Long-acting lenacapavir plus cabotegravir kept all 46 patients with HIV virally suppressed in recent trial

Every patient in a 46-person cohort of people with HIV, many of whom had drug resistance, unstable housing or active substance use, reached or maintained viral suppression on an off-label long-acting combination of lenacapavir and cabotegravir, according to a research letter published recently in JAMA Network Open by University of California, San Francisco (UCSF) researchers.

Monica Gandhi, M.D., M.P.H., is the senior author of ‘Long-Acting Lenacapavir and Cabotegravir and Viral Suppression Among People With HIV,’ as well as a UCSF professor of medicine. She and her team describe their study as the largest case series of the two-drug injectable combination to date, to their knowledge.

Why clinicians are pairing lenacapavir with cabotegravir

Cabotegravir plus rilpivirine is the only FDA-approved long-acting injectable HIV treatment. That combination was first approved in 2021 for patients who were already virally suppressed, but clinicians have since used it off-label for patients with viremia and adherence challenges, an approach now endorsed by the International AIDS Society–USA and the Department of Health and Human Services guidelines. Wider use has been held back by logistical, financial and infrastructural barriers, Gandhi and her team wrote, as well as by the low genetic barrier to resistance of rilpivirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI). NNRTI resistance is present in up to 10% of people with HIV globally.

Lenacapavir, a first-in-class capsid inhibitor, was approved in 2022 for multidrug-resistant HIV. Because it acts at several discrete steps of the viral life cycle, it may carry a higher barrier to resistance than NNRTIs, the authors noted. Clinicians have increasingly paired it with other long-acting agents, though outcome data remain limited. In an earlier four-clinic case series of 34 patients, the same research group reported that viral suppression roughly doubled, from 47% to 94%, on long-acting lenacapavir and cabotegravir.

The Ward 86 lenacapavir cohort

The retrospective case series drew on electronic medical record data, verified through clinician review, from the Ward 86 HIV Clinic, a Ryan White Program-funded clinic affiliated with UCSF. It included patients who started long-acting lenacapavir with other long-acting agents between March 2023 and May 2025, with follow-up extended through November 2025.

Participants had a mean age of 47.1 years, and 32 (69.6%) were men. Sixteen patients (34.8%) were Black or African American and 16 (34.8%) were Hispanic or Latino. Nineteen (41.3%) had unstable housing, such as a single-room occupancy hotel, shelter or living outdoors, and 15 (32.6%) reported current methamphetamine or amphetamine use.

Most patients in the cohort (71.7%) had baseline NNRTI resistance. Thirty-three patients (71.7%) had baseline NNRTI resistance, while four (8.7%) had integrase strand transfer inhibitor resistance. Seventeen patients (37.0%) had rilpivirine included in their long-acting regimen.

Viral suppression results with lenacapavir and cabotegravir

At the start of lenacapavir, 22 patients (47.8%) were virally suppressed and 24 (52.2%) were viremic, defined as HIV RNA of 200 copies/mL or more. More than half of the viremic group, 14 patients (58.3%), had a CD4+ count of 200 cells/mm³ or fewer.

All patients who started suppressed stayed suppressed, and all patients who started viremic achieved suppression by 13 weeks. Over a median follow-up of 100 weeks from the first lenacapavir injection, no patient had consecutive viral loads above 200 copies/mL.

“This study represents the largest case series of long-acting LEN/CAB and adds to the growing evidence supporting its use for patients with adherence challenges and resistance,” Gandhi and her team wrote.

What the findings mean for HIV care and payers

Gandhi and her team cited the study’s retrospective design, small sample and single-center setting as limitations. Ryan White-funded clinics report higher viral suppression rates (91.4%) than the U.S. national average (67.2%), they noted, and the support infrastructure at those clinics may limit how well the results generalize. Nationally, 68.5% of people with diagnosed HIV were virally suppressed in 2024, according to the Centers for Disease Control and Prevention’s latest national HIV prevention and care objectives report.

Still, the authors argued that their cohort reflects the population for whom long-acting lenacapavir was originally developed. The combination is not approved for HIV treatment, and two trials of the approach are planned within the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections clinical trials network.

“Clinicians are already starting to use these two drugs together, and until now we’ve had very little evidence to guide us,” Gandhi said in a news release.