An investigational 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 to rodents.
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.
The investigators 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.
Concentrations of 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 tolerated.
The investigators 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.
A long-acting 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.
The investigators 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.
Grobler J et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis. Conference on Retroviruses and Opportunistic infections, abstract 98, 2016.