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- Title
No Evidence of Pritelivir Resistance Among Herpes Simplex Virus Type 2 Isolates After 4 Weeks of Daily Therapy.
- Authors
Edlefsen, Paul T.; Birkmann, Alexander; Meei-Li Huang; Magaret, Craig A.; Jia Jin Kee; Diem, Kurt; Goldner, Thomas; Timmler, Burkhard; Stoelben, Susanne; Ruebsamen-Schaeff, Helga; Zimmermann, Holger; Warren, Terri; Wald, Anna; Corey, Lawrence; Huang, Meei-Li; Kee, Jia Jin
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>This study demonstrates evidence of retained susceptibility of HSV-2 to pritelivir in immunocompetent persons following daily therapy for up to 28 days.
- Subjects
HERPES simplex virus; HERPESVIRUSES; HUMAN herpesvirus 1; THERAPEUTICS; CLINICAL medicine; ANTIVIRAL agents; COMPARATIVE studies; DRUG resistance in microorganisms; HERPES genitalis; RESEARCH methodology; MEDICAL cooperation; GENETIC mutation; PROTEINS; PYRIDINE; RESEARCH; RESEARCH funding; THIAZOLES; EVALUATION research; RANDOMIZED controlled trials; SEQUENCE analysis; PHARMACODYNAMICS
- Publication
Journal of Infectious Diseases, 2016, Vol 214, Issue 2, p258
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiw129