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Safety and efficacy of VRC07-523LS plus
long-acting cabotegravir in the phase II ACTG A5357 trial
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Long-Acting bNAb Plus CAB Keep HIV in Check in 92.5% for 48 Weeks
CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver
Mark Mascolini
Long-acting cabotegravir (CAB) plus the long-acting broadly neutralizing monoclonal antibody (bNAb) VRC07-523LS kept HIV in control for 48 weeks in a large majority of people who suppressed HIV with an all-pill regimen [1]. Five people (7.5%) met virologic failure criteria, and AIDS Clinical Trials Group (ACTG) investigators cautioned that use of this novel long-acting combination "will require a better understanding of the mechanisms underlying breakthroughs."
Long-term injectable antiretrovirals have become a valuable option for maintaining HIV control in people who prefer injections every few months over daily pill taking. Long-acting CAB (an integrase inhibitor) plus long-acting rilpivirine (a nonnucleoside) won the first license for every-other-month anti-HIV dosing. But so far long-acting small-molecule antiretrovirals like CAB and rilpivirine have not been combined with a long-acting bNAb to treat HIV infection.
Scientists designed the bNAb VRC07-523LS to have strong, broad, and prolonged activity against HIV (half-life 38 days after intravenous dosing) [2,3]. Babafemi Taiwo (Northwestern University, Chicago) and ACTG colleagues conducted a phase 2, single-arm, open-label study whose participants switched from an effective oral antiretroviral combination to long-acting injected VRC07-523LS plus CAB.
The trial had three steps: Step 1-daily oral CAB plus two nucleos(t)ide inhibitors (NRTIs) for 4 weeks. Step 2-40 mg/kg of intravenous VRC07-523LS every 8 weeks plus intramuscular CAB every 4 weeks for 48 weeks. Step 3-standard-of-care antiretroviral therapy for 48 weeks. Trial participants had to have HIV susceptible to VRC07-523LS, a CD4 count of 350 or higher, and a viral load below 50 copies for at least 2 years while taking a protease inhibitor, a nonnucleoside, or an integrase inhibitor plus 2 NRTIs. The trial excluded people who had switched antiretrovirals earlier because of virologic failure.
Among 75 people who began Step 1, 71 completed that step and began VRC07-523LS plus CAB in Step 2. Of the 11 people who did not complete Step 2, 8 jumped from that step to Step 3 early, and 3 stopped early and did not move to Step 3. Among the 68 people who entered Step 3 and returned to the standard-of-care regimen, 54 completed the study, 12 remained in the study at the time of Taiwo's presentation, and 2 dropped out of the study early.
The researchers defined baseline characteristics for 74 people, including 55 men and 19 women. Their median age stood at 54, 51% were non-Hispanic white, 34% non-Hispanic black, 11% Hispanic, and 4% some other race or ethnicity. Median weight measured 28 kg/m2 (in the overweight range), and 32% were obese. Seventy-one of 74 people (96%) had an initial viral load below 50 copies, and median CD4 count stood at 720. About 70% of people tested for VRC07-523LS susceptibility had VRC07-523LS-susceptible HIV.
Twelve of 71 participants (17%) had met the primary safety outcome measure-a grade 3 or 4 adverse event or an event of any grade that led to stopping treatment for a reason at least possibly related to VRC7-523LS or CAB. Only 1 of 71 participants (1.4%) had an adverse event leading them to stop treatment. Twelve people had an adverse event at least possibly related to VRC07-523LS, 2 had an event at least possibly related to CAB, and 2 had events at least possibly related to both drugs.
The ACTG team recorded 5 virologic failures (7.5%, 95% confidence interval 3.2% to 16.0%), defined as a confirmed viral load at or above 200 copies at or before week 44 of Step 2. Two of these 5 people regained viral control while continuing VRC07-523LS plus CAB, 2 had virologic failure within 14 days of getting a monkeypox vaccine, and 1 had low-level detectable HIV after switching back to the oral standard-of-care combination. All 5 people with virologic failure had CAB trough levels within the therapeutic range, and all 5 had VRC07-523LS levels more than 100-fold higher than the 80% inhibitory concentration when screened for the trial.
No trial participant had anti-VRC07-523LS antibodies, which the researchers tested for at weeks 28 and 48 of Step 2. The R263K integrase inhibitor-related mutation evolved in the HIV of 1 person with a relatively high initial VRC07-523LS 50% inhibitory concentration.
The ACTG investigator suggested that the long-acting bNAb VRC07-523LS plus CAB could have a place in maintaining HIV control, but probably only after research establishes a better understanding of what causes virologic breakthroughs with this agent.
References
1. Taiwo B, Zheng YE, Rodriguez K, et al. Safety and efficacy of VRC07-523LS plus long-acting cabotegravir in the phase II ACTG A5357 trial. CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver. Abstract 119.
2. Gaudinski M, Houser KV, Doria-Rose NA, et al. Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS. Lancet HIV. 2019;6:e667-e679. doi: 10.1016/S2352-3018(19)30181-X.
https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(19)30181-X/abstract
3. Asokan M, Dias J, Liu C, et al. Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody. Proc Natl Acad Sci USA. 2020;117:18754-18763. doi: 10.1073/pnas.2008236117. https://www.pnas.org/doi/10.1073/pnas.2008236117
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