CROI 2025 Abstract eBook

Abstract eBook

Oral Abstracts

103

AZD5582 and Venetoclax Reduce SIV Reservoirs in ART-Suppressed Macaques Benedicth Ukhueduan 1 , Elizabeth Lampros 1 , Soham Sonawane 1 , Danielle Lin 1 , Kedan Endrias 1 , Zain Siddiqi 1 , Lakshita Lopez Lopez 2 , Amanda Schauer 3 , Lauren A. Tompkins 3 , Mackenzie Cottrell 3 , Jeffrey D. Lifson 4 , Brandon Keele 4 , Ann M. Chahroudi 1 1 Emory University, Atlanta, GA, USA, 2 Children's Healthcare of Atlanta, Atlanta, GA, USA, 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 Frederick National Laboratory for Cancer Research, Frederick, MD, USA Background: We explored the potential of combining the cIAP inhibitor AZD5582 with the BCL-2 inhibitor Venetoclax (VTX) to reverse latency and clear reactivated infected CD4+ T cells in a nonhuman primate model of HIV. Methods: Thirty SIVmac239M-infected rhesus macaques (RMs), 18 males and 12 female, began antiretroviral therapy (ART) at 4 weeks post-infection (wpi). At 68 wpi, they were divided equally into three groups: A) ART-only, B) ART + VTX, and C) ART + VTX + AZD5582. VTX was given either intramuscularly (15 mg/ kg) or orally (300 mg) in 3 cycles of 4 daily doses to Groups B and C. Group C also received weekly intravenous AZD5582 (0.1 mg/kg) for 10 weeks, followed by an analytical treatment interruption (ATI) 4 weeks after the final AZD5582 infusion. Additionally, plasma concentrations for AZD5582 and VTX were measured by HPLC MS/MS in a subset of RMs in groups B and C (N=5 RMs per group). Results: AZD5582 effectively reversed latency, with on-ART viremia exceeding 60 copies/ml in 6/10 RMs in the ART + VTX + AZD5582 group. The level of intact SIV proviruses in mononuclear cells isolated from peripheral blood and bone marrow was significantly lower after intervention with ART + VTX + AZD5582 (p<0.0001 for both sites), while levels remained stable in ART-only controls. Despite this impact on the intact reservoir, RMs from all groups experienced viral rebound after ATI within a similar timeframe. Area under the curve of on-ART viremia in the ART + VTX + AZD5582 group was not associated with post-intervention reservoir size, suggesting that the decline in intact proviral DNA was due more to VTX than to AZD5582. Indeed, AUC of VTX concentrations was positively correlated with the fold decline in intact reservoir size in PBMCs (Spearman r=0.9, p=0.08). A weak negative association between VTX AUC and post-ATI rebound viremia AUC (Spearman r= -0.60, p=0.350) was also observed. Conclusions: The combination of AZD5582 and VTX reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ATI. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound. HIV GAG x CD3 Soluble TCR Bispecific Reduces the Active HIV Reservoir in a Phase I/II Trial Lucy Dorrell 1 , Marta Boffito 2 , Santiago Moreno 3 , Julie Fox 4 , Borja Mora Peris 5 , Linos Vandekerckhove 6 , Alison Uriel 7 , Matthew Adam 8 , Frank Post 9 , Vicente Estrada 10 , Haseeb Rahman 1 , Adel Benlahrech 1 , Beatriz Mothe 11 , Sarah Fidler 12 , Sabine Allard 13 1 Immunocore Ltd, Oxfordshire, UK, 2 Chelsea and Westminster NHS Foundation Trust, London, UK, 3 Hospital Universitario Ramon y Cajal, Madrid, Spain, 4 King's College London, London, UK, 5 Imperial College Healthcare NHS Trust, London, UK, 6 HIV Cure Research Center, Ghent University, Ghent, Belgium, 7 North Manchester General Hospital, Manchester, UK, 8 NHS Lothian, Edinburgh, UK, 9 King's College Hospital NHS Foundation Trust, London, UK, 10 Hospital Universitario Clínico San Carlos, Madrid, Spain, 11 Fundació Lluita contra la SIDA, Badalona, Spain, 12 Imperial College London, London, UK, 13 Vrije Universiteit Brussel, Brussels, Belgium Background: ImmTAV® are soluble bispecific T cell engagers that kill virus infected cells presenting extremely low target peptide-HLA levels. IMC-M113V (GAGxCD3) is the first HIV ImmTAV in the clinic; a single dose study demonstrated safety and biological activity in antiretroviral therapy (ART)-suppressed PLWH. We investigated the effect of multiple ascending doses of IMC-M113V on HIV reservoir size and post-treatment viral control off ART. Methods: HLA-A*02:01 positive PLWH on ART ≤7 years were enrolled in this open-label Phase 1/2 trial (EudraCT: 2021-002008-11). After step dosing during weeks (W) 1-2, escalating target IMC-M113V doses were administered IV Q1W to sequential cohorts during W3-12. Participants paused ART (analytical therapy interruption, ATI) during W13-W24. ART was resumed at W24 or earlier if plasma viral load (pVL) copies/ml exceeded 103 for >4 weeks or 105 x2 weeks, or CD4 count fell <350 cells/μl. Primary objectives were safety and tolerability; secondary and exploratory analyses include quantification of serum cytokines and cell-associated HIV RNA (CA-RNA), duration of pVL <103 during ATI and time to The figure, table, or graphic for this abstract has been removed.

ART resumption. Change in CA-RNA from baseline to W13 was analysed by mixed effects models. Results: Sixteen males were enrolled to 3 target dose cohorts of IMC-M113V: 60 μg, n=5; 120 μg, n=5; 300 μg, n=6. Doses were well tolerated and there were no serious adverse events or treatment-related discontinuations. Transient (<24 h duration) fever ≥38 °C was observed in 5/6 PLWH only after the first 300 μg dose, in tandem with a rise in serum IL-6, IFN-γ and CXCL10 (peak 16-, 4- and 264-fold respectively). At W13, IMC-M113V was not detectable in serum. During ATI (n = 13), post-rebound viremia control was observed in 3/13 PLWH: 0 at 60 µg; 1 at 120 μg (pVL <10 3 x7/12 weeks); 2 at 300 μg (1 with pVL <10 3 x10 weeks, enabling ATI extension to W28; 1 with rebound at W17, followed by a 3-log decline in pVL at W18-21). Of the remaining 3 at 300 mcg dose, 2 are due to start ATI and 1 withdrew prior to ATI. HIV CA-RNA (mean ±SD copies/10 6 TBP) was significantly reduced from baseline (2374 ±2733) to W13 (1175 ±1809), p = 0.019. Conclusions: IMC-M113V was well tolerated with initial evidence of post rebound viral control off-ART. We observed a reduction in the active reservoir (CA-RNA) during treatment, the most substantial reported to date. This study provides the first evidence of antiviral efficacy for this novel mechanism of action. Doses >300 μg and longer ATI duration will be evaluated. The figure, table, or graphic for this abstract has been removed. Evaluation of 2 bNAbs Plus Vesatolimod in Early-Treated South African Women With HIV-1 During ATI Krista Dong 1 , Villeshni Asari 2 , Vaneshree Govender 3 , Vanessa Pillay 4 , Siphesihle Ngcobo 5 , Nasreen Ismail 6 , Lucio Gama 7 , Elena Vendrame 8 , Megha Mehrotra 8 , Xiang Liu 8 , Lisa Selzer 8 , Mary Wire 8 , Devi Sengupta 8 , Thumbi Ndung'u 9 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 South African Medical Research Council, Cape Town, South Africa, 3 The Aurum Institute, Johannesburg, South Africa, 4 Females Rising in Education Support and Health (FRESH), Durban, South Africa, 5 Females Rising in Education Support and Health (FRESH), Boston, MA, USA, 6 University of KwaZulu-Natal, Durban, South Africa, 8 Gilead Sciences, Inc, Foster City, CA, USA, 9 Africa Health Research Institute, Mtubatuba, South Africa Background: Antiretroviral therapy (ART) can reduce morbidity and mortality but does not eradicate HIV. Developing new therapies that induce HIV remission is crucial to end the epidemic. African women bear a disproportionate burden of the global epidemic yet are rarely included in clinical trials. We conducted a phase 2a HIV cure study to evaluate the safety of a regimen of 2 broadly neutralizing antibodies (bNAbs), VRC07-523LS and CAP256V2LS, and a TLR7 agonist, vesatolimod (VES), in acutely treated women with HIV-1 in South Africa (NCT05281510). Methods: Twenty women from the Females Rising through Education, Support, and Health (FRESH) acute HIV infection cohort, who were suppressed on ART for ≥12 months and sensitive to at least 1 bNAb, were enrolled. Participants received up to 10 oral doses of VES (6 mg, dose escalation to 8 mg) every 2 weeks starting on day 0 and IV infusions of VRC07-523LS (20 mg/kg) and CAP256V2LS (20 mg/kg) on day 7. Participants began an analytical treatment interruption (ATI) on day 35 and remained off ART until day 336 or until they met ART restart criteria (HIV-1 RNA ≥1000 copies/mL for 8 consecutive weeks and without a drop of 0.3log 10 ; or confirmed HIV-1 RNA >100,000 copies/mL; or confirmed CD4 count <350 cells/µL). The primary endpoint was safety. Secondary endpoints included time to viral rebound (HIV-1 RNA >200 copies/mL), time to ART restart, and pharmacokinetics. Results: As of September 18, 2024, all 20 participants had received study treatment and started ATI. There were no treatment-related serious adverse events. One participant experienced grade 1 cytokine release syndrome that led to discontinuation of VES. Eighteen experienced infusion-related reactions (16 grade 1; 2 grade 2); all resolved within 2 days. Five participants completed the 43-week ATI without meeting ART restart criteria, 2 of whom were completely suppressed (HIV-1 RNA <50 copies/mL); 14 met ART restart criteria; and 1 remained in ATI. Eight participants had evidence of partial virologic control with oscillating rebound, characterized by fluctuating levels of viremia with periods of undetectable viral load. Conclusions: This first-in-Africa HIV cure trial demonstrates that complex cure studies can be successfully conducted in resource-limited settings with great unmet need. VES, VRC07-523LS, and CAP256V2LS were safe and well tolerated in acutely treated South African women. Potential mechanisms for the variable patterns of virologic control observed in this novel study are under investigation.

Oral Abstracts

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CROI 2025