The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients

Abstract

Purpose Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV. Methods Adult patients receiving a kidney or kidney‐pancreas transplant were included if they developed CMV viremia and initiated letermovir 480 mg daily as part of a dual therapy regimen with valganciclovir 900 mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log10 < 3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels. Results Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73–355) IU/ml and did not clear or change significantly after 2, 4 and 12 weeks of adjunctive letermovir (132.5 [range: 34.5–513] IU/ml vs. 68.7 [range: 34.5–574] IU/ml vs. 78.3 [range: 34.5–347] IU/ml, p > 0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir‐tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6 ng/ml vs 8.0 ± 4.6 ng/ml). Conclusion In kidney and kidney‐pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed.

New Insights on CMV Management in Solid Organ Transplant Patients: Prevention, Treatment, and Management of Resistant/Refractory Disease

“…Stopping VGCV can increase the risk of CMV infection, especially in D+/R− patients, and requires starting strict weekly CMV DNAemia monitoring to prevent CMV disease [ 13 ]. Reducing the dose of VGCV means giving a dose below the recommended dose adapted to kidney function, which can increase the risk of antiviral drug resistance [ 1 , 14 ].…”

Letermovir conversion after valganciclovir treatment in cytomegalovirus high‐risk abdominal solid organ transplant recipients may promote development of cytomegalovirus‐specific cell mediated immunity

“…Currently, insurance denial is common, and the appeal process is arduous and time-consuming resulting in delays in therapy and extended courses of valganciclovir causing progressive toxicity. By sharing our results with the transplant community and providing data to support the safety and efficacy of letermovir for conversion monotherapy over alternative strategies 13 we can optimize its use and hopefully, improve patient outcomes. It is clear that improvement in the treatment of persistent CMV infection is needed.…”

“…Failure of secondary prophylaxis was defined as breakthrough replication detected on prophylaxis. 13 When this was found to be an ineffective strategy, likely due to ongoing myelosuppressive effects of valganciclovir and the counterproductive resultant rise in tacrolimus despite empiric dose adjustment, our CMV Task Force modified our approach to (val)ganciclovir withdrawal and conversion to letermovir 480 mg daily for monotherapy in this clinical setting.…”

Cytomegalovirus antiviral stewardship in solid organ transplant recipients: A new gold standard

“…This strained the stewardship process, in some cases resulting in monitoring failures and progressive replication. These obstacles required creative solutions and resulted in novel strategies utilizing alternative approaches 12,13 . In this way, the stewardship initiative grew from a simple pharmacist‐based dosing service to an established, multidisciplinary program that formalized and provided structure for quality improvement initiatives related to the prevention and treatment of CMV in SOT recipients.…”