The future of ART regimens for HIV is in long-acting agents

Recent developments in antiretroviral therapy (ART) include longer-acting therapies that don’t require a daily oral pill and two-drug regimens that could decrease toxicity associated with standard triple-drug regimens.

The approval of cabotegravir plus rilpivirine (Cabenuva) in January 2021 was the first to provide both benefits as a monthly ART injection. The approval was expanded to use every 2 months a year later, and remains the only long-acting two-drug combination option.

“There’s a tremendous desire to develop an all-parenteral regimen for people with HIV, and Cabenuva is one of them, but Cabenuva is not right for everybody,” Barry Zingman, MD, of the Albert Einstein College of Medicine and medical director of the AIDS Center at Montefiore Medical Center in the Bronx, New York, told MedPage Today.

Its downsides include the fact that it’s an injection, since some people prefer pills, and the strict schedule requirement of dosing every 2 months. Also, patients with existing resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) are not candidates for it, since rilpivirine is an NNRTI.

“We really need options that work, particularly globally, where there’s a lot of resistance to rilpivirine,” Matthew Spinelli, MD, of the University of California San Francisco, told MedPage Today. “You really need a long-acting option that’s not in that class.”

One off-label solution, Zingman and Spinelli said, has been giving people long-acting cabotegravir and rilpivirine with lenacapavir (Sunlenca), a single-drug ART injection every 6 months that treats multi-resistant HIV. Lenacapavir is typically taken with other oral ART combinations. For those without resistance to NNRTIs, however, long-acting cabotegravir and rilpivirine is increasingly becoming a way to help address adherence challenges.

Expanding Use of Long-Acting Injectable ART

When the cabotegravir and rilpivirine regimen was approved, it was recommended for individuals with HIV who were already virally suppressed on an oral ART regimen. This requirement, however, leaves out many people who could particularly benefit from a long-acting injectable because of adherence difficulties, Spinelli said.

“The group you really want to be giving these long-acting drugs to are the people with the greatest adherence challenges,” he said.

Zingman agreed, describing groups of individuals who can often benefit most from long-acting injectable ART.

“The best candidates are people who are struggling taking their medicine right now,” he said. “Maybe they’re getting just enough in their bodies to control HIV, but they’re missing frequently enough that, over time, they may develop resistance, and we want to head that off.”

Others who would find long-acting cabotegravir and rilpivirine helpful are people who may experience anxiety or depression from the daily reminder of their HIV status that comes with taking a daily oral ART.

“That could be really triggering for some people and cause significant stigma, so if we can relieve the stigma of shame by a long-acting agent, they don’t have to think about it every day,” Zingman said. “Then there’s another group who don’t have security around their medicine” — either they live in a shelter or lack a place to store it securely at home or they live with people who aren’t aware of their HIV status.

These challenges mean that a lot of people have begun taking long-acting cabotegravir and rilpivirine while not virally suppressed. Over time, evidence for this group with off-label use has suggested that it is a viable option for people whose adherence difficulties are the main reason for not achieving viral suppression.

Based on that data, the International Antiviral Society (IAS)-USA treatment guidelines were updated in March 2024 to state that injectable cabotegravir and rilpivirine could be considered for people with viremia if they are unable to take oral ART consistently despite extensive efforts and support and if they are at high risk of HIV disease progression, as long as their virus is susceptible to both drugs and they receive intensive follow-up and case management services.

Since then, even more data have emerged for this approach. Spinelli and colleagues published a study in JAMA earlier this year that compared 48-week viral load outcomes between people who started long-acting cabotegravir and rilpivirine with and without viral suppression at initiation (less than 30 copies/mL). Of the 370 participants, 40% had housing instability and 46% had substance use, with higher rates in those with viremia.

Those with viremia had a median baseline viral load of 45,600 copies/mL and half had a CD4 count under 200 cells/mm³, but they reached an undetectable viral load in a median 32 days with cabotegravir and rilpivirine. Based on available data at 24 weeks, 97% of 118 patients with viremia at initiation achieved viral suppression compared with 99% of 212 starting without viremia (P=0.12), with similar results at 48 weeks.

The most recent data come from this year’s International AIDS Society (IAS) Conference on HIV Science, where Ricky Hsu, MD, of NYU Langone Medical Center in New York City, presented real-world effectiveness data for people with viremia who began long-acting cabotegravir and rilpivirine. He noted that of prior real-world cohort studies of people starting the regimen in the U.S., including Spinelli’s study, 9% to 35% started with viremia.

However, Hsu’s study was larger, with data from the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort including more than 150,000 people with HIV, approximately 14% of whom lived in the U.S. Among the 3,304 people who had received at least one injection of cabotegravir and rilpivirine from January 2021 to December 2023, there were 368 who had at least 50 copies/mL at their first injection.

More than half of participants were Black (57%), 18% were Latino/Hispanic, 27% were 50 and older, and 63% were from the Southern U.S.; nearly half (49%) were men who have sex with men, and 30% were women. It had been a median 9 years since their HIV diagnosis, and they had a median CD4 count of 579 cells/mm³. Their median viral load was 120 copies/mL, and 40% had more than 200 copies/mL. Most (68%) had been on a regimen of integrase strand transfer inhibitors before switching to cabotegravir and rilpivirine.

Among the 90% of participants who completed initiation (two injections within 67 days), 78% remained on it for a median follow-up of 12 months, mostly receiving doses every 2 months. Data from 293 people receiving maintenance injections showed that 59% received all their injections on time, 33% had a median of one delayed dose, and 13% had a median of one missed dose. In the 313 people who initiated cabotegravir and rilpivirine with viremia and had available data over follow-up, 88% achieved viral suppression (less than 50 copies/mL). Three patients had confirmed virologic failure.

“These findings add support to the use of this long-acting injectable antiretroviral regimen in a population of people with HIV that have been refractory to achieving viral suppression,” Joseph McGowan, MD, the medical director of the HIV Service Line Program at Northwell Health in New York, told MedPage Today. “This is the critically important population that, for varying reasons, may have barriers to adherence,” such as gastrointestinal intolerance, social determinants of health, and comorbid conditions, including mental illness or substance use.

Including nearly a third of female participants helps with extrapolating the findings, McGowan said, noting the high percentage with a body mass index over 30 (29%), “which has been a factor associated with treatment failure with this combination.” The fact that 93% of participants were on a 2-month dosing schedule is also reassuring, he added, “as there would be a temptation to start on a monthly dosing schedule, which appears unnecessary.” There could be a concern of risk for viral resistance among the 12% of non-responders if they were not switched to an active oral regimen, he said, but those data were not reported.

“Use of long-acting injectable therapy in viremic patients must include wrap-around support services to address the barriers that have made oral therapy unsuccessful,” McGowan said. “While it removes the burden of daily pill taking from the people with HIV, it is not a passive intervention for the clinical team. Missed doses can have long-term consequences due to the long washout tail and could impact future options when they are critically needed.”

Beyond Long-Acting Cabotegravir and Rilpivirine

While cabotegravir and rilpivirine, with or without lenacapavir, is the only complete long-acting combination right now, others are in the pipeline. One of those is the investigational once-weekly oral combination of islatravir and ulonivirine, with recent results presented at the IAS meeting in July. Another once-weekly oral ART being studied is a combination of lenacapavir and islatravir.

“These could be game-changing in terms of oral regimens,” Zingman said. “It could be amazing for people who don’t want to get an injection but would love the option of a regimen they can just take every Wednesday morning and be done.”

Research has also continued in developing two-drug combinations to add to existing dolutegravir plus rilpivirine (Juluca), approved in 2017, and dolutegravir plus lamivudine (Dovato), approved in 2019. MK-8591A — doravirine plus islatravir — is currently under review. But those are both daily ART regimens, and, as Spinelli said, “the frontier is really in long-acting now.”

Disclosures

Zingman is an investigator on clinical trials with payments to his institution from GSK/ViiV Healthcare, Gilead Sciences, and Merck.
Hsu reported research grants, speaker honoraria, and/or advisory board participation with Gilead Sciences, ViiV Healthcare, Merck, and Epividian.
Spinelli and McGowan had no conflicts of interest.

By Tara Haelle

All MedPage Today reports from IAS 2025 can be accessed here.