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Safety of teropavimab and zinlirvimab with lenacapavir once every 6 months for HIV treatment: a phase 1b, randomised, proof-of-concept study & Commentary
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Download the PDF here
Download the PDF here
Summary
Background
Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen.
Methods
This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per μL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040.
Findings
Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per μL at study entry. No serious adverse events occurred.
Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1.
One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL.
Interpretation
Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1.
One virological breakthrough occurred in a participant who received the lower dose of zinlirvimab. In this individual, no resistance to any of the three agents was detected at baseline and concentrations of all study drugs were maintained at levels predicted to be therapeutic.10, 11, 16 A low level of ADAs to zinlirvimab developed before virological rebound but did not alter antibody concentration relative to other participants. Phenotypic susceptibility testing of bNAbs on HIV DNA, as was done in this study, might help identify people who will respond to treatment but is not widely available and resulted in more than 50% of participants screened being ineligible, either due to assay failure or susceptibility above our cutoff for one or both antibodies. Different groups are working on assay optimisation or alternative screening methods that can lower the rate of assay failure. In addition, there are limited data on the performance of the available methods to predict clinical outcomes and optimal interpretation criteria (eg, an IC90 threshold) have not been established. Whether susceptibility to both antibodies is required for success or whether a clinically validated cutoff can be established will require additional research. Importantly, individuals with a viral rebound on this novel regimen can resume oral ART without risk of cross-resistance to one or more established standard-of-care antiretroviral classes.3, 29
In addition to direct antiviral activity, bNAbs engage immune effector cells and can produce targeted killing of HIV-infected cells, which are mechanisms that have led to the investigation of bNAbs in HIV cure research.30, 31, 32 Whether the regimen of lenacapavir, teropavimab, and zinlirvimab results in measurable changes in the HIV-specific immune responses or effects on the HIV-1 viral reservoir is currently being explored.
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