CROI 2022: Lenacapavir in treatment-experienced participants, and as PrEP in macaques
Lenacapavir is a capsid inhibitor given by 6-monthly subcutaneous injections that is currently in phase 2/3 studies for HIV treatment and prevention.
CROI 2022 includes six studies that focus on this long-acting compound. These include results in treatment-experienced participants with multi-drug resistance (CAPELLA study, reported below) and people who are treatment-naive (CALIBRATE study, reported separately – both with results out to one year. [1, 4]
CAPELLA included both a randomised (Cohort 1, n=36, randomised 2:1) and open label cohort (Cohort 2, n=36), with 24-week results, including drug resistance reported at IAS 2021 and EACS 2021 meetings (including 4 cases of breakthough with lenacapavir drug resistance, linked to either resistance or low adherence to the optimised background regimen (OBR). [2, 3]
Baseline demographics based on earlier reports include: 25% women, 38% Black, median age 52 years. Median baseline viral load was 4.5 log copies/mL (range: 1.3 to 5.7), with 28/72 >75,000 copies/mL. Median baseline CD4 count was 150 cells/mm3 (range: 3 to 1296) with 64/72 <200 cells/mm3. Approximately 46% had resistance to all four major classes (NRTI, NNRTI, PI, INSTI), and 17% had no fully active agents in the OBR.
At week-52, viral load was undetectable in 83% (30/36) although most of Cohort 2 have not yet reached this endpoint. Median overall follow-up was 376 days (IQR: 306 to 501).
CD4 count increased by a median 83 cells/mm3 (IQR: +21 to +142, n=41). In addition to the four participants from Cohort 1 with breakthrough drug resistance reported at EACS 2022  another four new cases were reported from Cohort 2, also related to limited support from the OBR.
All eight continue on lenacapavir, with 3/8 re-suppressing (2/3 after a change in OBR).
There were no discontinuations due to serious adverse events, but one participant stopped due grade 1 injection site nodules. ISRs occurred in 63% (45/72) and were mostly mild or moderate (43/45). Diarrhoea, nausea and COVID-19 were all reported at <10%.
Results from the CALIBRATE study in treatment-naive participants will be reported separately after the oral presentation on the third day of CROI 2022. 
Other studies include posters related to drug interactions and drug resistance, and a late-breaking macaque study supporting use as PrEP.
A phase 1 study in 54 HIV negative individuals reported no significant drug interactions between lenacapavir and the investigational long-acting compound islatravir. This promising compound with ideal PK to support use with lenacapavir now appears uncertain since the US FDA suspended islatravir studies due to unexpected side effects that reduced total and CD4 lymphocytes. [5, 6]
Even though lenacapavir is not excreted renally, a poster from a phase 1 study reported slightly increased lenacapavir PK in ten people with severe renal impairment (CrCl 15 to ≤ 29 mL/min) compared to ten unimpaired HIV negative controls. The increases however, due to a minor p-gp pathway, were not judged clinically significant. 
The poster on drug resistance reported the activity of lenacapavir was similar to wild-type (mean susceptibility 1.0; range 0.3 to 1.7) in HIV-1 isolates from 72 people regardeless of their phenotypic resistance to entry inhibitors (maraviroc, fostemsavir, ibalizumab, and enfuvirtide (T20). 
Efficacy and PK as PrEP
The macaque PrEP study included efficacy and PK results. 
Protection again infection occurred in all animals (n=4 dosed at 25 mg/kg with lenacapavir 30 days before a high-dose IV challenge and, interestingly, three animals given an active PrEP control of daily sc TDF/FTC/dolutegravir for 3 days before), followed for 8 months. This compared to early infection in all four placebo animals within 10 days.
In the PK study, plasma concentrations in six animals given two injections six weeks apart using either 15 mg/kg and 50 mg/kg dosing. Drug levels peaked 3-4 weeks after the second dose with mean levels maintained above the paEC95 (1.46 nM) for approximately 4.8 and 6.6 months (>145 and >200 days) after the second 15 mg/kg and 50 mg/kg doses, respectively. 
These results support potent viral efficacy and broad safety of lenacapavir for HIV treatment and prevention.
Longer follow up is needed from CAPELLA to confirm rates of viral suppression in Cohort 1 of 67%, 79% and 94% with 0, 1 and 2 active drugs in the OBR, especially in those with no active drugs.
Phase 3 PrEP studies are already ongoing, although lenacapavir is currently on clinical hold related to a technical concern about glass vials used in these studies. A press statement from Gilead outlines further details to resolve this. 
Unless stated otherwise, references are to the 29th Conference on Retroviruses and Opportunistic Infections, 12–16 and 22–24 February 2022, virtual meeting. Depending on CROI policy, links might require conference registration and might only be active for a limited time on this platform after the meeting.
- Ogbuagu O et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: week 52 results. CROI 2022. 12-16 February 2022, virtual. Poster abstract 491.
- Lenacapavir: drug resistance after viral rebound in treatment experienced participants. HTB (30 November 2021).
- IAS 2021: lenacapavir studies show impressive results in naive, extensive drug resistance and potential as PrEP. HTB (1 August 2021).
- Lenacapavir: 54 week results in treatment-naive participants of CALIBRATE study. CROI 2022 reports. HTB (1 March 2022).
- Gupta S et al. Lenacapavir as part of a combination regimen in treatment naive PWH: week 54 results. CROI 2022. 12-16 February 2022, virtual. Oral abstract 138.
- Zhang H et al. Evaluation of potential drug-drug interactions between islatravir and lenacapavir. CROI 2022. Poster abstract 433.
- FDA further limit use of islatravir in ongoing studies. HTB (December 2021).
- Weber E et al. Pharmacokinetics of lenacapavir in participants with severe renal impairment. CROI 2022. Poster abstract 434.
- Margot N et al. Absence of cross-resistance to lenacapavir in HIV entry inhibitor-resistant isolates. CROI 2022. Poster abstract 508.
- Swanstrom AE et al. Long-acting lenacapavir protects against intravenous challenge with simian-tropic HIV. CROI 2022. Poster abstract 860.
This report was first published on 14 February 2022.