Fast selection of maribavir resistant cytomegalovirus in a bone marrow transplant recipient

Axel Schubert,Detlef Michel,Karoline Ehlert,Thomas Mertens,Susanne Schuler-Luettmann,Eva Gentner

doi:10.1186/1471-2334-13-330

Abstract

BackgroundHuman cytomegalovirus infections are still significant causes of morbidity and mortality in transplant recipients. The use of antiviral agents is limited by toxicity and evolving resistance in immunocompromised patients with ongoing viral replication during therapy. Here, we present the first documented case of genotypic resistance against maribavir in a bone marrow transplant (BMT) recipient.Case presentationThe female 13-year-old patient was suffering from a refractory cytopenia. Ganciclovir, foscarnet, cidofovir, leflunomide and maribavir, an inhibitor of the cytomegalovirus UL97 protein, were administered to treat a therapy-resistant cytomegalovirus infection. Viral mutations conferring resistance against nucleotide and pyrophosphate analogs as well as maribavir (MBV) have evolved sequentially. Particularly, impressive was the fast emergence of multiple mutations T409M, H411Y and H411N conferring maribavir resistance after less than 6 weeks.ConclusionWe describe the fast emergence of cytomegalovirus variants with different maribavir resistance associated mutations in a bone marrow transplant recipient treated with MBV 400 mg p.o. twice per day. The results suggest that a high virus load permitted a selection of several but distinct therapy-resistant HCMV mutants. Since a phase II study with MBV is intended for the treatment of resistant or refractory HCMV infections in transplant recipients this has to be kept in mind in patients with high viral loads during therapy (NCT01611974).

Highlights

Human cytomegalovirus infections are still significant causes of morbidity and mortality in transplant recipients
We describe the fast emergence of cytomegalovirus variants with different maribavir resistance associated mutations in a bone marrow transplant recipient treated with MBV 400 mg p.o. twice per day
The results suggest that a high virus load permitted a selection of several but distinct therapy-resistant human cytomegalovirus (HCMV) mutants

Summary

Introduction

Human cytomegalovirus infections are still significant causes of morbidity and mortality in transplant recipients. All compounds approved for systemic treatment of human cytomegalovirus (HCMV) infections target the viral DNA polymerase [1,2,3]. All of these compounds are limited by dose related toxicities and the emergence of resistant virus mutants. MBV is orally bioavailable and was shown to have anti-HCMV activity in early clinical trials [6,7,8] This activity could not be confirmed in a phase III prophylaxis trial involving transplant recipients who obtained 100 mg twice per day [9]. MBV was used in a salvage treatment study using a higher dosage of 400 mg twice per day in 6 cases, who had failed to respond to other therapies and/or had known ganciclovir-

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Discussion

Conclusion