Medication level variability index predicts rejection, possibly due to nonadherence, in adult liver transplant recipients

Abstract

Nonadherence to immunosuppressants may play a role in late rejection in liver transplant recipients. In children, emerging data suggest that adherence can be measured by computing the standard deviation (SD) of consecutive blood levels of tacrolimus, resulting in a number that reflects the degree of variability between individual measures (the Medication Level Variability Index, MLVI). A higher MLVI value means erratic immunosuppression, likely due to less adherence. Data on this method in adults are limited. We obtained data from the medical charts of 150 randomly selected adult recipients. The MLVI was significantly higher in patients who had biopsy-confirmed rejection (mean MLVI=3.8, SD=3.2) as compared with the rest of the cohort (mean MLVI=2.3, SD=1.5; p<0.01), and it was significantly higher in patients who had a rejection as compared with patients who had a biopsy that was not read as a rejection (mean MLVI=2.6, SD=1.6; p<0.01). The MLVI was both associated with rejection and predicted its occurrence. A threshold MLVI of 2.0 resulted in 77% sensitivity and 60% specificity in predicting rejection; a threshold of 1.8 resulted in a sensitivity of 92% and specificity of 48%. The Area Under the Curve (AUC) in a Receiver Operating Characteristic (ROC) curve analysis was 0.71 (95% CI: 0.61–0.81). The MLVI is associated with and can predict rejection, possibly related to nonadherence, in adult liver transplant recipients.

The Medication Level Variability Index (MLVI) Predicts Poor Liver Transplant Outcomes: A Prospective Multi-Site Study

“…29 Tacrolimus trough levels are routinely obtained, at least quarterly, as standard care in all participating centers. Centers prospectively reported conditions that might lead to changed drug absorption or metabolism.…”

Advancing Transplantation

“…163 Another study described a "medication level variability index" (MLVI); MLVI was defined as the standard deviation of tacrolimus blood levels for each patient from a minimum of 4 readings during the study period. Not only was the MLVI associated with rejection, it actually predicted it, 164 making this method a robust measure of consistency of exposure. A reduction in interpatient and intrapatient variability may, in part, contribute to the significant improvements in graft and patient survival achieved with prolonged-release versus immediate-release tacrolimus that have recently been described.…”

“…Variability of tacrolimus exposure posttransplant is well established, but its implications for liver transplant recipients are less well characterized than for kidney transplant recipients, even though high variability of tacrolimus exposure has been associated with late allograft rejection after liver transplantation. 163,164 High intrapatient variability of tacrolimus exposure has also been associated with nonadherence to treatment. 251 It is important to recognize that the immunosuppression regimen is not only specific for the drug dose, targeted to predefined trough levels, but also for the intervals between doses.…”

Untitled

“…We analyzed MLVI both as a continuous (higher MLVI = less adherence) and a categorical measure, using a predefined threshold of MLVI > 2.5 for the determination of nonadherence, based on past analyses in different cohorts. 21,22 We used the MLVI cutoff of 2.5 instead of 2.0 as a more conservative threshold of measuring nonadherence.…”

“…In addition, we used an objective measure of nonadherence, the medication level variability index (MLVI), which represents the degree of fluctuation between individual medication blood levels. The MLVI, as described below, has been shown to be predictive of poor outcomes after adult LT independently in 2 centers 21,22 and has also been examined in several centers in pediatric recipients. [23][24][25] Medication level variability index values above 2 to 2.5 have been associated with rejection and are highly correlated with electronic measurements of adherence, 26 suggesting that it is a reliable objective measure of clinically significant nonadherence.…”