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, Janssen, and ViiV Healthcare.
The HIV treatment armamentarium currently includes many effective ARV agents and strategies, making the bar for introducing a new agent higher. Future agents will need to have unique properties and potential for novel applications, such as two-drug regimens or long-acting agents that may offer the potential for less frequent dosing.
Three examples of agents in phase II or III development with less frequent dosing are injectable cabotegravir and rilpivirine (an INSTI + NRTI combination), injectable leronlimab (an anti-CCR5 monoclonal antibody in the same class as ibalizumab), and parenteral or subdermal islatravir (MK-8591, in a new class of nucleoside reverse transcriptase translocation inhibitors [NRTTIs]).
As it is the first NRTTI, what I find intriguing about islatravir is that both the 3′-OH and 4’-ethynyl groups allow unique multiple mechanisms for inhibiting the reverse transcriptase enzyme. HIV inhibition by islatravir occurs at subnanomolar concentrations, and preclinical in vitro studies showed that the drug’s potency is greater than 10 times that of any currently available ARV drug. The active triphosphate of islatravir has an intracellular half-life of up to 128 hours.
Early studies showed that a single 10-mg oral dose of islatravir produced antiviral effects for 10 days and that parenteral dosing as infrequently as once per year may be feasible. These promising results have been extended in small studies of islatravir for HIV prevention and treatment that were presented at IAS 2019.
Islatravir also has a high barrier against HIV resistance—it is more potent against some NRTI-resistant strains than some other NRTIs are against wild-type virus. And the dose of islatravir being investigated for daily oral administration is much lower than the dose of other daily ARV drugs, suggesting that single-tablet, two-drug regimens with islatravir may have an advantage in pill size.
What don't we know about islatravir? A lot. Like every new drug, the adverse event profile has yet to be fully characterized. In both studies that I mentioned, islatravir was generally well tolerated but adverse events were experienced by study participants. Regarding prevention, it is unknown whether patients will prefer a surgical implant over other potential modalities. In reality, an implant could turn out to be paradoxically stigmatizing—if visible, it could be erroneously interpreted as a physical marker of high-risk sexual behavior. Nevertheless, it is exciting to see islatravir and other new compounds in the HIV prevention and treatment pipeline.
Do you foresee patient interest in less frequent dosing ART in the future? I invite you to join the discussion by posting a comment. Answer the polling question and add your thoughts to the discussion section.