Acute rejection rates and short-term graft survival have improved substantially as a result of advances in immunosuppression (IS), though longer-term graft survival rates have improved more modestly. Chronic immune-mediated injury driven by de novo donor-specific antibodies (dnDSA) has emerged as an important factor in longer-term graft loss. Using recently-published long-term data on adherence, dnDSA formation, and graft failure, the clinical effects of non-adherence associated with IS using prolonged-release tacrolimus (PR-TAC), immediate-release tacrolimus (IR-TAC), and cyclosporine (CsA) were modeled in Canadian renal transplant recipients.

A decision tree was developed to capture differences in adherence between IR-TAC, PR-TAC and CsA, and was combined with a five-state Markov model of dnDSA formation, graft failure and patient survival. Transition probabilities were determined by a series of Weibull, logistic, and least squares regression models. Adherence, quality of life, and patient and graft survival were derived from Canadian sources. Analyses were run over a 25 year time horizon.

Irrespective of IS treatment, reduced dnDSA incidence resulted in lower graft failure rates, increased life expectancy, and increased quality-adjusted life expectancy. In a population of exclusively non-adherent patients, the proportion experiencing dnDSA was 43.6% (CsA), 42.6% (IR-TAC) and 34.3% (PR-TAC). In these patients, use of PR-TAC resulted in a reduction in dnDSA of 19.4% relative to IR-TAC, and number needed to treat (NNT) of 12 to avoid dnDSA. In a more generalized population including both adherent and non-adherent patients (13% non-adherent with PR-TAC; 20% CsA and IR-TAC), dnDSA developed in 22.3% (CsA), 22.1% (IR-TAC) and 20.5% (PR-TAC) of patients. Relative to IR-TAC, NNT with PR-TAC to avoid dnDSA was 63; mean time to dnDSA onset was delayed to 7.9 years (difference 0.24 years).

Based on modern clinical data in adherent vs non-adherent patients, a modeling analysis projected that PR-TAC would reduce the incidence of dnDSA, and improve graft and patient survival relative to IR-TAC or CsA in Canadian renal transplant patients. Moreover, the beneficial effect of PR-TAC on dnDSA and clinical outcomes was most pronounced in non-adherent patients.

CITATION INFORMATION: Howell J, Pollock R, Schwartz J. Impact of Immunosuppression Adherence on De Novo Donor-Specific Antibody Formation in Renal Transplant Recipients in Canada: A Modeling Analysis. Am J Transplant. 2017;17 (suppl 3).

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