CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

T cell receptor (TCR) and transcriptome profiling of paired CSF and blood from PWH to gain insights into the dynamics of rare HIV-1 RNA-producing T cells in both compartments, and under the pressure of ART. Methods: We enrolled eight PWH; seven were on suppressive ART and one had chronic HIV profiled before and 3, 7, and 9 months after ART. We also enrolled six HIV-uninfected controls, demographically matched to PWH. We profiled single cell TCR and RNA from paired CSF and blood using 5' V(D)J 10x Genomics scRNA- seq and scTCR-seq. To identify whether there were detectable transcriptionally active HIV-1 RNA producing cells in CSF and blood, we aligned the single cell transcriptome sequencing reads against consensus and autologous HIV-1 genomes. Results: In total, we examined the single-cell transcriptomes of 129,544 CSF cells and 262,818 PBMCs from PWH and controls. We detected transcriptionally active HIV-1 RNA producing cells in 8/11 (72.7 %) CSF samples and 6/11 (54.5 %) blood samples, with a higher frequency of infected single CD4+ T cells in CSF than in blood. Among infected CD4+ T cells, a majority (83.6 %) were identified as CD4+ central memory T cells. Differential expression analyses revealed infected CSF T cells displayed a unique transcriptional profile compared to uninfected CSF T cells. We utilized scTCR data to identify 36 T cell clones containing infected cells. Most (78%) of these T cell clones were tissue specific (found in blood or CSF but not both), but some (22%) clones containing infected cells were found in both CSF and blood. Most infected cells belonged to singletons (unique TCR clones), but 28% belonged to TCR clones with evidence of clonal expansion. Longitudinally following one PWH before and at three time points after initiating ART, we found infected T cell clones that persisted after ART initiation, in both CSF and blood, including a T cell clone that expanded in the CSF several months after ART initiation. Conclusion: By tracking T cell clones across times and tissue, we find that T cell clones persist in the CNS over time. Infected, identical, and expanded T cell clones are found across tissue compartments. Our findings suggest that maintenance and expansion of infected T cell clones contributes to the CNS reservoir in PWH on ART.

assessed. Data were analyzed and presented per dosing panel; data for the 1-mg dose group were pooled from both studies. Incidence of adverse events were descriptively summarized. Results: A total of 31 participants have been enrolled and completed dosing. Following single doses of 0.5 to 10 mg, the mean decrease in HIV-1 RNA at Day 7 following dose administration was ≥1.0 log 10 copies/mL (Table). The inhibitory quotient (defined as the ratio of geometric mean of MK-8527-TP C168 and IC 50 ) exceeded 3 at all doses assessed. MK-8527 at all dose levels was generally well tolerated, with a limited number of mild to moderate adverse events determined by investigators to be unrelated to the study treatment; there were no serious adverse events, events of clinical interest, or deaths. Conclusion: In treatment-naive persons with HIV-1, single doses of MK-8527 as low as 0.5 mg achieved ≥1 log 10 decreases in HIV-1 RNA at Day 7 following dose administration.

Oral Abstracts

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Antiviral Activity, Safety, and Pharmacokinetics of GS-1720: A Novel Weekly Oral InSTI Carl J Fichtenbaum 1 , Mezgebe Berhe 2 , Jose Bordon 3 , Jacob P. Lalezari 4 , Godson Oguchi 5 , Gary Sinclair 6 , Furong Wang 7 , Brie Falkard 7 , Haeyoung Zhang 7 , Eva Mortensen 7 , Jared Baeten 7 , Moti Ramgopal 8 1 University of Cincinnati, Cincinnati, OH, USA, 2 North Texas Infectious Diseases Consultants, Dallas, TX, USA, 3 Washington Health Institute, Washington, DC, USA, 4 Quest Clinical Research, San Francisco, CA, USA, 5 Midland Florida Infectious Disease Specialists, Orange City, FL, USA, 6 Prism Health North Texas, Dallas, TX, USA, 7 Gilead Sciences, Inc, Foster City, CA, USA, 8 Midway Immunology and Research Center, Fort Pierce, FL, USA Background: Significant medical need exists for antiretroviral agents that can be administered less frequently. GS-1720 is an orally bioavailable integrase strand transfer inhibitor (INSTI) with potent antiviral activity and physiochemical properties well-suited for a long-acting formulation. We are investigating the antiviral activity, safety, and pharmacokinetics (PK) of GS-1720. Methods: An open-label, multi-cohort Phase 1b study is being conducted in participants with HIV who are treatment-naïve or viremic and off antiretroviral therapy for at least 12 weeks. Based on safety and PK data from a Phase 1a study in healthy volunteers, participants are being administered GS-1720 on Day 1 and 2 and followed for a total of 10 days. The primary endpoint is plasma HIV-1 RNA (log 10 copies/mL) change from baseline to Day 11. Secondary endpoints include plasma HIV-1 RNA change at Day 8 in addition to PK parameters and safety assessments. Genotypic and phenotypic sensitivity testing to drugs from the INSTI class is also being conducted from samples collected during screening and Day 11 visits. Results: Preliminary PK from the Phase 1a study showed a median half-life of 9.4 days with a single GS-1720 dose of 450 mg. In the first Phase 1b cohort (n=7; 6 males, 1 female and mean age 35) dosed daily on Day 1 and Day 2 with 450 mg, GS-1720 demonstrated an HIV-1 RNA mean log 10 copies/mL reduction at Day 11 of 2.44 (95% confidence interval [CI] 2.04, 2.83) and at Day 8 of 2.04 (95% CI 1.72, 2.36). No participants experienced any serious adverse events (AEs), Grade 3 or higher treatment-emergent AEs, or AEs related to study drug. No treatment-emergent INSTI resistance was observed. Conclusion: GS-1720 demonstrated potent antiviral activity and PK supportive of once weekly oral dosing while being well-tolerated. The observed >2 log 10 copies/mL decline in HIV-1 RNA and half-life >1 week in this cohort demonstrates the potential of GS-1720 as part of an oral weekly INSTI-based regimen.

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Single Dose Administration of MK-8527, a Novel nRTTI, in Adults With HIV-1 Russ P Carstens 1 , Yash Kapoor 1 , Ryan Vargo 1 , Arinjita Bhattacharyya 1 , Graigory Garrett 1 , Jean- Francois Denef 2 , Kemira Naidoo 1 , Liliana Preotescu 3 , Richard Kaplan 4 , Mohammed Rassool 5 , Johannes Lombaard 6 , Randolph P. Matthews 1 , S. Aubrey 0 . Stoch 1 , Marian Iwamoto 1 , Gillian Gillespie 1 1 Merck & Co, Inc, Rahway, NJ, USA, 2 MSD Belgium, Brussels, Belgium, 3 National Institute for Infectious Diseases, Bucharest, Romania, 4 Desmond Tutu Health Foundation, Cape Town, South Africa, 5 University of the Witwatersrand, Johannesburg, South Africa, 6 Josha Research, Bloemfontein, South Africa Background: MK-8527 is a novel oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) under clinical development as an antiretroviral for HIV-1 infection. Based on previous preclinical and phase 1 clinical studies, the pharmacokinetic properties of MK-8527 support extended once-weekly or longer dosing. Two phase 1 single dose monotherapy studies were conducted to evaluate the antiretroviral activity of MK-8527 in treatment-naive participants with HIV-1. Methods: Eligible participants were treatment-naive adults 18–60 years of age with HIV-1. In two phase 1 studies (NCT03615183 and NCT05494736), participants received a single oral dose of MK-8527 (0.5, 1, 3, or 10 mg). Reduction in viral load (measured as log 10 plasma HIV-1 RNA copies/mL), safety, tolerability, and intracellular pharmacokinetics of MK-8527-triphosphate (TP, the active form of MK-8527) in peripheral blood mononuclear cells were

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CROI 2024