A FIRST-in-human study evaluating a novel long-acting injectable antiretroviral therapy (LA-ART) has provided promising early results on its safety and pharmacokinetics, offering insights into the potential for sustained HIV treatment. Developed as part of the Targeted Long-Acting Combination Antiretroviral Therapy (TLC-ART) Program, this investigational drug formulation contains lopinavir, ritonavir, and tenofovir encapsulated within lipid nanoparticles for extended-release administration.
The open-label trial enrolled 12 healthy participants (mean age: 37 years), who received a single subcutaneous injection in one of three dosing cohorts: LOW (1.5 mL), MID (2 × 1.5 mL), and HIGH (2 × 2 mL). Blood samples were collected over 63 days to assess pharmacokinetics and monitor adverse events. A dose-adjustment protocol was implemented based on participant responses, with the HIGH Dose cohort experiencing a 25% dose reduction following a case of anaphylaxis. Safety monitoring included evaluation of systemic and local reactions, with a particular focus on hypersensitivity markers.
The formulation was generally well tolerated, with injection site reactions occurring in 10 participants, most at mild (Grade 1) or moderate (Grade 2) severity. One case of anaphylaxis occurred at the highest dose, requiring intervention with epinephrine, leading to dose reduction for subsequent participants. Other reported adverse events included lip swelling, erythematous rash, and pruritus, but no significant gastrointestinal symptoms or Type I hypersensitivity reactions were observed.
Pharmacokinetic analysis revealed drug-specific half-lives: lopinavir (33 days), ritonavir (1 day), and tenofovir (4 days), with detectable drug levels persisting for up to 63 days for lopinavir, 20 days for tenofovir, and 4 days for ritonavir. Notably, ritonavir did not exhibit a boosting effect, suggesting a novel long-acting protease inhibitor formulation that functions independently of a pharmacokinetic enhancer.
This proof-of-concept study highlights the feasibility of long-acting protease inhibitors for HIV treatment, though refinement is needed before clinical application. While TLC-ART 101 will not progress further, the findings will inform the development of a new investigational therapy, TLD, which is set to enter early-phase trials with support from global health organisations.
Ada Enesco, EMJ
Reference
Bender Ignacio RA et al. First-in-human study of a long-acting injectable 3 antiretroviral drug combination nanoparticle. Poster 639. CROI 2025. 9-12 March, 2025.
