Kirsten Stray1, Michel Perron1, Danielle P Porter1, Francisco Anderson2, Sandra A Lewis1, Jason Perry1, Michael Miller1, Tomas Cihlar1, John DeVincenzo3,4,5, Jason W Chien1, Robert Jordan1. 1. Gilead Sciences, Inc, Foster City, California, USA. 2. Pivot Bio, Berkeley, California, USA. 3. Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee, USA. 4. Department of Microbiology, Immunology and Biochemistry, University of Tennessee College of Medicine, Memphis, Tennessee, USA. 5. Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
Abstract
BACKGROUND: Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner. METHODS: Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed. RESULTS: Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease. CONCLUSIONS: Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.
RCT Entities:
BACKGROUND: Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner. METHODS: Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed. RESULTS: Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease. CONCLUSIONS: Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.
Authors: Danielle P Porter; Ying Guo; Jason Perry; David L Gossage; Timothy R Watkins; Jason W Chien; Robert Jordan Journal: Antimicrob Agents Chemother Date: 2020-08-20 Impact factor: 5.191
Authors: Michael H J Rhodin; Nicole V McAllister; Jonathan Castillo; Sarah L Noton; Rachel Fearns; In Jong Kim; Jianming Yu; Thomas P Blaisdell; Joseph Panarese; Brian C Shook; Yat Sun Or; Bryan Goodwin; Kai Lin Journal: PLoS Pathog Date: 2021-03-15 Impact factor: 6.823