CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

at Week 26; secondary endpoints included virologic outcomes (VS or ≥50 copies/mL) at Week 26 by FDA Snapshot analysis. Results: Eleven participants were randomized & treated (Group 1, n=5; Group 2, n=6). Age range was 28–63 years; 3/11 were female; 4/11 were Black; & median CD4 count was 916 cells/μL. There was 1 serious adverse event of soft tissue infection not related to study treatment. No adverse events led to study drug. Safety outcomes were similar between groups. One participant restarted baseline ART due to a protocol violation (chronic hepatitis B infection) & was excluded from the efficacy analysis. At Week 26, 8/10 participants maintained VS (Group 1, 2/4; Group 2, 6/6). Of the two participants in Group 1 who had virologic rebound, one had sensitivity to TAB & was diagnosed with acute COVID-19 at the time of rebound, & one had sensitivity to ZAB & rebounded at Week 26; both had HIV RNA <100 copies/mL. Conclusion: The long-acting combination of LEN+TAB+ZAB was well tolerated, with a favorable safety profile. All participants in the higher ZAB dose group maintained VS for 6 months, which suggests that more inclusive sensitivity criteria may be appropriate for treatment studies of LEN+TAB+ZAB when higher bNAb levels are maintained. Therapeutic Efficacy of a Triple Combination of HIV-1 Broadly Neutralizing Antibodies Boris D Juelg 1 , Victoria E. Walker-Sperling 2 , Kshitij Wagh 3 , Kathryn Stephenson 2 , Jinyan Liu 2 , Malika A. Boudries 2 , Roberto C. Arduino 4 , Lucio Gama 5 , Elena Giorgi 6 , Richard A. Koup 7 , Michael S. Seaman 2 , Charlotte-Paige M. Rolle 8 , Edwin DeJesus 8 , Bette Korber 3 , Dan H. Barouch 2 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Beth Israel Deaconess Medical Center, Boston, MA, USA, 3 Los Alamos National Laboratory, Los Alamos, NM, USA, 4 University of Texas at Houston, Houston, TX, USA, 5 National Institute of Allergy and Infectious Diseases, Washington, DC, USA, 6 Fred Hutchinson Cancer Center, Seattle, WA, USA, 7 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 8 Orlando Immunology Center, Orlando, FL, USA Background: Human immunodeficiency virus type 1 (HIV-1) specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown limited therapeutic efficacy when administered as monotherapy or as a cocktail of two antibodies. A combination of three bNAbs provides improved neutralization coverage of global viruses. Here we show that a triple bNAb cocktail targeting three distinct epitopes on HIV-1 Env results in long- term virologic control in persons living with HIV-1 (PLWH) following discontinuation of antiretroviral therapy (ART). Methods: We first evaluated the pharmacokinetics of the bNAbs PGT121, PGDM1400, and VRC07-523LS, which target the V3 glycan supersite, V2 apex, and CD4 binding site, respectively. We then assessed the therapeutic efficacy of up to six monthly infusions of this triple bNAb cocktail in 12 PLWH who discontinued ART after the first antibody infusion (NCT03721510). Participants were not screened for bNAb sensitivity at baseline. Results: 83% of participants (10 of 12) maintained virologic suppression for the duration of the antibody dosing period for at least 28 weeks. Moreover, 42% of participants (5 of 12) demonstrated virologic suppression for the duration of follow-up for at least 38-44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. Early viral rebound in 2 individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas late viral rebound in 5 participants in the context of declining bNAb levels was characterized by both sensitive and resistant rebound virus. Conclusion: Our data demonstrate the potential of a triple HIV-1 bNAb cocktail to provide long-term virologic control in the majority of PLWH in the absence of ART. Long-acting versions of these three bNAbs are currently being developed for HIV-1 prevention and therapy. The figure, table, or graphic for this abstract has been removed. Randomized Trial of Cabotegravir and Rilpivirine Long-Acting in Africa (CARES): Week 48 Results Cissy M. Kityo 1 , Ivan K. Mambule 1 , Simiso Sokhela 2 , Reena Shah 3 , Caroline Otike 1 , Joseph Musaazi 4 , Kimton Opiyo 1 , Fiona Cresswell 5 , Charity Wambui 6 , Gilbert Ategeka 1 , Josphat Kosgei 7 , Logashvari Naidoo 8 , Fafa A. Boateng 9 , Nicholas Paton 5 1 Joint Clinical Research Centre, Kampala, Uganda, 2 University of the Witwatersrand, Johannesburg, South Africa, 3 Aga Khan University, Nairobi, Kenya, 4 Infectious Diseases Institute, Kampala, Uganda, 5 London School of Hygiene & Tropical Medicine, London, United Kingdom, 6 Moi University, Eldoret, Kenya, 7 Walter Reed Project–Kericho, Kericho, Kenya, 8 South African Medical Research Council, Durban, South Africa, 9 Johnson & Johnson, Accra, Ghana Background: Long-acting injectable therapy (LA) is a recommended option for individualized treatment of human immunodeficiency virus type 1

and received intravenous VRC07- 523LS (40 mg/kg) Q8 weeks plus intramuscular LA CAB (600mg load followed by 400mg Q4 weeks). At the end of 48 weeks on Step 2 or premature treatment discontinuation, participants returned to a standard of care regimen for 48 weeks in Step 3. The primary outcomes were: 1) grade 3 adverse event (AE) or treatment discontinuation related to VRC07-523LS and LA CAB; and 2) virologic failure (VF) defined as confirmed viral load (VL) ≥200 c/mL at or prior to week 44 of Step 2. Efficacy analyses were as-treated; participants with VL<200 c/mL at the treatment discontinuation were censored. Results: Analysis included complete Step 1/2 follow-up for 74 participants: 26% cis-female, 51% White (non- Hispanic), median age 54. At baseline, 96% had VL <50 c/mL, median CD4 count 720 cells/mm 3 . Median IC 50 was 0.076 μg/mL, median MPI 99.9%. Seventy-one (96%) participants initiated Step 2 treatment; 61 (86%) completed Step 2 treatment and 10 (14%) prematurely discontinued the regimen (5 VFs, 1 death, and 4 participant/physician request). Twelve (16.9%) participants met the primary safety endpoint: 11 (15%) had grade ≥3 AEs (mostly chills, myalgia, fatigue) and one discontinued therapy due to a grade 1 infusion-related reaction. The only death was unrelated to study treatment. The five VFs (Table) include two of the three participants with VL 51-200 c/mL at week 4. The cumulative probability of VF at or prior to week 44 of Step 2 treatment was 7.3% (95% CI 3.2-16.0%). The integrase R263K mutation was seen in a participant at VF. Pharmacokinetics and anti-idiotype antibodies results are expected in late 2023 Conclusion: The parenteral maintenance ART regimen of VRC07-523LS plus LA CAB was safe. Most participants maintained viral suppression. Observed potential vulnerabilities should inform future bNAb based ART strategies.

Oral Abstracts

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Lenacapavir Plus bNAbs for People With HIV and Sensitivity to Either Teropavimab or Zinlirvimab Joseph J Eron 1 , Paul P. Cook 2 , Megha Mehrotra 3 , Hailin Huang 3 , Marina Caskey 4 , Gordon Crofoot 5 , Edwin DeJesus 6 , Linda Gorgos 7 , Laurie VanderVeen 3 , Olayemi O. Osiyemi 8 , Cynthia Brinson 9 , Sean E. Collins 3 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 East Carolina University, Greenville, NC, USA, 3 Gilead Sciences, Inc, Foster City, CA, USA, 4 The Rockefeller University, New York, NY, USA, 5 The Crofoot Research Center, Houston, TX, USA, 6 Orlando Immunology Center, Orlando, FL, USA, 7 AXCES Research Group, Santa Fe, New Mexico, 8 Triple O Research Institute, West Palm Beach, FL, USA, 9 Central Texas Clinical Research, Austin, TX, USA Background: Lenacapavir (LEN) is a first-in-class, long-acting HIV-1 capsid inhibitor approved for treatment of HIV-1 infection in adults with multidrug resistance. Teropavimab (TAB) & zinlirvimab (ZAB) are long-acting broadly neutralizing antibodies (bNAbs), targeting the CD4-binding site & V3 loop of gp120, respectively. In a phase 1b study (NCT04811040), LEN+TAB+ZAB maintained virologic suppression (VS) for 6 months in 18/20 participants with HIV with high-level sensitivity to both bNAbs. We evaluated safety & efficacy of LEN+TAB+ZAB for maintenance of VS in a cohort of participants who met viral sensitivity criteria to either TAB or ZAB. Methods: Virologically suppressed adults with HIV on antiretroviral therapy (ART; HIV-1 RNA <50 copies/mL for ≥18 months), with high-level sensitivity to TAB or ZAB but not both by HIV proviral DNA phenotype (PhenoSense monoclonal antibody assay IC 90 ≤2μg/mL), a CD4 nadir of ≥350 cells/μL, & CD4 ≥500 cells/μL at baseline were randomized 1:1 to one of two active treatment groups: LEN (927 mg subcutaneously after oral loading) + TAB (30 mg/kg intravenously [IV]) + ZAB (Group 1, 10 mg/kg IV; Group 2, 30 mg/kg IV). The primary endpoint was incidence of treatment-emergent serious adverse events

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CROI 2024