but that conversion must be performed with care. Adjunctive MPA (and probably induction with an interleukin-2 receptor antagonist) is advisable, with stepped CNI elimination instead of abrupt switch. mTOR monotherapy represents a higher-risk approach.
mTOR Inhibition in Hepatitis C Virus–positive Patients
No prospective study has examined mTOR inhibition solely in patients transplanted for hepatitis C virus (HCV) infection, a group known to be at high risk for poor outcomes. Similar rates of treated BPAR have been reported using everolimus and reduced-exposure tacrolimus versus standard tacrolimus in the HCV-positive subpopulation of the H2304 study (n = 164).25 One analysis of US registry data reported higher 3-year mortality under sirolimus than in sirolimus-free regimens for HCV-positive liver transplant patients (hazard ratio 1.29, P = 0.005) that was not seen in HCV-negative recipients.26 However, the study period spanned 2000 to 2006, a period when sirolimus loading doses and target blood concentrations were considerably higher than today, and only 153 patients were receiving sirolimus monotherapy, so the relevance of this finding may be questionable.
Preclinical data from animal models of liver fibrosis have shown potent antifibrotic effects of mTOR inhibitors,27-29 raising interest in a possible beneficial effect on HCV-related fibrosis. Delayed fibrosis in HCV-positive recipients has been reported in de novo patients treated with mTOR inhibitors versus controls in nonrandomized trials,30-32 and a trend to less fibrosis progression in HCV-positive patients was observed in the H2304 study for those given everolimus with reduced CNI.33 One exploratory randomized trial in 43 maintenance patients with recurrent HCV infection also indicated a slower rate of fibrosis under everolimus versus CNI therapy.34 Any beneficial effect of mTOR inhibition, however, is now largely irrelevant after the adoption of direct-acting antiviral therapies so further research is unlikely.
Prevention of De Novo Posttransplant Malignancies
The antitumor effects of mTOR inhibition and their proven efficacy in treating nontransplant cancers, such as renal cell carcinoma, have focused attention on a possible role in prevention of posttransplant malignancy.35 A recent meta-analysis concluded that sirolimus therapy was associated with a reduced risk for both malignancy overall, and for nonmelanoma skin cancer specifically, after kidney transplantation.36 Data from the large Collaborative Transplant study have demonstrated a reduction for nonmelanoma skin cancer under mTOR inhibition, but not for nonskin cancers.5 Comparable analyses in liver transplantation, however, are lacking, and the number of patients required to provide statistical power to detect an effect of mTOR inhibition precludes any meaningful interpretation of data from individual randomized trials. One meta-analysis of 4 randomized trials in which de novo liver transplant patients were switched from CNI to everolimus, or received everolimus with reduced-exposure CNI, found a trend to lower risk of either neoplasms or tumor recurrence under mTOR inhibitor therapy (relative risk, 0.60; P = 0.06)20 but while encouraging cannot permit any firm conclusions.
The high rate of HCC recurrence after liver transplantation has permitted a closer examination of whether inclusion of an mTOR inhibitor in the immunosuppressive regimen has a preventative effect.7 Geissler et al37 recently reported the findings of the randomized SiLVER trial of 525 patients with histologically confirmed HCC at time of transplant. At 4 to 6 weeks posttransplant, patients were randomized to continue without any mTOR inhibitor or to start sirolimus. At year 5, 67% of patients randomized to sirolimus were still under sirolimus therapy. The primary endpoint was HCC recurrence-free survival, with a minimum follow-up of 5 years. By last follow-up, the difference in recurrence-free survival was not significant (70.2% with sirolimus vs 64.5% without mTOR inhibition; hazard ratio, 0.84; 95% confidence interval, 0.62-1.15; P = 0.280).37 Thus, the study outcome was negative although there was evidence for higher recurrence-free survival and overall mortality in the first few years after transplantation for patients with tumor features within Milan criteria.
Initiating mTOR Inhibitor Therapy in Maintenance Liver Transplant Patients
Switching maintenance liver transplant patients to an mTOR inhibitor—either with CNI withdrawal or reduced exposure—may be prompted by various clinical triggers including deteriorating renal function, CNI-related neurotoxicity, onset of diabetes mellitus, development of skin or nonskin tumors, or recurrent HCC.
Abdelmalek and colleagues17 performed a randomized, open-label trial in which 607 patients more than 6 months postliver transplant, all with mild to moderate renal dysfunction (mean eGFR 66 mL/min), were randomized to remain on CNI therapy or switch directly to sirolimus (starting with 2 loading doses) with no overlap with CNI treatment. Approximately 40% of patients were receiving either MPA or azathioprine; steroids was optional. The mean time posttransplant was 4 years. At month 12, BPAR had occurred in 11.7% of the sirolimus conversion group versus 6.1% of controls (P = 0.02), and between-group differences in the decline in eGFR were not significant (4.5 vs 3.1 mL/min, P = 0.34).17 Another randomized trial, by de Simone et al,6 evaluated progression of renal dysfunction after switching gradually from CNI therapy to mTOR inhibition (everolimus), dependent on adequate everolimus exposure, without concomitant MPA or azathioprine in 145 liver transplant patients. However, it was complicated by the fact that 20% of patients remained on CNI after starting everolimus and three quarters of the control arm received substantial reductions in CNI exposure. Furthermore, similar to the trial by Abdelmalek et al,17 the study population was a mean of 3 years posttransplant at the time of randomization (minimum 1 year), by which time irreversible CNI-related damage may have occurred. No renal advantage was detected under mTOR inhibition, although neither was there any increase in BPAR versus controls (1 patient in each group experienced BPAR by month 6) (Table 1).6 Where conversion is undertaken, a gradual switch with close monitoring of mTOR inhibitor exposure is advisable.
Overall, data from these 2 trials indicate that there is little to be gained from switching liver transplant patients more than 6 or 12 months posttransplant to mTOR inhibitors in an attempt to preserve renal function.
Effect on Existing Malignancies
Randomized trials assessing an effect on existing malignancy after switching to mTOR inhibitors after liver transplantation have not been performed. One retrospective study assessed five-year survival rates in 83 patients transplanted for alcoholic liver disease who subsequently developed de novo solid tumors, and found survival to be significantly higher after starting everolimus (with CNI discontinuation in 64% of cases) compared with controls who remained on standard CNI immunosuppression (Figure 3).38 Other retrospective series have also shown encouraging results, but patient numbers have been small.
For recurrent HCC, data on the impact of introducing an mTOR inhibitor (with or without concomitant sorafenib) are again restricted to single-center retrospective series; results have suggested an improvement in outcomes.39,40 In the absence of well-designed trials, it seems reasonable to consider starting an mTOR inhibitor in liver transplant patients who have a poor prognosis after developing malignancy or HCC to increase short-term survival, and to consider gradual CNI tapering and discontinuation over time depending on risk of rejection.
Another area of potential interest is Kaposi sarcoma. Everolimus has shown encouraging results in the treatment of Kaposi sarcoma in nontransplanted patients41 and based on case reports and small series, initiation of an mTOR inhibitor is recommended in kidney transplant patients who develop Kaposi sarcoma.42 In liver transplantation, several cases of successful resolution of Kaposi sarcoma after switch from CNIs to sirolimus have been published in the literature.43-45
In general, mTOR inhibitors in solid organ transplant recipients are regarded as a safe alternative to standard CNI-based therapy with MPA.46 Mild adverse events such as hyperlipidemia, anemia, edema, proteinuria, and stomatitis can often be managed by close monitoring and adjustment of exposure levels.46,47 Recent reviews have discussed the incidence and management of mTOR inhibitor-related adverse events.3,4,46 Some key issues are considered below.
Tolerance of mTOR Inhibitors
Tolerance of mTOR inhibitors is affected by the setting and choice of agent. In general, switch to an mTOR inhibitor in a CNI-free regimen is associated with intolerance – not unexpectedly, because higher mTOR inhibitor exposure is required than in combination regimens. Everolimus also appears to be better tolerated than sirolimus.9
Randomized trials have consistently shown a higher rate of discontinuation due to adverse events after conversion to mTOR inhibitors patients compared with the control arms (Table 1).12,13,15,19 In studies of maintenance patients switched to an mTOR inhibitor from CNI therapy after months or even years, this is not unexpected, and even in conversion studies of de novo patients results could be skewed by discontinuations of CNI in the short period (eg, 1 month) before starting mTOR inhibitor. It is also possible that there is a tendency to revert to more familiar CNI-based regimens in the face of intolerance, or inexperience in managing mTOR inhibitor-related adverse events. Nevertheless, the rates of discontinuation due to adverse events after switch to mTOR inhibitors are strikingly high, affecting at least a quarter of patients in early conversion studies and a fifth of maintenance patients (Table 1). In a recent meta-analysis, Glover et al24 assessed study discontinuation due to adverse events in a total of 10 randomized trials of adult liver transplant patients converted from CNIs to mTOR inhibitor-based immunosuppression, regardless of the time posttransplant at which switch occurred, that is, including both de novo and maintenance patients. Overall, there was more than a twofold increase in the risk for discontinuation after switching to mTOR inhibitor therapy compared with remaining on CNIs (relative risk, 2.17). Intolerance can be due to various adverse events, but often edema, myelosuppression, mouth ulcers and proteinuria are culpable. The risk for discontinuation and reversion to CNI therapy remains a clear disincentive to initiate mTOR inhibition.
Concerns about impaired wound healing under mTOR inhibitors arose in kidney transplantation. An early randomized comparative trial with sirolimus versus tacrolimus, published in 2004, highlighted a significantly higher rate of healing complications in kidney transplant patients under sirolimus when given with a substantial loading dose and targeting a high trough concentration.48 Lowering target trough concentration resulted in a substantial reduction in event rates. Since then, exposure levels for mTOR inhibitors have fallen and the risk of an mTOR-related impairment of healing after kidney transplantation is now considered relatively minor.49 A pooled analysis of 3 randomized trials in kidney transplant patients found no difference in the rate of wound healing complications compared with a control group receiving MPA when the everolimus target trough level was 3 to 8 ng/mL,50 the recommended range in liver transplant patients given everolimus in combination with tacrolimus.
The surgical procedure for liver transplantation is relatively complex, and complications arise more frequently than in kidney transplantation, including incisional hernias, biliary fistulas, or a delayed skin healing. As a result, randomized trials of early everolimus12,16,18 or sirolimus15 in liver transplant patients have delayed their start until at least week 4 posttransplant. None of these studies has reported increased wound healing complications versus the standard CNI control groups. Data on mTOR inhibition earlier after liver transplant are currently limited. Two retrospective series in which rates of wound healing complications were compared in liver transplant patients given everolimus with concomitant tacrolimus either before or after day 5,51 or before or after month 1,52 both concluded that early initiation of everolimus was not associated with any meaningful effect on wound healing events. The HEPHAISTOS study, in which everolimus is started by the end of week 1,14 will provide more robust data on this question.
In certain high-risk situations—for example, surgical complications, requirements for prolonged postprocedural hyperventilation or transplantation of obese patients—it may be advisable to delay antiproliferative drugs such as mTOR inhibitors or MPA until healing is complete, and to switch temporarily to standard CNI-based immunosuppression before major elective surgery.
Hepatic Arterial Thrombosis
Concerns have been expressed that mTOR inhibitor therapy increases the risk for hepatic arterial thrombosis (HAT) after liver transplant. An early phase II randomized trial of sirolimus with reduced-exposure tacrolimus versus standard tacrolimus, both given with steroids, showed a trend to more frequent HAT under sirolimus/tacrolimus (8% versus 3%, P = 0.065).53 However, a high loading dose of sirolimus was used (15 mg), with higher exposure to both sirolimus and tacrolimus in the combined-therapy arm than would be typical today. Neither in a phase II trial in liver transplant patients,54 nor in renal studies, has there been evidence of an increased risk of HAT using de novo everolimus. Recent trials in which everolimus or sirolimus were started no sooner than week 4 (and at lower exposure ranges) have shown no increased risk for HAT or hepatic artery stenosis versus conventional CNI-based regimens.12,15,16,18,19 Indeed, 1 randomized trial of 78 patients observed a lower rate of HAT under everolimus than CNI therapy.18 As is the case for wound healing complications generally, the risk of HAT is not a barrier to use of mTOR inhibitors using current regimens. Of note, however, robust data regarding risk for HAT under mTOR inhibition given immediately after liver transplantation are still lacking.
The evidence base concerning inclusion of everolimus in the immunosuppression regimen after liver transplantation has expanded dramatically in recent years, and certain conclusions can be drawn. First, early introduction of everolimus with a concomitant reduction in CNI exposure can be undertaken safely, and is associated with a substantial long-term improvement in renal function. This appears a preferable strategy to CNI withdrawal after initiating mTOR inhibitor, an approach which requires careful handling and adequate adjunctive immunosuppression if an increased risk for BPAR is to be avoided. Second, concerns about an increased risk for HAT or wound healing complications under mTOR inhibition now appear to be unfounded using modern regimens.42 A black box warning for sirolimus remains in place for its use in liver transplantation, relating to an increased incidence of HAT in early studies but the current validity of this warning has been questioned.55 Lastly, the known antioncogenic actions of mTOR inhibitors merit further investigation regarding an effect on de novo cancers or progression of existing malignancies in this setting.
The evidence base for mTOR inhibitors in liver transplantation is by no means complete. Well-designed head-to-head studies of everolimus and sirolimus, for example, are awaited. The substantial differences in their toxicodynamic properties9—particularly on the mTOR pathway9—suggests that everolimus is most useful in combination with low-exposure CNI therapy while the risk of CNI-related nephrotoxicity potentiation under sirolimus points to its use in CNI-free regimens. The high rate of mTOR inhibitor discontinuation reported widely in clinical trials remains an important caveat: in the future more targeted selection of candidate patients may be helpful but this requires careful examination in prospective trials.
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