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In the William Shakespeare tragedy King Lear, Edmund, the illegitimate son of the Duke of Gloucester, turns the Duke against his legitimate son Edgar who is subsequently disinherited. Ultimately, Edgar exacts revenge by wounding Edmund, who acknowledges that “the wheel is come full circle, I am here” [1].

The circular wheel analogy is fitting for the story of mTOR inhibitors (mTOR-Is) in liver transplantation (LT). The promise of an effective non-nephrotoxic alternative to calcineurin inhibitors (CNIs) was shattered by a single study conducted approximately a decade ago and, at long last, reported in this issue of AJT [2]. This phase II, multicenter, randomized, open-label trial demonstrated an association between sirolimus and hepatic artery thrombosis, resulting in early trial termination and a black box warning, thereby setting a dim stage for mTOR-Is in LT.

In the wake of this trial, many studies, predominantly single center and retrospective in design, were published that attempted to refute this association with admittedly modest impact on mTOR-I use in LT. Only recently has a definitive trial of mTOR-Is been conducted in the early post-LT setting [3], but with everolimus instead of sirolimus. Notably, the design of this registration trial strongly reflected the lessons learned from the sirolimus study. The protocol stipulated delayed (30 days after LT) introduction of everolimus and targeted moderate trough levels (3–8 ng/mL), all to minimize the risks of hepatic artery thrombosis, compromised wound healing and intolerable side effects. The exposure to standard, high-dose tacrolimus for the first 30 days, inherent in this strategy, however, risked diminished efficacy with respect to renal protection. Nevertheless, compared to the standard dose/trough tacrolimus control arm, the investigational arm—maintenance everolimus and reduced tacrolimus (target trough levels of 3–5 ng/mL)—was noninferior for the primary efficacy endpoint (treated biopsy-proven acute rejection, graft loss or death) but superior for renal function and biopsy-proven rejection at 12 and, recently, 24 months after LT [4]. These favorable results have justified an indication for the combination of everolimus and reduced-dose tacrolimus when initiated 30 days or more after LT. Thus, in the past decade, the role and the utility of mTOR-Is in LT have truly come “full circle,” from great enthusiasm to dashed hopes and now back to renewed optimism.

So, has all been said? Move on, forget the past… or are there lessons learned from this circle of failure and success? Indeed, there are important messages. The authors should be commended for taking on the task of reporting the study data from nearly a decade ago. However, it must be emphasized that prompt reporting of the results of pivotal, well-designed clinical trials, whether positive or negative, is critical for full disclosure and transparency and is the responsibility of study sponsors and principal investigators [5]. Moreover, leading journals must commit to disseminate outcomes of such important clinical trials as long as the data and analyses are sound, irrespective of the findings. Placing detailed results of the sirolimus trial in the literature years ago would likely have benefited not only the LT but also the entire transplantation community. Data from abstracts at national meetings, which until now were the sole source of information about this trial, are less informative than the fully disclosed, final publication.

Like any other drug with a narrow therapeutic window, mTOR-Is must be used in the right amount, time period and patient. For LT recipients, the right amount is without a loading dose and targeting moderate trough levels. The right time is neither too early nor too late after LT, early enough to preserve renal function and late enough to avoid hepatic artery thrombosis and wound dehiscence. Additional toxicities of mTOR-Is, including oral ulcers, edema, proteinuria and hyperlipidemia, are similarly mitigated with an optimized administration strategy. These are important considerations as the tolerability of mTOR-Is has historically represented another major deterrent to widespread use. Without a doubt, the issue of hepatic artery thrombosis has been the central pillar of debate regarding the mTOR-I use in LT. Even when considering reports that have contested this association [6] along with no clear mechanistic explanation, this black box warning still represents the haunting legacy of the sirolimus trial.

Finally, who is the right patient? Should we administer m-TOR-Is to a broad swathe of LT recipients to reduce CNI nephrotoxicity, as the everolimus trial would suggest, or only to those with early post-LT renal dysfunction? As not all CNI-treated patients develop nephrotoxicity, predictors identifying at-risk patients who are most likely to derive renal benefit are needed. Another potential application of mTOR-I therapy is in patients transplanted for hepatocellular carcinoma (HCC). The LT community eagerly awaits data from SiLVER [7], an international, prospective, randomized trial based on sirolimus to justify the use of mTOR-Is in preventing HCC recurrence.

Our charge now is to truly come full circle, learning the lessons of this trial to move forward and determine the right way to use mTOR-Is in LT. Thoughtful trial designs to explore novel strategies are the only way to maximize the benefits and minimize risks of mTOR-Is, allowing us to truly say that mTOR-Is are “here” again… but perhaps to stay this time around.

Disclosure

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The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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