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Selected Presentations from CROI 2018
 

Low-Dose Oral MK-8591 Protects Monkeys From Rectal SHIV Infection

25th Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2018, Boston
 

Mark Mascolini


 - "The researchers concluded that MK-8591 remains completely protective against rectal SHIV at doses of 1.3 and 0.43 mg/kg weekly..."suggesting MK-8591 utility in extended-duration prophylaxis against HIV infection…..strong antiviral activity with weekly oral dosing"


At an oral dose of 1.30 or 0.43 mg/kg  weekly, the nucleoside reverse transcriptase inhibitor (NRTI) MK-8591 protected 8 of 8 macaques from simian HIV (SHIV) infection after rectal exposure [1]. MK-8591 levels reached in this monkey study should be attainable in humans at doses under 250 ug weekly.

MK-8591 (EFdA) inhibits HIV-1 reverse transcriptase via multiple mechanisms [2,3]. In lab studies, the NRTI remains active against an array of NRTI-resistant clones and patient isolates.
Studies in macaques and humans indicate strong antiviral activity with weekly oral dosing, a trait suggesting MK-8591 could find use as preexposure prophylaxis (PrEP). Previous work by researchers at the Aaron Diamond AIDS Research Center and collaborators found that a weekly oral MK-8591 dose of 3.9 mg/kg completely protected 8 macaques from weekly rectal challenges of SHIV 109CP3, a pathogenic R5-using subtype C virus [4].

Aiming to determine the MK-8591 dose at which MK-8591 loses its protective capacity, the new study involved 8 male macaques rectally exposed weekly to a 50 TCID dose SHIV 109CP3 for up to 4 challenges. The animals received MK-8591 or inert vehicle (no MK-8591) weekly by oral gavage up to 6 times starting 1 week before the SHIV challenge and ending 1 week after the last challenge. Researchers sequentially tested three doses: 1.30, 0.43, and 0.10 mg/kg weekly.

Eight of 8 macaques receiving a dose of 1.30 or 0.43 mg/kg weekly remained uninfected after SHIV challenges. Two of 8 animals receiving a dose of 0.10 mg/kg became infected, 1 after 3 SHIV challenges and 1 after 4 challenges. Combining these results with those of the earlier study, in which macaques got MK-8591 at a dose of 3.9 mg/kg weekly [4], the researchers determined that animals receiving the NRTI had a 41.47-fold lower risk of SHIV infection than animals not getting the drug (P < 0.0001).

At the time of the SHIV challenge, average intracellular levels of MK-8591 triphosphate (the active form of the drug) were 810 fmol/million cells with 3.9 mg/kg of MK-8591, 282 fmol/million cells with 1.3 mg/kg, 102 fmol/million cells with 0.43 mg/kg, and an estimated 24 fmol/million cells with 0.10 mg/kg.


The researchers concluded that MK-8591 remains completely protective against rectal SHIV at doses of 1.3 and 0.43 mg/kg weekly. The 0.1-mg/kg dose "remains highly protective," they added, at intracellular levels affording 92% protection from SHIV. In the 2 animals who became infected with the 0.1-mg/kg dose, viral loads were lower than those seen in infected animals not receiving MK-8591.

Protective MK-8591 levels attained in this study can be reached in humans, the investigators estimated, at doses below 250 ug weekly or 10 ug daily, calculations "suggesting MK-8591 utility in extended-duration prophylaxis against HIV infection."

References
1. Markowitz M, Gettie A, St. Bernard L, et al. Low dose MK-8591 protects rhesus macaques against rectal SHIV infection. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 89LB.
2. Michailidis E, Marchand B, Kodama EN, et al. Mechanism of inhibition of HIV-1 reverse transcriptase by 4'-ethynyl-2-fluoro-2'-deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor. J Biol Chem. 2009;284:35681-35691.
3. Michailidis E, Huber AD, Ryan EM, et al. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem. 2014;289:24533-24548.
4. Markowitz M, Gettie A, St. Bernard L, et al.  Weekly oral MK-8591 protects male rhesus macaques against repeated low dose intrarectal challenge with SHIVC109P3. 9th IAS Conference on HIV Science (IAS 2017), July 23-26, 2017, Paris. Abstract MOAX0203LB. http://www.natap.org/2017/IAS/IAS_10.htm