title: The emergence of cytomegalovirus resistance to ganciclovir therapy in kidney transplant recipients.
abstract: Transplant recipients that have not been previously exposed to the cytomegalovirus (CMV) are highly susceptible to viral diseases while under immunosuppression therapy. CMV disease requires prolonged therapy, facilitating the emergence of resistant strains. Persistence of positive antigenemia represents clinical evidence of the presence of resistant strains, although its frequency is unknown. These strains may present amino acid deletions or substitutions in conserved regions of the UL97 protein, point mutations in the DNA polymerase (UL54), or both. In this study we aimed to analyze the prevalence of mutations associated with ganciclovir resistance in transplant recipients. Fifteen kidney transplant recipients and four kidney-pancreas transplant recipients, with a positive and oscillating CMV viremia detected by sequential antigenemia test, were enrolled. The UL97 gene was amplified by Nested-PCR and enzymatically digested in samples of these patients in order to detect mutations in the most common codons, such as 460 (M460V), 594 (A594V) and 595(L595S/F). The end-product fragments were further sequenced. Nine (47.4%) out of 19 patients presented with mutations in UL97 at codons L595S (55.6%), A594V (11.1%), A595F/A594V (11.1%) and L595S/A594V (22.2%). None presented with mutation at the M460V codon. Renal transplant patients with oscillation in viral load for more than 2 weeks might have developed viral resistance to anti-drug therapy. Its detection might aid physicians in their clinical plan of tapering the patient's immunosuppression.
authors.affiliation: Laboratório de Imunologia Clínica e Experimental, Nephrology Division, Brazil.
authors.forename: Eliana
authors.initials: E
authors.lastname: Nogueira
authors.forename: Kikumi S
authors.initials: KS
authors.lastname: Ozaki
authors.forename: Helena
authors.initials: H
authors.lastname: Tomiyama
authors.forename: Celso F H
authors.initials: CF
authors.lastname: Granato
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Camara
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pacheco-Silva
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000209:etiology / Q000821:virology; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use*; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D015774:Ganciclovir