CROI 2023: Six-monthly ART – lenacapavir + dual bNAbs maintains undetectable viral load for 26 weeks after single doses
Simon Collins, HIV i-Base
CROI 2023 included the first results from an ART combination that only needs to be given once every six months. 
This study involved switching people who had been undetectable on stable oral ART for at least two years to a combination of lenacapavir plus two long-acting broadly neutralising antibodies (bNAbs). Results were detailed in an oral presentation by Joe Eron from the University of North Carolina at Chapel Hill.
Lenacapavir is a long-acting capsid inhibitor that has already been approved in Europe and the US with an indication to treat multidrug resistant HIV, but studies earlier in infection are still ongoing. It is given as a sub-cutaneous injection every six months, but it is also being developed as a weekly oral pill.
The bNAbs in this study involved single infusions of teropavimab (TAB, previously 3BNC117-LS and GS-5423) and zinlirvimab (ZAB, previously 10-1074-LS and GS-2872), both developed at Rockefeller University before being acquired by Gilead in 2020. 
This blinded, phase 1b proof-of-concept study randomised 20 adults on suppressive ART to either 30 mg or 10 mg of ZAB IV plus TAB 30 mg/kg IV and LEN (927 mg SC after loading dose). Entry criteria also included current CD4 >500, nadir CD4 >350 and phenotypic sensitivity at baseline to both bNAbs. Viral load was monitored every four weeks.
Out of 124 people screened, 55/124 were susceptible to both bNAbs and 21 were enrolled. This left 34/55 who were not included due to not meeting other entry criteria, and one withdrew consent. Ten participants were therefore randomised into each dosing group. Detailed results on susceptibility screening were also reported in a separate poster. 
Baseline characteristics included median age 44 years (IQR: 34 to 51); 14% were women; 14% Black, 14% Asian, 33% Hispanic/Latinx. Median CD4 count was 909 cells/mm3 (IQR: 687 to 1270, range: 547 to 1391). Median time since HIV diagnosis was 8.2 years (range: 2.6 to 26.3). Most people had started ART within a year of being diagnosed and median time on current ART was 2.6 years (range 2.0 to 5.5). Median BMI was 30 kg/m2 (range 21 to 54).
The primary endpoint was safety with no serious adverse events (AEs), no grade 4 or 5 AEs, and no AEs leading to study drug discontinuation. Two participants had grade 3 injection site reactions: one with cellulitis and one with erythema.
The secondary endpoint of viral load <50 copies/mL at week 26 was achieved by 9/10 participants in each arm. One person in the low dose group had confirmed viral load >50 copies/mL at week 16 (initially at 155 and confirmed at 524 copies/mL). Resistance tests failed to amplify at this level but did not find resistance. Viral load re-suppressed after switching to baseline ART. One person in the high-dose arm withdrew consent at week 12 with viral load <40 copies/mL.
Although CD4 counts remained stable over the study, these participants had already been on stable ART for more than two years so CD4 increases would not have been expected if they remained on oral ART.
Although median CD4 counts dropped by approximately –50 cells/mm3 from baseline at week 4 (n=20) and week 12 (n=18) and increased by about +50 cells/mm3 from baseline to week 26 (n=18), these changes are unlikely to be significant, especially as CD4 counts were already very high at baseline.
Therapeutic drug levels of all three compounds remained above IC90 (>2 ug/mL) for all participants at weeks 24 to 26. Lenacapavir levels reached IQ of 5 ng/mL by week 4 and were maintained throughout. This included for the participant with viral rebound.
Data on antiviral activity of these two bNAbs were also reported in a cure-related study presented at CROI 2023. Although this was a very different study design, participants in two groups receiving the bNAbs who were also screened for sensitivity at baseline, maintained undetectable viral load for a median of 119 days (IQR: 77 to 175) and 98 days (IQR:70 to 119) before viral rebound. Two participants have maintained viral load <50 copies/mL for over a year off-ART. 
These results are exciting for showing the potential for very long-acting ART.
Participants needed to be sensitive to both bNAbs at baseline with a high CD4 count and to have been suppressed to <50 copies/mL for at least two years.
These data show results after only a single treatment, but longer studies using multiple doses are currently planned or underway. All participants in the current study returned to oral ART, as roll-over to second doses were not allowed.
Unless stated otherwise, references are to the Programme and Abstracts of the 30th Conference on Retroviruses and Opportunistic Infections, 19 – 22 February 2023, Seattle and hybrid. Some 2023 abstracts are available via the online CROI abstract database, generally posters do far rather than for oral presentations.
- Eron J et al. Lenacapavir with bNAbs GS-5423 and GS-2872 dosed every 6 months in people with HIV. CROI 2023, Seattle. Oral abstract 193.
- Gilead announces licensing agreement for Rockefeller University bNAbs. HTB (January 2020).
- Selzer et al. Susceptibility screening to bNAbs GS-5423 and GS-2872 in ART-suppressed participants. CROI 2023, Seattle. Poster abstract 580.
- Gunst JD et al. The impact of 3BNC117, 10-1074, and lefitolimod on HIV-1 persistence: the TITAN trial. CROI 2023, Seattle. Oral abstract 136.
This report was first posted on 25 February and was updated to include new details about timing and duration of previous ART.