PORTLAND—The investigational drug islatravir “could be a game changer in the field of HIV," said David H. Spach, MD, Professor of Medicine, Division of Infectious Diseases, University of Washington, Seattle, in a session called, "Antiretroviral therapy 2019 update: Mechanism of action, new medications, current guidelines, and controversies."
Dr. Spach reported that islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), is highly potent, is well tolerated, has a high genetic barrier to resistance, and has an extremely long half-life, according to the findings of preliminary studies. Its long half-life enables subdermal implantation and maintenance of therapeutic levels even after a year in place. Researchers are studying the compound in combination with other agents for treatment and independently for preexposure prophylaxis.
Another noteworthy investigational agent, according to Dr. Spach, is cabotegravir, an integrase strand transfer inhibitor (INSTI) with the potential for intramuscular administration every 4 to 8 weeks. Dr. Spach explained that researchers are studying the agent in 3 different clinical situations: oral cabotegravir in combination with rilpivirine for lead-in therapy; an extended-release injectable of cabotegravir and rilpivirine for maintenance antiretroviral (ARV) treatment every 4 weeks; and an extended-release cabotegravir injectable for preexposure prophylaxis every 8 weeks. The agent is highly potent, with a high genetic barrier to resistance.
ARV: The current state of affairs
"We are in an era now where everyone who is living with HIV ideally should be receiving fully suppressive antiretroviral therapy," remarked Dr. Spach. He explained that not only does this benefit the person living with HIV by reducing the onset and progression of chronic inflammatory disease states that occur along with HIV, such as cardiovascular disease, stroke, and cancer, but also "fully suppressive ARV therapy virtually eliminates sexual transmission of HIV to another person."
Spach explained that the most recent (2018) Health and Human Services ARV therapy guidelines have greatly simplified the choices for ARV therapy. The current recommendations for initial ARV therapy for most people are to use a 2-drug backbone regimen, consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs), combined with a single anchor drug, which should be an INSTI. The INSTI should have the highest potency and highest genetic barrier to resistance available, which effectively means using a regimen that contains either dolutegravir or bictegravir. The latter is available only in combination with emtricitabine and tenofovir alafenamide as a single-tablet regimen.
Spach also explained that "the guidelines have moved away from using boosted regimens for initial therapy, so elvitegravir boosted with cobicistat and protease inhibitors (PIs) boosted with ritonavir or cobicistat are no longer recommended as preferred initial therapy, although boosted PIs are still very useful as second- or third-line therapies."
Newer medications
Doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), was approved by the FDA in 2018. "It probably won't have a big impact on initial therapy, but it is likely to have a significant effect on second- and third-line therapy," Dr. Spach said. "Because of its high potency and high genetic barrier to resistance, those taking etravirine twice a day, for example, may be able to simplify to once-a-day doravirine." In addition, "Doravirine may have advantages over rilpivirine in that it has no restrictions when used with acid-suppressing agents such as H2 blockers or proton pump inhibitors."
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