title: The time course of development and impact from viral resistance against ganciclovir in cytomegalovirus infection.
abstract: (Val)ganciclovir is used to treat cytomegalovirus (CMV) infection following solid organ (SOT) or hematopoietic stem cell (HSCT) transplantation. Treatment failures occur, but the contribution from 39 known ganciclovir-related mutations (GRMs) in the CMV-UL97 gene remains controversial. We propose a categorization of these GRMs potentially useful when interpreting sequence analyses in clinical settings. The UL97 gene was sequenced from first/recurrent CMV infections among consecutive SOT or HSCT recipients during 2004-2009. GRMs were categorized as: Signature GRM (sGRM) if in vitro ganciclovir IC(50)  ratio for mutated versus wild-type virus >2 (n = 24); polymorphic GRM (pGRM) if ratio <2 (n = 15). (Val)ganciclovir treatment failure was defined as persistent viremia for 30 days or switch to foscarnet within this period. Of 99 (49 HSCT and 50 SOT) recipients with one CMV infection episode, 15 (13 HSCT and 2 SOT) experienced a total of 19 recurrent infection episodes. The prevalence of sGRM was 0% at start of first episode, whereas at start of recurrent episodes, prevalence was 37%. Only one sGRM was present at a time in individual patients. Patients with CMV containing an sGRM (vs. wild type)-but not with a pGRM-were at excess risk of treatment failure (odds ratio = 70.6 [95% CI:8.2-609.6]; p < 0.001). sGRMs emerged only following longer termed use of antiherpetic drugs and usually in recurrent CMV infection episodes. Risk of ganciclovir treatment failure was raised if an sGRM was detected.
authors.affiliation: Center for Viral Diseases, Department of Infectious Diseases, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark. cdb@cphiv.dk
authors.forename: C da
authors.initials: Cd
authors.lastname: Cunha-Bang
authors.forename: N
authors.initials: N
authors.lastname: Kirkby
authors.forename: M
authors.initials: M
authors.lastname: Sønderholm
authors.forename: S S
authors.initials: SS
authors.lastname: Sørensen
authors.forename: H
authors.initials: H
authors.lastname: Sengeløv
authors.forename: M
authors.initials: M
authors.lastname: Iversen
authors.forename: A
authors.initials: A
authors.lastname: Rasmussen
authors.forename: F
authors.initials: F
authors.lastname: Gustafsson
authors.forename: C M
authors.initials: CM
authors.lastname: Frederiksen
authors.forename: J
authors.initials: J
authors.lastname: Kjaer
authors.forename: A Cozzi
authors.initials: AC
authors.lastname: Lepri
authors.forename: J D
authors.initials: JD
authors.lastname: Lundgren
mesh_terms: D000328:Adult; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000209:etiology; D024882:Drug Resistance, Viral; D005260:Female; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D016377:Organ Transplantation / Q000009:adverse effects* / Q000379:methods; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D015995:Prevalence; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D017245:Foscarnet; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D015774:Ganciclovir