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Lenacapavir Shots or Tabs Control HIV in First-Line ART Combinations
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2022 CROI, February 12-16 and 22-24, 2022
Mark Mascolini
Lenacapavir, a multimechanism HIV inhibitor, controlled HIV well at 54 weeks with subcutaneous or oral dosing and combined with emtricitabine/tenofovir alafenamide (F/TAF), TAF-only maintenance, or bictegravir-only maintenance in an ongoing US trial [1].
This novel agent appears to act at several steps in the viral lifecycle: transport of HIV into the target cell nucleus, viral assembly and release from the target cell, and viral capsid assembly outside the cell. The capsid-the conical shell shrouding the viral genome-"facilitates virtually every step of infection through a series of interactions with multiple host cell factors" [2]. Research is evaluating lenacapavir in HIV-positive people with deep antiretroviral experience, in people still naive to antiretrovirals, and as PrEP to prevent HIV infection.
CALIBRATE is an ongoing US phase 2 trial in previously untreated people [3]. Participants had to have a viral load at or above 200 copies and a CD4 count of 200 or higher. In an open-label format researchers randomized 182 people in a 2:2:2:1 ratio: Group 1 receives subcutaneous lenacapavir every 6 months plus daily oral F/TAF then daily TAF alone if reaching a viral load under 50 copies with the 3-drug combination. Group 2 gets subcutaneous lenacapavir every 6 months plus daily oral F/TAF then daily oral bictegravir if reaching a viral load below 50 copies with 3 drugs. Group 3 takes once-daily oral lenacapavir with daily oral F/TAF. And Group 4 takes once-daily bictegravir and F/TAF.
Overall the study group had a median age of 29, 7% were women, 52% black, and 45% Hispanic. Median CD4 count stood at 437 cells and median viral load at 4.37 log (about 23,000 copies). Only 2% of the study group had a CD4 count below 200.
In a week-54 FDA snapshot analysis, similar proportions in each study arm had a viral load below 50 copies: 90% in Group 1, 85% in Group 2, 85% in Group 3, and 92% in Group 4. In the combined Groups 1 and 2-people taking subcutaneous lenacapavir-88% had a sub-50-copy viral load at week 54. Among people with virologic suppression at week 28, proportions with a viral load under 50 copies at week 54 in FDA snapshots were 94% in Group 1, 92% in Group 2, 90% in Group 3, and 92% in Group 4.
Through 54 weeks CD4 count rose an average 206 cells in Group 1, 212 cells in Group 2, 220 cells in Group 3, and 193 cells in Group 4.
One person in Groups 1, 2, and 4 and 3 people in Group 3 met resistance testing criteria. Lenacapavir-resistant virus could be detected in 1 of 1 person in Group 2 and 1 of 3 in Group 3 (2 of 157 participants overall or 1.3%). Both people with emergent resistance regained virologic control with a regimen combining an integrase inhibitor with 2 nucleos(t)ide reverse transcriptase inhibitors.
When the researchers excluded injection site reactions, the only adverse event affecting at least 10% of participants and affecting a higher proportion in the 3 combined lenacapavir arms than in the bictegravir control arm was nausea (13% vs 4%). The researchers saw no serious or grade 4 adverse events related to study drugs, and no one stopped treatment for an adverse event except injection site reactions. Three people stopped treatment because of injection site reactions: 2 because of grade 1 induration (skin hardening) after the first shot and 1 because of grade 1 erythema and swelling after the second shot. There was a single grade 3 injection site reaction, nodules, after the second shot. But nodules and induration persisted for long times-medians of 195 days for nodules and 212 days for induration.
Any grade 3 or 4 lab abnormality affected 25% in the 3 combined lenacapavir arms and 24% in the bictegravir control arm. The investigators reported no clinically relevant grade 3 or 4 lab abnormalities, and no one stopped treatment because of a grade 3 or 4 abnormality.
An ongoing but no longer recruiting trial, CAPELLA, is evaluating lenacapavir in people with heavy antiretroviral experience [4].
References
1. Gupta S, Sims J, Brinson C, et al. Lenacapavir as part of a combination regimen in treatment-naive PWH: week 54 results. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 138.
2. Campbell EM, Hope TJ. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol. 2015;13: 471-483. doi: 10.1038/nrmicro3503. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876022/
3. ClinicalTrials.gov. Study to evaluate the safety and efficacy of lenacapavir in combination with other antiretroviral agents in people living with HIV (CALIBRATE). ClinicalTrials.gov identifier NCT04143594. https://clinicaltrials.gov/ct2/show/NCT04143594
4. ClinicalTrials.gov. Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen (OBR) in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (CAPELLA). ClinicalTrials.gov identifier NCT04150068. https://clinicaltrials.gov/ct2/show/NCT04150068
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