Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3

J Infect Dis. 2020 Apr 7;221(9):1398-1406. doi: 10.1093/infdis/jiz271.

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.

Keywords: MK-8591 (EFdA); SHIV intrarectal challenge; preexposure prophylaxis; rhesus macaques.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Rectal
  • Animals
  • Deoxyadenosines / therapeutic use*
  • Macaca mulatta
  • Male
  • Rectum / virology
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Simian Acquired Immunodeficiency Syndrome / prevention & control*
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / drug effects*

Substances

  • Deoxyadenosines
  • Reverse Transcriptase Inhibitors
  • islatravir