Use of lenacapavir in people with HIV who are heavily treatment-experienced resulted in high levels of virologic suppression, according to two small studies presented at the Infectious Disease Week (IDWeek) 2025 Annual Meeting.

In one study, 77% of participants were on a complex regimen of at least two core antiretroviral agents before starting lenacapavir, and over half (56%) saw their regimens simplify when they started or over the course of taking it. Most remained on the drug with high adherence to the injection schedule. In the other study, over half the participants were not virologically suppressed when they started lenacapavir, but the majority of those patients (82%) achieved and maintained suppression once starting.

Lenacapavir received an FDA indication in 2022 for heavily treatment-experienced people with multidrug-resistant HIV-1 who are failing their current antiretroviral therapy (ART) regimen because of resistance, intolerance, or safety considerations, based on the CAPELLA trial, explained Karam Mounzer, MD, clinical professor of medicine at the Perelman School of Medicine at the University of Pennsylvania and physician with Philadelphia Fight Community Health Centers, both in Philadelphia, when introducing the first study.

Yet “in real-world settings, a high proportion of individuals are starting lenacapavir while virologically suppressed,” unlike CAPELLA participants, Mounzer told attendees. That suggests that factors other than virologic control are driving people’s decision to start lenacapavir, he said. Regardless, the findings show lenacapavir to be an effective long-acting option.

Grace Haser, MD, infectious disease fellow at the University of California, San Francisco, told Medscape Medical News that she found the real-world data to be very encouraging, “to know that it’s tolerated and that people achieve or maintain virologic suppression.” Haser, who was not involved with either study, said it allows providers to consider using lenacapavir in highly treatment-experienced people with HIV.

“It’s hard to tell from a really large cohort study the motivations for adding lenacapavir or switching, but it was interesting to me that a number of people were virologically suppressed at the time that lenacapavir was added,” she said. “I don’t know if it was pill burden or just interest in modernizing the regimen, but it was good to see, regardless of pre-LEN virologic suppression, that most patients did pretty well with it.”

Mounzer’s real-world study assessed 2-year outcomes among 116 ART-experienced adults enrolled in the Observational Pharmaco-Epidemiology Research & Analysis Cohort, which includes more than 157,000 people with HIV at 101 clinics in 23 states, or approximately 14% of those with HIV in the US. The participants included 22% women and had an average age of 54 years. Nearly half (49%) were Black, and 13% were Hispanic. All had received at least one set of lenacapavir injections between December 2022 and September 2024.

The participants had been diagnosed with HIV for a median of 16 years, and about half (52%) had had a history of AIDS-defining events. Most (64%) had a viral load under 200 copies/mL, but 9% had a viral load between 200 and 999 copies/mL, and 28% had a viral load of 1000 copies/mL or more. Their median CD4 count was 406 cells/µL, and nearly a quarter (23%) had a CD4 count below 200 cells/µL.

Before starting lenacapavir, just less than a quarter of the participants were only taking one core antiretroviral drug (23%), half (51%) were taking two core agents, and 26% were taking three or more core agents. Most (82%) were taking integrase strand transfer inhibitors (INSTI), which rose to 84% at lenacapavir initiation. The proportion taking nonnucleoside reverse transcriptase inhibitors (NNRTI) and entry inhibitors also increased, from 42% to 43% and 34% to 35%, respectively, when they started lenacapavir. However, the proportion taking nucleoside reverse transcriptase inhibitors (NRTI) fell from 63% to 53%, and those taking protease inhibitors (PI) fell from 46% to 34%, when they started lenacapavir.

Though the regimens of most participants (61%) did not change when they started lenacapavir, more than half (56%) of the participants overall eventually experienced simplification of their regimen, with fewer total agents, classes, or pills per day. That included 18% whose regimen simplified only when they started, 34% whose regimens simplified while taking it, and 4% whose regimens simplified both at the start and while taking lenacapavir.

Participants with a baseline viral load below 200 copies/mL were 92% likely to maintain that viral load over 12 months of taking lenacapavir. Those starting the drug with a viral load of 200 copies/mL or more were 76% likely to reach a viral load below 200 copies/mL within a year, taking a median 2 months before first reaching it. Most participants (86%) also had on-time injections after their first one, with only 11% receiving maintenance injections late, and 91% of those who started the drug and received at least two injections stayed on it for at least 28 weeks.

In the other study, Chris Kaperak, MD, infectious disease fellow at the University of Chicago Medicine, Chicago, and his colleagues assessed the real-world use of lenacapavir in 70 heavily treatment-experienced people with HIV at various Chicago clinics and at the University of Pittsburgh between November 2020 and June 2025. The participants had an average age of 52 years, and it had been an average 24 years since their HIV diagnosis. Over half (54%) were male, 73% were Black, 14% were Hispanic, and 73% were on Medicaid or Medicare. More than a third (37%) had a history of substance use disorder.

Just over half the participants (54%) were not virologically suppressed when they started lenacapavir, and four patients had viral loads above 100,000 copies/mL. As in the other study, a high proportion of participants (61%) were on at least two active agents before starting lenacapavir, and most had resistance to at least two NRTI (79%) or NNRTI (74%). Additionally, 40% had resistance to an INSTI and 23% to a PI.

Similar to the previous study, the most common drug class participants were taking was INSTI (70%), followed by NRTI (50%) and NNRTI (31%). Again, a high proportion of participants (89%) remained on lenacapavir once starting, and 82% of unsuppressed participants achieved and maintained virologic suppression. No virologic failures occurred among those supposed at baseline.

Although participants’ total number of ART medications did not change much before and after starting lenacapavir, the average number of pills they took per day did decrease.

While Haser was not surprised by the findings, they “reaffirmed my thoughts about seeing the pill burden decrease for a lot of individuals, and that might be a motivation for switching or adding lenacapavir,” she said. Receiving twice yearly injections while taking fewer daily pills is likely easier for most people, she said, but it will still be important to find ways of supporting those who still struggle with adherence to oral drugs.

“There are questions about how to best manage the combination of injectable and oral regimens, particularly in those that have had adherence challenges to oral meds, and how to help support adherence to oral regimens since we don’t have too many long-acting drugs available right now, and so a number of these patients are not able to be on a fully injectable regimen,” Haser said.

Kaperak’s study did not note external funding; one of his coauthors reported receiving consulting or advising honoraria and/or research support from Abbott Laboratories, Gilead Sciences, and GSK/ViiV. Mounzer’s study was funded by Gilead Sciences, and he reported receiving research grants and honoraria for speaking or advising from Gilead, Merck, GSK/ViiV, and Epividian. Haser had no disclosures.

Tara Haelle is a science/health journalist based in Dallas.