• Paul T Edlefsen, Alexander Birkmann, Meei-Li Huang, Craig A Magaret, Jia Jin Kee, Kurt Diem, Thomas Goldner, Burkhard Timmler, Susanne Stoelben, Helga Ruebsamen-Schaeff, Holger Zimmermann, Terri Warren, Anna Wald, and Lawrence Corey.
• Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Biostatistics.
• J. Infect. Dis. 2016 Jul 15; 214 (2): 258-64.

BackgroundPritelivir 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.MethodsTo 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.ResultsWe 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.ConclusionsThis study demonstrates evidence of retained susceptibility of HSV-2 to pritelivir in immunocompetent persons following daily therapy for up to 28 days.© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

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