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  ID Week
Oct 19, -23 2022
Washington DC

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Lenacapavir: 75% Sub-50 Response at 52 Weeks Despite Heavy ART Experience
  IDWeek 2022, October 19-23, 2022, Washington, DC
Mark Mascolini
Three quarters of lenacapavir trial participants with heavy antiretroviral therapy (ART) experience and multidrug-resistant HIV had a viral load below 50 copies after 52 weeks even when the regimen included 1 or 0 fully active drugs [1]. Only 1 of 72 people stopped lenacapavir because of an injection site reaction.
Lenacapavir is a novel antiretroviral that thwarts HIV replication at multiple steps in the viral life cycle-HIV entry of the target cell nucleus, viral assembly and release, and viral capsid assembly outside the cell [2]. Because no other antiretrovirals work this way, lenacapavir will not share resistance pathways with other antiretroviral classes.
To be eligible for this lenacapavir trial, people had to have a viral load at or above 400 copies, resistance to two or more antiretrovirals, and two or fewer active drugs from the four main antiretroviral classes. Researchers randomized 24 people to lenacapavir and 12 to placebo. They also created a nonrandomized cohort of 36 people, all of whom got lenacapavir. Everyone took oral lenacapavir (or placebo) for 14 days, then switched to subcutaneous lenacapavir every 6 months for 52 weeks. (People who started with placebo switched to oral lenacapavir for 14 days, then went to the injected drug.)
Of the 72 total trial participants, median age stood at 52 years, 25% were female, 38% black, and 21% Hispanic. Median viral load measured 4.5 log10 copies (about 32,000 copies), and 19% had a viral load above 100,000 copies. Median CD4 count stood at 150 and ranged from 3 to 1296. Two thirds of the group had a CD4 count below 200.
Trial participants had taken a median of 11 prior antiretrovirals. While 47% of these people had 2 or more fully active antiretrovirals to take with lenacapavir, 36% had only 1, and 17% had 0. Almost everyone had known resistance to 2 or more nucleos(t)ides and 2 or more nonnucleosides, while 81% had resistance to 2 or more protease inhibitors, and 69% had resistance to 2 or more integrase inhibitors.
At week 52 in 72 randomized and nonrandomized participants, 78% had a viral load below 50 copies, 15% had virologic failure (viral load 50 copies or more), and 7% had no virologic data. In these 72 people, 82% had a 52-week viral load below 200 copies, 11% had virologic failure, and 7% had no virologic data.
Twenty-seven of 34 people (79%) who took 2 or more active antiretrovirals with lenacapavir had a 52-week viral load below 50 copies, 20 of 26 (77%) with only 1 active antiretroviral had a load below 50 copies at week 52, and 9 of 12 (75%) with no active antiretroviral to take with lenacapavir had a load below 50 copies at week 52.
After 52 weeks, 21 of 72 people met trial criteria for resistance testing and had data available. Nine of those 21 (43%) had a lenacapavir resistance mutation emerge during treatment with this antiretroviral. CD4 count gains averaged 97 cells through 52 weeks, a meaningful gain for the many people who began the trial with a CD4 count below 200. The proportion of participants with a CD4 count at or above 200 rose from 36% when the trial began to 68% at week 52.
Tabulating adverse events except injection site reactions through a median 498 days of follow-up, the researchers found that no study drug-related adverse event occurred in more than 5% of participants and no serious adverse events were related to study drugs. Three quarters or more trial participants had no injection site reactions after the first and second shot of lenacapavir. No one had a grade 4 injection site reaction. The three grade 3 reactions were swelling and erythema in 1 person, which resolved in 4 and 8 days, and pain, which resolved in 1 day. One person stopped taking lenacapavir at week 52 because of an injection site reaction, a grade 1 nodule.
Lenacapavir studies will continue in people with heavy antiretroviral experience and multidrug-resistant HIV, and also in people with moderate or no antiretroviral experience.
1. Ogbuagu O, Segal-Maurer S, Ratanasuwan W, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in heavily treatment-experienced people with multi-drug resistant HIV: Week 52 results. IDWeek 2022, October 19-23, 2022, Washington, DC. Abstract 1585.
2. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17:15-21. doi: 10.1097/COH.0000000000000713. https://www.natap.org/2022/HIV/Lenacapavir__a_first_in_class_HIV_1_capsid.4.pdf