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Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3
Martin Markowitz1, Agegnehu Gettie1, Leslie St Bernard1
1Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, New York, New York.
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.
Insights
MK-8591 (EFdA) shows promise as a pre-exposure prophylaxis (PrEP) agent. This novel reverse transcriptase inhibitor protected macaques against SHIV infection, even at low doses, supporting its potential for HIV prevention.
Area of Science:
- Virology
- Pharmacology
- Infectious Diseases
Background:
- MK-8591, also known as 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is a novel reverse transcriptase-translocation inhibitor.
- This compound represents a new class of antiretroviral agents with potential for HIV prevention.
Purpose of the Study:
- To evaluate the efficacy of MK-8591 as a pre-exposure prophylaxis (PrEP) against simian/human immunodeficiency virus (SHIV) infection.
- To determine the protective dose range of MK-8591 in a rhesus macaque model.
Main Methods:
- Rhesus macaques were administered varying oral doses of MK-8591 weekly.
- Animals were subjected to intrarectal challenge with SHIV109CP3 up to 12 times.
- Infection status and risk reduction were compared between treated groups and vehicle controls.
Main Results:
- MK-8591 demonstrated significant protection against SHIV infection in rhesus macaques across multiple studies.
- A dose-dependent protective effect was observed, with higher doses showing complete protection.
- Even a low dose of 0.1 mg/kg/week resulted in a statistically significant 7.2-fold lower risk of infection.
Conclusions:
- MK-8591 is a potent pre-exposure prophylaxis agent with demonstrated efficacy in a relevant animal model.
- The findings support the further development of MK-8591 for human use in HIV prevention strategies.
- MK-8591's effectiveness at low doses suggests a favorable pharmacokinetic profile for PrEP.
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