CROI 2025 Abstract eBook

Abstract eBook

Oral Abstracts

Conclusions: The multi-dose strategy of 5 mg DTG q48 from Day 1 to 14 of life, followed by 5 mg DTG q24 through day 28, was safe and achieved target concentrations for both DTG-DT and DTG-OF. This is the first evidence in neonates supporting the extension of DTG dosing recommendations from birth through week 4 of life. The figure, table, or graphic for this abstract has been removed. Genotypic Resistance in the African Paediatric CHAPAS-4 Trial of Second-Line Antiretroviral Therapy Alasdair Bamford 1 , Ellen White 2 , Cissy Kityo 3 , Mutsa Bwakura-Dagarembizi 4 , Chishala Chabala 5 , Abbas Lugemwa 6 , Wedu Ndebele 7 , Bwendo Nduna 8 , Mary Nyathi 9 , Veronica Mulenga 5 , Mwate Mwamabazi 8 , Anna Turkova 2 , Victor Musiime 3 , Alexander J. Szubert 2 , Diana M. Gibb 2 , for the CHAPAS-4 Trial Team 1 Great Ormond Street NHS Foundation Trust, London, UK, 2 MRC Clinical Trials Unit at UCL, London, UK, 3 Joint Clinical Research Centre, Kampala, Uganda, 4 University of Zimbabwe Clinical Trials Research Centre, Harare, Zimbabwe, 5 University of Zambia, Lusaka, Zambia, 6 Joint Clinical Research Centre, Mbarara, Uganda, 7 National University of Science and Technology (NUST), Bulawayo, Zimbabwe, 8 Arthur Davison Children's Hospital, Ndola, Zambia, 9 Mpilo Central Hospital, Bulawayo, Zimbabwe Background: In the CHAPAS-4 trial of second-line antiretroviral therapy following NNRTI-based first-line, 96-week efficacy was superior for tenofovir alafenamide (TAF) vs standard-of-care (SOC: abacavir (ABC)/zidovudine (ZDV)), and for dolutegravir (DTG) vs ritonavir-boosted lopinavir (LPV/r)/atazanavir (ATV/r). We present data on emergent resistance and associations between baseline resistance and virological failure at week 96 (W96). Methods: Randomisation was simultaneously to TAF vs ABC/ZDV, and DTG vs darunavir (DRV/r) vs LPV/r vs ATV/r. Baseline samples and those with viral load (VL)≥400c/ml at W96 were sequenced for resistance, defined using Stanford Algorithm (v9.6) with scores categorised into susceptible/low-/intermediate-/ high-level resistance. Results: Of 919 children, age 10 (range:3-15) years, 5.6 (IQR:3.3-7.8) years on first-line, 713 (78%) had baseline sequencing: 665 (93%) had M184V/I; intermediate/high-level resistance to allocated NRTI was present in 30% ABC, 10% ZDV, and 15% TAF. At W96, 14% (124/908) had VL≥400c/ml: 17% SOC (12% ABC; 21% ZDV) vs 11% TAF and 19% LPV/r, 16% ATV/r, 12% DRV/r, and 8% DTG (Table). At W96, 0/17 ABC, 14% (5/36) ZDV, 9% (3/33) TAF had intermediate/high-level resistance to NRTI initiated; 59% ABC, 78% ZDV, 36% TAF, to FTC/3TC. Intermediate/high level resistance to anchor was: 0/29 LPV/r, 4% (1/26) ATV/r (1 TAF/FTC), 0/18 DRV/r and 22% (2/9) DTG (2 ZDV/3TC). 54% (67/124) children with VL≥400c/ mL at W96 had reverse transcriptase sequencing at baseline and W96; resistance categorisation to allocated NRTI remained the same in all, although score worsened in 16. Three children on ZDV/3TC (2 DTG,1 LPV/r) developed new high level emtricitabine/lamivudine (FTC/3TC) resistance (M184V). Odds ratios (95% confidence interval) of VL≥400c/ml at W96 in those with intermediate/high vs low/susceptible baseline resistance to allocated NRTI were 0.23 (0.05-1.03) on ABC, 1.61 (0.53-4.92) on ZDV, and 1.01 (0.37-2.76) on TAF. Conclusions: TAF resistance at baseline was less common than ABC resistance, supporting TAF in second-line. No new intermediate/high-level resistance to allocated NRTI occurred. W96 intermediate/high-level anchor drug resistance was uncommon, and as in second-line adult and paediatric trials, resistance to DTG only occurred in children taking ZDV. These results will inform second-line treatment guidelines for children.

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Abemaciclib, a CDK4/6 Inhibitor, in HIV-Associated and HIV-Negative Kaposi Sarcoma Jose R. Mercado-Matos 1 , Kathryn Lurain 2 , Anaida Widell 1 , Irene Ekwede 1 , Ijeoma Agwu 1 , Margaret Namubiru 1 , Thomas Odeny 1 , Crystal Lu 1 , Seth Steinberg 1 , Denise Whitby 3 , Robert Yarchoan 2 , Ramya Ramaswami 2 1 National Cancer Institute, Bethesda, MD, USA, 2 National Institutes of Health, Bethesda, MD, USA, 3 AIDS and Cancer Virus Program, Frederick, MD, USA Background: Kaposi sarcoma (KS), caused by KS herpesvirus (KSHV), is a multicentric angioproliferative tumor seen in people with and without HIV. Abemaciclib (Abema) is an oral cyclin-dependent kinase (CDK) inhibitor that targets CDK4 (cyclin D1) and CDK6 (cyclin D3) that is FDA-approved for breast cancer. In vitro studies of KSHV-infected cells have shown that CDK4/6 inhibitors enhance T-cell activation and host immune cell surface expression, hindering immune evasion. Here, we investigate the safety and activity of Abema in participants (pts) with KS. Methods: This is a Phase 1/2 study of Abema in pts with KS. Phase 1 evaluated safety and tolerability of Abema using a 3+3 dose de-escalation design to identify a maximum tolerated dose (MTD). Pts were treated at dose level 1 of 200mg twice daily in 28-day cycles. Phase 2 assessed overall response rate of Abema of all pts and stratified by previously treated (Arm 1) or untreated KS (Arm 2). Eligibility criteria included adherence to antiretroviral therapy in people with HIV (PWH) for > 8 weeks prior to enrollment and no concomitant strong CYP3A4 inhibitors. Dose de-escalation was permitted for pts who experienced toxicities. KS response was evaluated using the modified AIDS Clinical Trials Group criteria. Results: Twenty-five cisgender men (18 PWH), median age of 47 years are enrolled in this ongoing study. Twenty pts had stage T1 KS. In Phase 1, 6 pts were enrolled at 200mg BID with no dose-limiting toxicities. In Phase 2, 12 pts (10 PWH) were enrolled to Arm 1, and 7 pts (4 PWH) enrolled to Arm 2. The most common grade 1/2 adverse events were anemia and diarrhea. Twelve pts had dose reductions for grade 3/4 neutropenia. Among 23 evaluable pts receiving >2 cycles, 18 pts had a partial response (PR) (78% [95% confidence interval: 56 93%]), 4 pts had stable disease and 1 pt had progressive disease. All 7 pts in Arm 2 with previously untreated KS had a PR. The median HIV viral load among PWH was <20 copies/ml. Among PWH, the median CD4 T-cell count was 279 cells/µL (interquartile range: 176-435 cells/µl) without significant changes prior to cycle 3 (P=0.23) or at the end-of-treatment (P=0.39, Figure 1). Conclusions: Abema is a novel therapeutic option in KS, with notable activity among pts with previously untreated KS. Adverse events were managed with dose reduction and supportive measures. Unlike chemotherapies for KS, there was no impact on CD4 T-cell counts among PWH.

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CROI 2025