Rachel A Bender Ignacio, Christine Jonsson, Simone Perazzolo, Zachary Stephen, Brett Hanscom, Eli Burnham, Phoebe Bryson-Cahn, Claborne Youngblood, Luqi Duan, Allysson Angeldekao, Gabrielle Wood, Emilda Padullo, Matthew Hartman, Kristina M Adams Waldorf, Edward P Acosta, Lane Bushman, Peter L Anderson, Pablo F Belaunzaran-Zamudio, Keith W Crawford, Ann Collier, Rodney J Y Ho, A Novel Injectable Drug Combination Nanoparticle Containing 3 Antiretrovirals Designed for Human Immunodeficiency Virus Treatment: A First-in-Human Trial, The Journal of Infectious Diseases, 2026;, jiag504, https://doi.org/10.1093/infdis/jiag504
Background
Long-acting antiretroviral therapy may improve adherence and decrease stigma, yet affordable combination formulations for global usage are lacking. The TLC-ART program engineered an injectable 3-drug combination in a novel nanoparticle (DcNP) product “TLC-ART 101,” composed of lopinavir (LPV), ritonavir (RTV), and tenofovir (TVF) and 2 lipid excipients. We report safety and pharmacokinetics from this first-in-human study.
Methods
Three dose cohorts of people without human immunodeficiency virus (HIV) received a single subcutaneous dose of 1.5, 3.0, or 4.0 mL in an adaptive trial of up to 64 days. LPV, RTV, and TFV were measured over time in plasma, peripheral blood mononuclear cells (PBMCs), and lymph nodes.
Results
All 12 participants completed the study. One participant experienced anaphylaxis, and 4 had nonserious hypersensitivity events (rash, lip swelling, generalized pruritus). All participants had grade 1–2 injection-site reactions. At the highest dose, median LPV half-life (T1/2) was 17 days, and LPV was detectable through 2 months in most participants. RTV T1/2 was 12 hours. Plasma TFV T1/2 was 3.5 days; TFV diphosphate was detected intracellularly through 14 days. Total exposure (area under the curve) was higher in PBMCs versus plasma for all 3 drugs.
Conclusions
The first human application of this novel HIV DcNP resulted in detection of LPV through 2 months and TFV up to 4 days in plasma, and no meaningful prolongation of RTV. Systemic hypersensitivity was common, and although IgE elevation was not observed, additional mechanistic understanding is required prior to further development of this DcNP pipeline.