Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques from Intrarectal Challenge with SHIV109CP3

Martin Markowitz, Agegnehu Gettie, Leslie St Bernard, Chasity D. Andrews, Hiroshi Mohri, Amir Horowitz, Brooke F. Grasperge, James L. Blanchard, Tao Niu, Li Sun, Kerry Fillgrove, Daria J. Hazuda, Jay A. Grobler

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Background: MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine [EFdA]) is a novel reverse transcriptase-translocation inhibitor. Methods: We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.9 mg/kg of MK-8591 orally on day 0 and once weekly for the next 14 weeks. Eight controls were treated with vehicle. All rhesus macaques were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in study 2 and further to 0.1 and 0.025 mg/kg/week in study 3. In studies 2 and 3, each dose was given up to 6 times once weekly, and animals were challenged 4 times once weekly with SHIV109CP3. Results: Control macaques were infected after a median of 1 challenge (range, 1-4 challenges). All treated animals in studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P <. 0001, by the log-rank test). In study 3, at a 0.1-mg/kg dose, 2 rhesus macaques became infected, consistent with a 7.2-fold lower risk of infection (P =. 0003, by the log-rank test). The 0.025-mg/kg dose offered no protection. Conclusions: These data support MK-8591's potential as a preexposure prophylaxis agent.

Original languageEnglish
Pages (from-to)1398-1406
Number of pages9
JournalJournal of Infectious Diseases
Volume221
Issue number9
DOIs
StatePublished - 7 Apr 2020

Keywords

  • MK-8591 (EFdA)
  • Preexposure prophylaxis
  • Rhesus macaques
  • SHIV intrarectal challenge

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