title: No Evidence of Pritelivir Resistance Among Herpes Simplex Virus Type 2 Isolates After 4 Weeks of Daily Therapy.
abstract: Pritelivir is a novel helicase-primase inhibitor in clinical development for treatment of herpes simplex virus type 2 (HSV-2) infections. In preclinical work, resistance-mediating mutations were identified in the HSV-2 genome at 3 loci in the UL5 gene and 1 locus in UL52.
  
  
  
  To evaluate whether daily pritelivir treatment results in emergence of resistance-mediating mutations, we analyzed HSV-2 strains detected in genital swab specimens from trial participants who were randomly assigned to receive different dosages of pritelivir. We sequenced resistance regions from 87 participants' samples, the UL5 gene in 73 samples from 44 participants, and the UL52 gene in 71 samples from 43 participants.
  
  
  
  We found no evidence that pritelivir induced known resistance-mediating mutations or for amino acid variation at other loci. In one participant's HSV-2 isolate, we found a previously unidentified mutation close to the putative resistance-mediating region in UL5 and subsequently determined in vitro susceptibility to pritelivir. We characterized mutations from 32 cultivated HSV-2 isolates previously found to be susceptible to pritelivir in vitro and identified several novel mutations that most likely reflect preexisting variation in circulating HSV-2.
  
  
  
  This study demonstrates evidence of retained susceptibility of HSV-2 to pritelivir in immunocompetent persons following daily therapy for up to 28 days.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Biostatistics.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Edlefsen
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Birkmann
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine.
authors.forename: Meei-Li
authors.initials: ML
authors.lastname: Huang
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Magaret
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Biostatistics.
authors.forename: Jia Jin
authors.initials: JJ
authors.lastname: Kee
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine.
authors.forename: Kurt
authors.initials: K
authors.lastname: Diem
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Goldner
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Timmler
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Stoelben
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Ruebsamen-Schaeff
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: Westover Heights Clinic, Portland, Oregon.
authors.forename: Terri
authors.initials: T
authors.lastname: Warren
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine Department of Epidemiology Department of Medicine, University of Washington, Seattle.
authors.forename: Anna
authors.initials: A
authors.lastname: Wald
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine Department of Medicine, University of Washington, Seattle.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D005260:Female; D006558:Herpes Genitalis / Q000188:drug therapy*; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D009154:Mutation; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013449:Sulfonamides; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; D014764:Viral Proteins; C453221:pritelivir
keywords: drug resistance; helicase-primase inhibitor; herpes simplex virus 2; viral genomics pritelivir