title: Fast selection of maribavir resistant cytomegalovirus in a bone marrow transplant recipient.
abstract: BACKGROUND
  Human 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.
  
  
  METHODS
  The 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.
  
  
  CONCLUSIONS
  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 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).
authors.affiliation: Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany. detlef.michel@uniklinik-ulm.de
authors.forename: Axel
authors.initials: A
authors.lastname: Schubert
authors.forename: Karoline
authors.initials: K
authors.lastname: Ehlert
authors.forename: Susanne
authors.initials: S
authors.lastname: Schuler-Luettmann
authors.forename: Eva
authors.initials: E
authors.lastname: Gentner
authors.forename: Thomas
authors.initials: T
authors.lastname: Mertens
authors.forename: Detlef
authors.initials: D
authors.lastname: Michel
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D003587:Cytomegalovirus / Q000187:drug effects* / Q000302:isolation & purification*; D003586:Cytomegalovirus Infections / Q000382:microbiology*; D024882:Drug Resistance, Viral; D005260:Female; D006801:Humans; D012263:Ribonucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D012263:Ribonucleosides; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole