Trough Levels of Everolimus Are Associated With Recurrence Rates of Hepatocellular Carcinoma After Liver Transplantation

Purpose

Everolimus, a mammalian target of rapamycin inhibitor, may have a protective role on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but data regarding the impact of its trough serum levels on HCC recurrence are missing.

Methods

Fifty-five patients (43 men, age 55 ± 8 years) who underwent LT for HCC were evaluated. Several demographic and clinical variables were recorded, including radiological and histological characteristics of HCC as well as dosages and trough levels of immunosuppressive regimens.

Results

HCC recurrence occurred in 11 (20%) patients: 5 (25%) of 20 patients under calcineurin inhibitors and 6 (17%) of the 35 patients under everolimus (P = .48). The patients with HCC recurrence (n = 11, group 1), compared to those without recurrence (n = 44, group 2), had significantly more frequent HCC in the explant: outside Milan criteria (P = .001), microvascular invasion (P < .001), and higher number of nodules (P = .001). In multivariate analysis, microvascular invasion was the only independent factor significantly associated with HCC recurrence (OR: 2.3, 95% CI: 1.4–10.5, P = .03). Among the patients who received everolimus-based immunosuppression, the recipients with HCC recurrence, compared to those without HCC recurrence, had significantly lower mean trough levels of everolimus at 7–12 months post-LT (3.9 vs 5.9 ng/mL, P = .001), while the patients with mean trough levels of everolimus >6 ng/mL had decreased HCC recurrence rates (log rank: 2.3, P = .007).

Conclusions

We found for the first time mean concentrations of everolimus between 7–12 months post-LT as the only modifiable variable related with HCC recurrence in LT recipients. However, larger studies are needed for final conclusions.