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More than 80% of heavily treatment-experienced HIV patients with multi-drug resistance who received long-acting subcutaneous lenacapavir along with an optimized background regimen experienced viral suppression at week 26, according to results of an ongoing randomized phase II/III trial.

Overall, 81% of patients randomized to the investigational agent lenacapavir with an optimized background regimen of antiretroviral therapy (ART) had viral loads below 50 copies/mL, and 89% of patients had a viral load below 200 copies/mL, reported Jean-Michel Molina, MD, of Hôpital Saint-Louis in Paris, during a late-breaking presentation at the virtual International AIDS Society Conference on HIV Science.

This trial initially made news at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) in March when investigators reported that 88% of patients in the intervention arm achieved at least a 0.5 log₁₀ reduction in HIV viral load within 15 days of treatment with the first-in-class HIV capsid inhibitor.

Molina said that these results were updated to week 26 for patients in the randomized part of the trial, but also included data from six participants in the non-randomized part of the trial who had 26 weeks of follow-up, for a total of 72 patients.

"It's still early to know what's going to happen with this drug, but the first results are really encouraging when you see the very high rate of people fully suppressed after 26 weeks, so the efficacy we've seen after 2 weeks is long-lasting," he added.

The trial was comprised of heavily treatment-experienced patients with HIV RNA of at least 400 copies/mL, who showed resistance to at least two agents from three of the main four ART classes. They were randomized 2:1 to receive oral lenacapavir or placebo and their failing ART regimen for 14 days. Both groups were then switched to an optimized background regimen plus either an injection of subcutaneous lenacapavir every 6 months for 52 weeks in the intervention group or 2 weeks of oral lenacapavir followed by subcutaneous lenacapavir every 6 months for 52 weeks in the placebo group.

A non-randomized group of 36 patients received an optimized background regimen with oral lenacapavir for 2 weeks, followed by subcutaneous lenacapavir every 6 months for 52 weeks.

Median age of participants was 52, three-quarters were male at birth, 38% were Black, and 21% were Hispanic/Latinx.

Molina noted that without any fully active agents, up to 67% of participants reached a viral load of less than 50 copies/mL at week 26. In addition, median CD4 count increased by 82 cells/μL, with Molina reporting that no patients had a CD4 count below 50 cells/μL at week 26, despite eight patients with a very low CD4 count at baseline.

Eleven participants met criteria for resistance testing. Four of the 11 had emerging resistance to lenacapavir; however, two of those patients re-suppressed without changes to their optimized background regimen, Molina said.

More research into resistance is needed in the future, though the number of people with resistance was low, he added.

No adverse events led to study drug discontinuation. Of the events reported in more than 5% of participants, diarrhea and nausea were the most common (8% each). There were no severe adverse events. There was one death from a malignant neoplasm unrelated to the study drug.

Fifty-six percent of participants reported injection site reactions, though most were grade 1, with swelling (26%) and erythema (24%) the most common. The two grade 3 reactions were swelling and erythema, both of which resolved within 4 to 8 days. All nodules were grade 1, and no participants discontinued treatment due to injection site reactions.

Subcutaneous lenacapavir may also be appealing for HIV prevention, Molina noted. Two large phase III trials are ongoing to assess the drug's preventive capabilities.

"The interest in the drug is clearly its long half-life, allowing a self-administered injection subcutaneously every 6 months, so for prevention, this looks really attractive," he said. The drug is administered as two subcutaneous injections in the abdomen.

Lenacapavir is currently being used in expanded access programs among patients with multi-drug resistance who usually have not been fully adherent to their ART regimen, Molina noted, since the 6-month administration timeframe provides "an ideal treatment for overcoming resistance and lack of adherence."

An ongoing phase II trial is also assessing the combination of lenacapavir and the investigational nucleoside reverse transcriptase translocation inhibitor islatravir to treat HIV, he said.

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