Liver Transplant Immunosuppression: Everolimus, Is it for All of Us?

Liver transplantation remains the definitive therapy for end-stage liver disease, and the long-term success of transplantation depends not only on surgical advances but also on durable and carefully tailored immunosuppression medications.1 In the United States and Europe, calcineurin inhibitors (CNIs) remain the backbone of post–liver transplant therapy, with mammalian target of rapamycin (mTOR) inhibitors, such as everolimus incorporated selectively to mitigate CNI-related toxicities, particularly nephrotoxicity, while preserving graft function.2 As posttransplant survival continues to improve, the clinical and economic implications of maintenance immunosuppressive strategies have become increasingly consequential. Jang et al3 are to be commended for conducting a comprehensive cost-effectiveness analysis of mTOR addition to CNI therapy using real-world national data from South Korea. Their analysis demonstrates that everolimus in combination with CNIs was cost-effective for an immunosuppression strategy as compared with CNI use alone when evaluating post–liver transplant risks of cancer, infection, and renal function in liver transplant recipients. Their use of a simultaneous multipathway Markov model capturing renal dysfunction, infection, and malignancy represents a methodological advance over prior transplant economic evaluations, which have generally focused on narrower endpoints or single-pathway structures. They also account for both healthcare costs (direct) and costs to society (indirect costs), which augment the analysis. Outside of the Italian trial-anchored model by Bianic et al,4 which emphasized renal outcomes in a dual liver–kidney framework, there has been a relative paucity of economic analyses comparing CNI monotherapy with mTOR-based combination strategies in liver transplantation, which is addressed in the novel work by Jang et al. In this study, renal injury is operationalized as progression to advanced chronic kidney disease (CKD): stage 4 or stage 5. Although this endpoint captures clinically severe nephropathy, it may incompletely reflect the broader burden of CNI-associated renal injury. Earlier stages of CKD, progressive decline in estimated glomerular filtration rate, and persistent proteinuria are associated with increased cardiovascular risk, healthcare utilization, and diminished quality of life, even in the absence of end-stage renal disease.5 The negative impact of proteinuria associated with mTOR inhibitors, such as everolimus, is not accounted for, which could potentially overestimate the benefit of mTOR inhibitors. Also, renal preservation appears to be a principal driver of incremental quality-adjusted life-year gains and the favorable incremental cost-effectiveness ratio (ICER) reported in this model; restricting clinically meaningful renal morbidity to late-stage CKD may also overestimate the modeled benefit of mTOR-based strategies. Greater transparency regarding how intermediate CKD states were weighed in both cost and utility calculations would strengthen the interpretation of the renal contribution to the ICER. Second, the incorporation of infection risk is an important feature of the model, given the immunologic consequences of dual immunosuppression with CNIs and mTOR inhibitors. In this study, however, infections are modeled as short-term events with a duration limited to 30 d and without durable sequelae. In clinical practice, posttransplant infections vary in severity and trajectory.6 Opportunistic infections, recurrent bacterial infections, prolonged intensive care unit stays, and infection-related multiorgan dysfunction may result in persistent functional decline and substantial downstream costs. If infectious complications are assumed to resolve within a single cycle, the burden of infection may be underestimated. As infection risk was a key contributor to increasing the ICER in sensitivity analyses, more detailed modeling of infection burden may better capture the long-term consequences of dual immunosuppression. Third, the analysis is conducted from the perspective of the South Korean healthcare system, which may limit the study’s applicability to similar single-payer healthcare systems. In the United States, drug prices are market driven and are paid for by a combination of public healthcare programs, private insurers, and out-of-pocket payments by patients. Prior studies have demonstrated that mTOR inhibitor pricing is significantly higher in the United States than in other nations such as South Korea.7 High medication costs for liver transplant patients have been associated with nonadherence and negative post–liver transplant outcomes.8 Thus, the true cost-effectiveness of everolimus is highly subject to its affordability and access, reducing the international generalizability of the ICER reported in this study. Findings from this study by Jang et al should be interpreted as context dependent as the ICER is sensitive to drug pricing assumptions that may not translate to more fragmented payer systems. One limitation of this study is its retrospective cohort design, which is reliant upon a claims database that may affect the accuracy of clinical outcomes and, therefore, cost estimates. Using claims-based endpoints limits important granular clinical data available and leads to outcome simplification. The clinical indications prompting everolimus initiation for liver transplant recipients are also not observable, introducing potential confounding by indication. Many countries use low-dose tacrolimus and mycophenolate mofetil (MMF) for maintenance immunosuppression as opposed to tacrolimus and everolimus therapy as used in this study. Compared with everolimus, MMF is better tolerated9; however, with regards to malignancy recurrence posttransplant, everolimus still demonstrates superiority.10 Given that malignancy recurrence was a factor included in the model in the study by Jang et al, future studies evaluating the economic and quality of life implications of MMF versus everolimus, in addition to tacrolimus, would be helpful to elucidate the impact of each regimen. Finally, as part of the model, the authors made multiple assumptions regarding medication adherence, a fixed death rate, and rates of multiple retransplantations. Without accounting for clinical deterioration, these assumptions, although necessary, may overestimate the gains in quality-adjusted life years reported in the study. Additionally, Jang et al provide an important contribution to the liver transplant literature by evaluating immunosuppressive medications within a unique framework of clinical and economic considerations. Their work underscores that cost-effectiveness is dynamic and contingent on which outcomes are prioritized. mTOR-based strategies may offer value in certain patient populations, such as those with CNI nephrotoxicity or hepatocellular carcinoma. However, the decision to start an mTOR inhibitor should be individualized on the basis of patient and healthcare system characteristics.