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Lenacapavir Sustains HIV Control
and Keeps Boosting CD4s Through 3 Years
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IDWeek, October 16-19, 2024, Los Angeles
Mark Mascolini
Among people with heavy antiretroviral experience and multidrug-resistant HIV, the every-6-month subcutaneous capsid inhibitor lenacapavir (plus other antiretrovirals) kept viral loads below 50 copies in 85% in a week-156 missing-data-excluded analysis, the same suppression rate seen since week 26 [1]. CAPELLA study investigators also reported that CD4 counts kept on climbing from week 104 through week 156-the 3-year mark-in these people with low initial CD4 tallies.
The FDA licensed lenacapavir for treatment of people with long antiretroviral histories and multidrug-resistant HIV, in combination with other antiretrovirals picked to fashion an optimized background regimen (OBR). This novel antiretroviral derails HIV replication by disrupting viral nuclear import, virion assembly, and capsid core assembly [2]. After a lead-in phase with oral lenacapavir, people get a subcutaneous shot of the drug every 6 months.
The ongoing CAPELLA trial (NCT04150068) established the efficacy of lenacapavir plus an investigator-selected OBR in people with multidrug-resistant virus: 82% of 52 participants analyzed attained a viral load below 50 copies at 26 weeks by FDA snapshot analysis [3]. At IDWeek, CAPELLA researchers spelled out week-156 results [1].
The trial enrolled people with a viral load at or above 400 copies while taking a failing antiretroviral regimen. All participants had HIV resistant to 2 or more antiretrovirals from 3 of
the 4 main antiretroviral classes (nucleos[t]ides, nonnucleosides, protease inhibitors, and integrase inhibitors). Researchers measured participants' viral loads twice before randomization. If their viral load did not drop 0.5-log10 copies/mL from the first viral load assay to the second or if their viral load lay below 400 copies, they went into cohort 1, People who did meet those prerandomization criteria went into cohort 2.
Cohort 1 included 36 people, 24 randomized in a double-blind fashion to oral lenacapavir plus the failing regimen for 14 days and 12 randomized to placebo plus the failing regimen. Then the lenacapavir group began subcutaneous dosing every 6 months (plus OBR) and people initially assigned to placebo started 2 weeks of oral lenacapavir lead-in then subcutaneous lenacapavir every 6 months (plus OBR). In the unblinded analysis of cohort 2, 36 participants took oral lenacapavir for 14 days then subcutaneous lenacapavir (plus OBR).
The total 72 participants had a median age of 52 years (range 23 to 78), 75% were male at birth, 41% white, 38% black, and 21% Asian. Median initial viral load stood at 4.5 log10 (about 32,000 copies) and median CD4 count at 150. Almost two thirds of study participants (63.9%) had an initial CD4 count below 200. Almost half of the study group (45.8%) had used drugs from all 4 major antiretroviral classes.
FDA snapshot analysis of 70 participants at week 156 determined that 43 people (61.4%) had a viral load below 50 copies, 11 (15.7%) had a load at or above 50 copies, and 16 (22.9%) did not have data in the week-156 window. When excluding missing data, CAPELLA statisticians charted a sub-50-copy response plateau starting at 82.9% at week 26, then holding at 85.1% at week 52, 81.5% at week 104, and 84.6% at week 156. Almost all subcutaneous injections, 98%, got administered within 14 days of the scheduled date.
The week-156 missing-data-excluded analysis included 52 participants, down from 70 at week 26. Participants fell from the analysis for reasons one would expect in people with hefty treatment histories, cobbled-together OBRs, and meager CD4 counts-including premature discontinuation, loss to follow-up (failure to keep appointments), and withdrawn consent. Researchers concur that a missing-data-excluded analysis can be biased if the people excluded differ systematically from the people included [4].
From the start of oral lenacapavir dosing to week 156, CD4 counts rose by an average 164 cells. Counts marched upward across the 156 weeks. From the first dose to week 156, the proportion of people with a count below 200 fell from 64% to 22%, and the proportion with a count below 50 drifted from 24% at baseline to 2% at week 156.
Lenacapavir-associated resistance mutations (M66I, Q67H/K/N, K70H/N/R/S, N74D/H/K, A105S/T, T107A/C/N/S) emerged in 14 people (19.4% of 72) during therapy with the capsid inhibitor. Four of these people with emergent resistance had no active antiretrovirals to put in an OBR, and the other 10 adhered inadequately to the OBR. Five people with virus resistant to lenacapavir regained a viral load below 50 copies despite continuing the capsid inhibitor; 2 did so after changing OBR drugs, and 3 did so with no OBR changes. Among 9 people who did not resuppress HIV after resistance to lenacapavir emerged, 6 continued study drugs and 3 stopped study drugs for reasons not related to efficacy. No new lenacapavir resistance mutations emerged between weeks 104 and 156.
Through a median 165 weeks of follow-up while taking lenacapavir, 71 of 72 people had any treatment-emergent adverse event and 31 (43.1%) had a grade 3 or worse treatment-emergent event. (Except for injection site reactions, emergent adverse events may be caused by any drug in these regimens.) Fifty-seven participants (79.2% of 72) had a treatment-related adverse event, and 6 of these (8.3% of 72) were grade 3. Twenty-two people (30.6%) had serious treatment-emergent adverse events, and in 2 (2.8%) these adverse events led people to drop out of the study.
Almost all injection site reactions were grade 1 or 2 (97%), and their frequency fell over time. Two people stopped lenacapavir because of grade 1 injection site nodules.
The CAPELLA investigators stressed that CD4 counts climbed throughout follow-up, even from week 104 to week 156 (year 2 to 3). They attributed emergence of lenacapavir-resistant virus to inability to construct an adequate OBR or to poor adherence to the OBR.
References
1. Ogbuagu O, McGowan JP, Stapleton A, et al. Long-acting subcutaneous lenacapavir in people with multi-drug resistant HIV-1: 3-year results of the CAPELLA study. IDWeek, October 16-19, 2024, Los Angeles. Abstract 155.
2. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020;584:614-618. doi: 10.1038/s41586-020-2443-1. https://jpet.aspetjournals.org/content/391/1/91.long
3. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N Engl J Med. 2022;386:1793-1803. doi: 10.1056/NEJMoa2115542. https://www.nejm.org/doi/10.1056/NEJMoa2115542
4. Raghunathan TE. What do we do with missing data? Some options for analysis of incomplete data. Annu Rev Public Health. 2004:25:99-117. doi: 10.1146/annurev.publhealth.25.102802.124410. https://www.annualreviews.org/content/journals/10.1146/annurev.publhealth.25.102802.124410
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