Merck MK-8591 is an experimental antiretroviral agent that maintains drug levels that are able to inhibit HIV for up to 6 months after dosing and could represent a prophylactic and therapeutic "paradigm shift" in HIV patients, according to Merck. with the research presented in the recent Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.
Jay Grobler of Merck reported that a single oral dose of MK-8591 maintained suppressed the simian immunodeficiency virus (SIV) with undetectable viral load in monkeys and was effective in keeping the body so for a week after dosing. The researchers also evaluated an oral dose of the drug in HIV-negative individuals whose diagnoses showed that the cellular levels of the drug were sufficient to suppress HIV and that this suppression could be maintained in the long run. Preliminary research results involving people with HIV were also encouraging. A formulation of the injected drug maintained excellent cellular levels for more than 6 months when administered in rodents.
The development of antiretroviral agents that require less frequent dosing have the potential to increase adherence to HIV treatment and use of anti-HIV drugs, such as Prevention (TasP) or PrEP.
MK-8591 is a reverse transcriptase inhibitor nucleoside (NRTIs) in the early stages of development. The drug's properties show that it has prolonged persistence in human peripheral blood mononuclear cells (PBMCs) and macrophages. Laboratory tests showed that these cells were protected against infection with HIV, even in the absence of continued antiretroviral exposure.
In the study presented in CROI, SIV-infected rhesus monkeys received weekly MK-8591 oral therapy, with doses ranging from 1,3 to 18,2 mg / kg. Plasma viral load was measured by post-dose 42 pre-dose dosing. Concentrations of MK-8591 were also evaluated throughout this period.
The researchers used the results from the animal study to select a weekly oral dose for evaluation in HIV-negative patients.
SIV viral load line in monkeys was between 106 to 108 copies / ml. After dosing with MK-8591, collective thicknesses with viral load below 108 copies / mL has fallen by up to 2 log in viral load, with suppression sustained for at least 7 days. Agent concentrations in 0,53 pmol / 10 experimental PBMCs6 and above were associated with maximum drop in viral load within one week after dosing.
In the study involving HIV-negative individuals, doses of 10 mg were able to achieve optimal drug levels required to prolong viral suppression. The drug was well tolerated.
The researchers also presented data from an early clinical trial involving people with HIV. These showed that a single oral dose 10 mg resulted in a drop log in 1.6 viral load for days 7 to 10. Intracellular levels of the drug were good and there were no signs of resistance.
An injected long-acting MK-8591 formulation continuously provided sufficient levels continuously, extending drug release in rodents. Plasma levels were similar to those observed in monkeys and humans, with drug release for periods longer than 6 months.
The researchers believe their findings show the potential for oral weekly dosing of MK-8591.
Formulations of long-acting (injected) oral and parenteral MK-8591 with potential for 6 months or longer "would represent a potential paradigm shift as a single agent for the prevention of HIV infection or as a component of a long dosing regimen for the treatment of HIV, "the researchers concluded. "Ongoing studies suggest the potential to provide coverage for periods of up to 1 year."
Translated into 16 April 2016 by Claudio Souza the original CROI 2016: Long-Acting MK-8591 Could Be Future Option for HIV Treatment and Prevention Written by Michael Carter on HIV and Hepatitis em collaboration with Aidsmap.com
reviewed by Mara T Macedo
J Grobler, and Friedman, SE Barrett, et al. Long-Acting oral and parenteral dosing of MK-8591 for the treatment of HIV or prophylaxis Jay Grobler. Conference on retroviruses and opportunistic infections. Boston, February 22-25, 2016. abstract 98.