title: Absence of rapid selection for acyclovir or penciclovir resistance following suboptimal oral prodrug therapy of HSV-infected mice.
abstract: BACKGROUND
  Acyclovir (ACV) resistant herpes simplex virus (HSV) isolates can be readily selected in animal infection models receiving suboptimal ACV treatment, however no comparative studies of the emergence of resistance following suboptimal treatment with valacyclovir (VCV) or famciclovir (FCV), the prodrugs of acyclovir and penciclovir, respectively, have been reported.
  
  
  METHODS
  Mice (n = 30) were infected with HSV type 1 or 2 in the ear pinnae and administered oral prodrugs at one fifth a dose previously shown to be effective. To select and amplify drug-resistant HSV, a total of seven consecutive in vivo passages with suboptimal treatment were performed for each virus sample and progeny virus from each passage was characterized by the plaque reduction (PRA) and plating efficiency assays (PEA).
  
  
  RESULTS
  No drug-resistant HSV-2 and only a single drug-resistant HSV-1 variant were identified. Virus recovered from the first three sequential passages of this HSV-1 sample was susceptible by PRA, although the proportion of resistant virus recovered gradually increased upon passage. The resistant HSV-1 phenotype was confirmed by PRA after four sequential passages in mice. Unexpectedly, this in vivo-selected drug-resistant HSV-1 failed to yield an infection completely refractory to treatment in subsequent passages.
  
  
  CONCLUSIONS
  Sub-optimal therapy of immunocompetent mice with either VCV or FCV did not readily select for HSV-mutants resistant to either ACV or PCV, suggesting that selection of resistance with either prodrug remains difficult using this system. Futhermore, this study suggests that the PEA may represent a useful adjunct to the PRA for monitoring alterations in the proportion of drug-resistant virus even when no change in IC50 is apparent.
authors.affiliation: Department of Host Defense, The Antimicrobial and Host Defense Center of Excellence for Drug Discovery, USA. robert_t_sarisky@gsk.com
authors.forename: R T
authors.initials: RT
authors.lastname: Sarisky
authors.forename: H R
authors.initials: HR
authors.lastname: Bartus
authors.forename: S A
authors.initials: SA
authors.lastname: Dennis
authors.forename: M R
authors.initials: MR
authors.lastname: Quail
authors.forename: T T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: R J
authors.initials: RJ
authors.lastname: Wittrock
authors.forename: W S
authors.initials: WS
authors.lastname: Halsey
authors.forename: T H
authors.initials: TH
authors.lastname: Bacon
authors.forename: J J
authors.initials: JJ
authors.lastname: Leary
authors.forename: D
authors.initials: D
authors.lastname: Sutton
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D005260:Female; D006147:Guanine; D006561:Herpes Simplex / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir