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Weekly Islatravir Protects Monkeys Against IV Challenge With SIV
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CROI 2020, March 8-11, 2020, Boston
Mark Mascolini
Two, 3, or 4 weekly oral doses of islatravir, a novel antiretroviral, protected 6 of 6 macaques intravenously (IV) challenged with SIVMAC251 24 hours earlier [1]. A single islatravir dose 24 hours after challenge protected 4 of 6 macaques. Merck researchers and collaborators who conducted this study believe their findings support islatravir as a simple postexposure prophylaxis (PEP) agent in humans.
Islatravir belongs to a new antiretroviral class: nucleoside reverse transcriptase translocation inhibitors (NRTTIs). Its mechanisms of action include translocation inhibition and delayed chain termination. A long half-life positions islatravir as a daily, weekly, or monthly oral drug. Researchers who presented the macaque study suggested islatravir may even work as a yearly implantable regimen for HIV treatment and prevention.
Previous work found once-weekly oral doses as low as 0.1 mg/kg highly protective against rectal SHIV109CP3 in macaques [2]. The new study involved macaques challenged intravenously with a simian immunodeficiency virus (SIVMAC251). Study animals received islatravir by oral gavage at a dose of 3.9 mg/kg. The study had four stages with 4, 3, 2, or 1 weekly dose of Islatravir. In each stage animals received the first dose 24 hours after SIV challenge.
Four, 3, or 2 weekly doses protected 6 of 6 monkeys from SIV infection, while 6 of 6 untreated animals became infected. A single dose of islatravir 24 hours after challenge protected 4 of 6 macaques from intravenous challenge. In the 2 infected animals, virus became detectable in blood 14 and 49 days after challenge.
Extrapolating pharmacokinetic results to humans suggested to the researchers that "a single oral dose given within 24 hours of HIV exposure in humans may provide effective PEP." Although the combined findings position islatravir as a simplified PEP agent for people exposed to HIV, the researchers cautioned that trials in humans will be challenging.
References
1. Markowitz M, Gettie A, St. Bernard L, et al. Weekly oral islatravir provides effective PEP against IV challenge with SIVMAC251. Conference on Retroviruses and Opportunistic Infections (CROI). March 8-11, 2020. Boston. Abstract 89LB.
2. Markowitz M, Gettie A, St Bernard L, et al. Once-weekly oral dosing of MK-8591 protects male rhesus macaques from intrarectal SHIV109CP3 challenge. J Infect Dis. 2019 Jun 7. pii: jiz271. doi: 10.1093/infdis/jiz271.
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