MBV Use in Practice for Cytomegalovirus (CMV) Infection at Six French Transplant Centres

Abstract

Introduction: MBV is a UL97 inhibitor with good oral bioavailability, low host cell toxicity and has theoretical benefits for inhibiting cross resistant viruses. We examined clinical and virological outcome of 9 patients treated with maribavir (MBV) in day to day use in France during 2011-2012. Methods: The CNR receives clinical information and resistance-suspected isolates from all transplant centers in France. During 2011-2012, 9 patients from 6 centers developed clinical (in 9/9) and/or genetic (in 6/9) resistance to CMV infection and were treated with maribavir (MBV). Data from these patients were collected including CMV viral load, resistance mutations in UL97 and UL54 genes, and clinical and virological responses to MBV therapy. Viral load was determined in each center using in house (n=3) or commercial assays (Argene n=2, Abbott n=1). Antiviral resistance (AVR) was determined by full-length sequencing of UL97 and UL54 genes using our published sequence-based methods, and GCV levels were measured when relevant. MBV response was considered adequate if viral load reduction was at least two logs or became undetectable. Results: Patients received bone marrow (n=3) and solid organ transplants (n=6 D+/R−) in 6 different centres, using similar standard immunosuppression regimens with CNI, mycophenolic acid, corticosteroids, with or without sirolimus. They received either ValGCV prophylaxis (n=5) or pre-emptive therapy (n=3), or ValACV prophylaxis (n=1). CMV UL97 or UL54 resistance mutations were present at the time of MBV treatment in 6 and 4 patients, respectively, without any MBV resistance mutation. Patients were given MBV in three cases following foscarnet (FOS) nephrotoxicity, in 1 case following UL54 mutation A809V which confers resistance to GCV/FOS, and in other cases for viral load plateauing on treatment. Two patients received MBV in association to FOS. An adequate MBV response was observed in 4/9 patients, with reduction in previously stable or increasing CMV viral load, in 5/9 patients there was either no response or uncertain response (slow decrease or efficient second prophylaxis) (see table) though clinical improvement in one patient. Conclusion: Our results showed good clinical and virological response to MBV in approximately half MBV-treated patients following CMV-resistant infection. There was variable response, although no clear parameter emerged as a clinical surrogate for non-response to MBV. These results are of great interest given the lack of efficacy in phase III trials of MBV prophylaxis in HSCT recipients, possibly due to low dosing regimens and drug initiation timing strategies used in the study. Additional clinical and surrogate laboratory markers are needed to determine antiviral response in order to guide MBV use, and dosage ranging studies would inform further MBV use.Table: [Summary table of MBV treated patients at six Frenc]