CROI 2025 Abstract eBook

Abstract eBook

Oral Abstracts

107

RIO: A Randomised Placebo-Controlled Study of 2 LS-bNAbs in People Treated in Early HIV Sarah Fidler 1 , Ming J. Lee 1 , Simon Collins 2 , Louise-Rae Cherrill 1 ,Emanuela Falaschetti 1 , Penny Zacharopoulou 3 , Mohammed Altaf 3 , Timothy Tipoe 3 , Graham Taylor 1 , Marcilio Jorge Fumagalli 4 , Kelly Seaton 5 , Marina Caskey 4 , Michel Nussenzweig 4 , John Frater 3 , for the RIO Trial Investigators 1 Imperial College London, London, UK, 2 HIV i-Base, London, UK, 3 University of Oxford, Oxford, UK, 4 The Rockefeller University, New York, NY, USA, 5 Duke Human Vaccine Institute, Durham, NC, USA Background: The extent to which LS-broadly neutralizing antibodies (LS-bNAbs) maintain viral control off ART remains unknown. RIO tested the frequency and durability of viral control of LS-bNAbs compared with placebo in people with treated early HIV. Methods: RIO is a double-blind randomised 1:1 placebo-controlled trial designed to investigate viral control in the absence of ART. Virally-suppressed participants (aged 18-60) who started ART during early HIV received up to two intravenous infusions >20 weeks apart of bNAbs (3BNC117-LS & 10-1074-LS) (Arm A) or placebo (Arm B), and undertook analytical treatment interruption (ATI). Participants were screened for resistance to 10-1074 based on HIV DNA env sequences. Viral rebound confirmed by an independent committee was based on the first date of 6 consecutive plasma HIV RNA >1,000 or two >100,000 copies/ ml. Primary outcome was time to viral rebound at Week 20 after stopping ART, assessed using a Cox proportional hazards model. Secondary outcomes included adverse events, longer term viral suppression, bNAb pharmacokinetics, anti-drug antibody levels, predicted bNAb resistance and T-cell immunity. Results: Of 145 participants screened, 68 were enrolled. 63/68 had no predicted significant baseline 10-1074 resistance; 5 failed to amplify. By Week 20, 25/68 had not rebounded: 22/34 in Arm A and 3/34 in Arm B. Arm A participants were 91% less likely to rebound over 20 weeks compared to Arm B (HR: 0.09; 95% CI: 0.04, 0.21, p<0.0001). In Arm A 13/34 and 7/34 had not rebounded out to 48 weeks and 72 weeks respectively after ATI, compared to 2/34 and 2/34 in Arm B. Nine SAEs were reported including one death, all unrelated to study drugs, ATI or protocol. There was no evidence of anti-drug antibodies or ART in plasma during the ATIs. Modelled 10-1074-LS and 3BNC117-LS levels remained above 10 µg/ ml for 48 (±13 2SD) and 47 (±12 2SD) weeks after last bNAb dose, respectively; 6 participants in Arm A remained virally suppressed off ART beyond week 48 after last bNAb dose. HIV Gag-specific T-cell responses were enhanced following bNAb dosing in those remaining suppressed. Conclusions: Two LS-bNAbs were safe and significantly improved viral control off ART compared to placebo. Sustained viral suppression after bNAb dosing associated with enhanced T cell immunity is consistent with an immunologically driven post-bNAb effect.

Oral Abstracts

106

A Single Infusion of CCR5-/- CD4 Tscm Cells Promotes Control of SIV Upon ATI Ashish A. Sharma 1 , Mojahidul Islam 1 , Justin Harper 2 , Joumana Zeidan 1 , Muhammad Bilal Latif 1 , Kevin Nguyen 2 , James Auger 2 , Hannah Flores 2 , Amelia C. Wilkes 1 , Rachelle L. Stammen 1 , Mirko Paiardini 1 , Steven G. Deeks 3 , Rafick P. Sekaly 1 , for the RID-HIV Collaboratory 1 Emory University, Atlanta, GA, USA, 2 Emory National Primate Research Center, Atlanta, GA, USA, 3 University of California San Francisco, San Francisco, CA, USA Background: ART suppresses HIV replication but fails to eliminate the virus, necessitating innovative strategies for curing HIV. CCR5-/- CD4+ T cells from CCR5Δ32 HSCT have eliminated HIV but are invasive and induce toxicity. Autologous CCR5 knockout (CCR5-/-) CD4 T cell therapy trials offer a safer alternative. We have shown that the persistence of CCR5-/- stem-like CD4 T (Tscm) cells post-infusion of CCR5 edited memory T cells was associated with reduced latent HIV and control of viremia upon Analytical Treatment Interruption (ATI). Here, we used a SIV-infection model to assess whether CCR5-/- CD4 Tscm can control viremia upon ATI. Methods: 20 non-human primates (NHPs) were infected with the stringent SIV SIV-mac239 for 4 weeks before being put on ART. 40 weeks post-ART, a single infusion of autologous CCR5-/- Tscm product (5M cells/kg) was infused after mild chemotherapy, along with B cell depletion using an anti-CD20 antibody (n = 10). Bi-allelic knockout of CCR5 in ~80% of the cells within the product was attained using CRISPR-Cas9 editing and Tscm phenotype was obtained using a cytokine mix. ATI was started 16 weeks after infusion and rebound was tracked for 12 weeks. Results: Nine NHPs infused showed significant control of viremia at 4 weeks post-ATI and maintained control of viremia (<5000 copies/mL) at 12 weeks; anti-CD20 did not impact this virological outcome. The enrichment of CD28+CD95+TCF1+CD27+CCR7+ Tscm cells that were Ki67- in the infused product was associated with the control of viremia at the 4th week post-ATI (p-val=0.06). While high viremia at 4 weeks of ATI was correlated with plasma levels of IL-15 and IL-17 (p-val<0.05) before product infusion; this cytokine milieu likely promotes persistence of effector CD4 T cells that are permissive to infection. Importantly, an enrichment of CD4 Tscm phenotype was detected 6-days post-product infusion in the controllers, where sustained viral control was observed 12 weeks post-ATI. Conclusions: We show that a single infusion of autologous CCR5 edited CD4 Tscm cells leads to sustained control of viremia for up to 12 weeks post-ATI. The efficacy of these cells is dampened if an effector cytokine milieu in the host, that promotes survival of virally permissive effector CD4 T cells, precedes the infusion of the product. These data show that the success of cell-based therapies depends on the stemness of infused product and an antiviral host environment that promotes innate and adaptive immune responses to control SIV dissemination.

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CROI 2025