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Long-acting oral antiretroviral MK-8591 could represent 'paradigm shift' in HIV treatment and prophylaxis
Michael Carter, 2016-04-01 08:00:00
antiretroviral agent that maintains drug levels that are able to inhibit HIV up
to six months after dosing could represent a “paradigm shift” in HIV therapy
and prophylaxis, according to research presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston, USA, last week.
A single oral dose
of MK-8591 suppressed simian immunodeficiency virus (SIV) viral load in monkeys and was effective one week after
dosing. The investigators also evaluated an oral dose of the drug in
HIV-negative individuals, finding that cellular levels sufficient to inhibit
HIV could be maintained in the long term. Results of preliminary research
involving people with HIV were also encouraging. An injected formulation
of the drug achieved excellent cellular levels over six months when administered
The development of antiretroviral agents that
require less frequent dosing have the potential to enhance adherence to both
HIV treatment and the use of anti-HIV drugs as prevention. MK-8591 is a
nucleoside reverse transcriptase inhibitor (NRTI) in the early stages of
development. The properties of the drug mean that it has protracted persistence
in human peripheral blood mononuclear cells (PBMCs) and macrophages. Laboratory
trials have shown that such cells were protected from infection with HIV, even
in the absence of continued antiretroviral exposure.
Investigators now presented
results of a study in which SIV-infected rhesus macaques received weekly oral
MK-8591 therapy, with doses ranging between 1.3 to 18.2mg/kg. Plasma viral load
was measured pre-dosing through to day 42 post-dose. Concentrations of MK-8591
were also evaluated through this period.
used the results of the animal study to select a once-weekly oral dose for
evaluation in HIV-negative people.
Baseline SIV viral load in the monkeys was between
106 to 108 copies/ml. After dosing with MK-8591, rhesus
macaques with a viral load below 108 copies/ml experienced an up to
2 log fall in viral load, with suppression sustained for at least seven days.
the investigational agent in PBMCs of 0.53pml/106 and above were
associated with maximal falls in viral load one week after dosing.
In the study
involving HIV-negative individuals, doses of 10mg were able to achieve optimal
drug levels needed for prolonged viral suppression. The drug was well
also presented data from an early clinical trial involving people with HIV. These showed that a single 10mg oral dose resulted in a 1.6 log fall
in viral load by days seven to ten. Intracellular drug levels were good and
there were no signs of resistance.
injected forumlation of MK-8591 had continuous, extended drug release in
rodents. Plasma levels were similar to those observed in monkeys and humans,
with release of the drug exceeding six months.
believe their findings show the potential for weekly oral dosing of MK-8591.
“MK-8591 oral and long-acting parenteral [injected] formulations with potential
for six months or longer duration would represent a potential paradigm shift as
a single agent for the prevention of HIV infection or as a component of an
extended dosing regimen for HIV treatment,” conclude the researchers. Ongoing
research suggests that a single dose may be able to achieve effective
concentrations for up to one year.