The arrival of long-acting injectable antiretroviral therapy (ART) has ushered in a new option for providers and patients with HIV, though limits on its use may present new challenges.

“Ultimately, this is about choice based on an individual’s preference,” said Samir Gupta, MD, of Indiana University in Indianapolis.

“Some people with HIV may not want to carry around pill bottles, have to swallow pills (especially if they are large), add to existing pill burdens if they are needing other medications for other conditions, or would have concerns about stigmatization from others regarding why they are taking oral pills,” he added.

Most of the research on long-acting ART has centered on cabotegravir-rilpivirine (Cabenuva), the first such therapy approved by the FDA, as a monthly injection for patients who have Achieved Virological Suppression with no history of treatment failure. A label change now allows for every 2-month dosing with a higher dose of the product as well.

Earlier this year at the Conference on Retroviruses and Opportunistic Infections, investigators detailed that higher-dose cabotegravir-rilpivirine injections every 2 months were non-inferior to a daily oral regimen of bictegravir-emtricitabine-tenofovir alafenamide (Biktarvy) for maintaining viral suppression among patients with an undetectable viral load.

In line with its approval, guidelines on HIV.gov only recommend long-acting injectable ART for people living with HIV who are virally suppressed, but rumblings from experts argue its use should be expanded.

“Disenfranchised populations have multiple barriers to taking [ART], including competing subsistence needs, housing insecurity, food insecurity…, inability to access transportation, forgetting pills, inability to store them safely, substance use, [and] mental health concerns,” said Monica Gandhi, MD, of University of California San Francisco.

And patients with HIV generally seem agreeable to the idea of long-acting therapy. A small French study surveyed patients in 2018 and found that 74% were interested in an every-other-month regimen. However, 29% expressed concern about potential side effects and 21% cited “a greater fear of too much a constraint” associated with an injectable therapy.

In a study published in July, Gandhi and colleagues examined long-acting ART in a safety-net population of 133 people living with HIV in San Francisco: about a third homeless, over two-thirds actively using drugs, nearly half with mental health issues. Notably, 43% had active viremia but the researchers projected that 97.5% overall would be virologically suppressed at a median 33 weeks.

Another small study published last month involving a dozen patients with active viremia found that all achieved virological suppression with injectable long-acting ART.

“The clinical implications of this finding for providers treating patients with challenges to taking daily oral ART are that any sort of therapy is better than not taking therapy at all for HIV,” Gandhi said. “Long-acting ART can overcome some of the challenges of needing to take a daily oral pill and can be effective for patients with multiple competing priorities.”

Injectable therapy is currently the only long-acting form available, but researchers are already examining other drug delivery mechanisms and treatment intervals.

“Current oral long-acting therapies in development are not designed to be taken every few months at a time, as are the current injectables,” Gupta said. “Right now, the oral long-acting treatments are designed for once per week or at most once per month.”

In December 2022, the FDA approved long-acting lenacapavir (Sunlenca), given orally at first then subcutaneously every 6 months in combination with daily oral ART, for heavily treatment-experienced patients with multidrug resistance.

Gupta and colleagues have analyzed the potential of lenacapavir in treatment-naive patients as well, and the capsid inhibitor is being investigated as part of a once-weekly combination with investigational islatravir. While research on the regimen was paused in 2021 over safety concerns, drug developers relaunched a phase III program using a lower dose of islatravir.

Longer studies of the capsid inhibitor are needed “to determine what ‘partner’ oral or injectable long-acting drugs would best be used with lenacapavir to provide long-lasting efficacy without development of virologic resistance,” said Gupta.

Gandhi noted that “once-weekly dosing may be helpful for vulnerable patients with multiple competing priorities if we can give the doses to them in clinic or in locations of congregation, but will not be as helpful as medications that can be given less often … if patients really cannot come into medical care that frequently.”