Gene Stollerman Professor of Medicine
Chief, Division of Infectious Diseases
Northwestern University Feinberg School of Medicine
Babafemi Taiwo, MBBS, has disclosed that he has received consulting fees from Gilead Sciences, Merck, and ViiV.
The 2018 IDWeek and Glasgow meetings featured the latest research into managing HIV infection. I was particularly interested in new data presented on 2 promising long-acting injectable antiretrovirals, GS-6207 and MK-8591, given their potential implications in the clinic.
GS-6207 (formerly GS-CA2) is a first-in-class HIV capsid inhibitor targeting both virion maturation and nuclear translocation after viral entry. This agent’s properties make it well suited as a potential long-acting antiretroviral. First, GS-6207 is highly potent, with a plasma protein binding–adjusted EC95 of 4.0 nM compared with an EC95 of 44 nM with efavirenz; therefore, only a small dose volume is needed. Second, GS-6207 has low water solubility and limited hepatic clearance—meaning that it should distribute widely in human tissue and persist long after injection. Indeed, Zheng and colleagues reported at IDWeek 2018 that a single subcutaneous injection of GS-6207 maintained plasma levels above the EC95 for at least 20 weeks in dogs and rats. The clinical safety and pharmacokinetics of GS-6207 in adults with HIV infection are under investigation in an ongoing phase I study. What could these results mean for our patients? Assuming human studies confirm these preclinical findings, then GS-6207 would truly be a long-acting ARV and an exciting addition to the treatment armamentarium. As a first-in-class agent with a novel mechanism of action and activity against the major HIV-1 subtypes, it could be a good option for treatment-experienced patients with drug-resistant disease. However, we would need to determine which other ARVs should be combined with GS-6207. Potential intriguing options for providing a complete regimen could be to combine GS-6207 with either an investigational monoclonal antibody with a long half-life or a novel formulation of MK-8951, which we will discuss now.
MK-8591 is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) that acts as an alternative substrate for HIV-1 reverse transcriptase and leads to either immediate or delayed termination of DNA synthesis. This agent is also highly potent against HIV-1, HIV-2, and NRTI-resistant strains. An early study in treatment-naive patients with HIV-1 infection reported that a single 10-mg injection of MK-8591 was associated with a rapid reduction in HIV-1 RNA levels that persisted for at least 10 days.
Because MK-8591 is cleared renally, there are questions about potential drug–drug interactions with ARVs such as dolutegravir (DTG), which inhibits the renal transporters OCT2 and MATE1, and tenofovir, which is also cleared renally. Rudd and colleagues assessed potential interactions in a standard 2-period pharmacokinetic study of MK-8591 coadministered with DTG plus tenofovir disoproxil fumarate (TDF) in healthy volunteers. The investigators presented their results at Glasgow 2018 showing no clinically meaningful pharmacokinetic effects with coadministration. A separate study presented at IDWeek 2018 by Matthews and colleagues also observed no clinically meaningful pharmacokinetic effects when MK-8591 was coadministered with doravirine in healthy volunteers. There were no concerning safety signals in either study.
Assuming MK-8591 continues to show positive results, what does this potentially mean in the clinic? For one, it appears that we could coadminister MK-8591 with DTG, TDF, and/or doravirine without major concerns for drug–drug interactions between them. Furthermore, because MK-8591 is potent against drug-resistant strains, this could be another good option for treatment-experienced patients when combined with GS-6207 or other long-acting ARVs. It might even work as a component in dual-therapy strategies.
As we can see from these emerging data, the HIV pipeline is far from dry. With the development of potent, safe, long-acting agents, my hope is that we will eventually have new options to address treatment fatigue and adherence issues in the clinic.
Do you think that long-acting injectable ART is a viable approach for some patients? Please share your thoughts in the comments box.