title: Clinical failure of CMV retinitis with intravitreal cidofovir is associated with antiviral resistance.
abstract: OBJECTIVE
  To determine the incidence of clinical resistance to intraocular cidofovir injection for treatment of acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis, and to identify virologic features associated with cidofovir treatment failure.
  
  
  METHODS
  Clinical resistance to intravitreal cidofovir was examined in 64 patients with CMV retinitis who received at least 1 injection of 20 pg of cidofovir. Histopathologic examination, culture, and polymerase chain reaction were used to detect CMV in ocular specimens. Antiviral resistance was assessed by plaque reduction assay and DNA sequencing.
  
  
  RESULTS
  Clinical resistance to intravitreal cidofovir injections was identified in 3 patients (5%) and was associated with prior oral ganciclovir or intravenous cidofovir use. Ganciclovir- and cidofovir-resistant CMV isolates were cultured from 2 patients and harbored resistance-associated mutations in the UL97 and polymerase genes. Resistance mutations were also detected by direct analysis of vitreous. In 1 patient, different resistance mutations were identified in ocular vs extraocular CMV strains.
  
  
  CONCLUSIONS
  Clinical failure of intravitreal cidofovir occurs infrequently, but may be associated with cidofovir-resistant CMV selected by prior ganciclovir or cidofovir treatment. Ocular CMV disease can result from a localized infection with a resistant CMV strain, and antiviral resistance may develop at a local site of infection independently from resistance that develops systemically.
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, USA.
authors.forename: I L
authors.initials: IL
authors.lastname: Smith
authors.forename: I
authors.initials: I
authors.lastname: Taskintuna
authors.forename: F M
authors.initials: FM
authors.lastname: Rahhal
authors.forename: H C
authors.initials: HC
authors.lastname: Powell
authors.forename: E
authors.initials: E
authors.lastname: Ai
authors.forename: A J
authors.initials: AJ
authors.lastname: Mueller
authors.forename: S A
authors.initials: SA
authors.lastname: Spector
authors.forename: W R
authors.initials: WR
authors.lastname: Freeman
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004279:DNA, Viral / Q000032:analysis; D004352:Drug Resistance, Microbial; D015774:Ganciclovir / Q000627:therapeutic use; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D017211:Treatment Failure; D014822:Vitreous Body
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D015774:Ganciclovir