Abstract

Human immunodeficiency virus pre-exposure prophylaxis had traditionally relied on daily oral tenofovir-based 
regimens, which demonstrated high efficacy when adherence is maintained but face substantial implementation 
challenges related to daily pill burden, stigma, and variable adherence patterns across diverse populations. Long
acting injectable cabotegravir represents a paradigm shift in biomedical prevention, offering sustained drug exposure 
through bimonthly intramuscular administration of a crystalline nanoparticle formulation that maintains 
therapeutic concentrations for extended periods. This review critically evaluated the efficacy, safety, implementation 
considerations, and global access challenges of long-acting cabotegravir as pre-exposure prophylaxis for human 
immunodeficiency virus prevention, examining pharmacological properties, clinical trial outcomes, real-world 
deployment experiences, and equity implications. A comprehensive synthesis of phase 3 clinical trials, 
pharmacokinetic studies, implementation science research, health economic analyses, and global health policy 
documents addressing cabotegravir pre-exposure prophylaxis through early 2025 was utilized in writing this article. 
Randomized controlled trials demonstrated superior efficacy of long-acting cabotegravir compared with daily oral 
tenofovir disoproxil fumarate/emtricitabine, with hazard ratios between 0.21 and 0.34 across diverse populations 
including cisgender women, men who have sex with men, and transgender women. Pharmacokinetic advantages 
included elimination of daily adherence requirements and prolonged terminal half-life exceeding two months. 
Implementation barriers included injection site reactions, requirement for specialized healthcare infrastructure, 
supply chain complexities, high costs limiting accessibility in resource-constrained settings, and potential for 
resistance emergence during tail phase concentrations following discontinuation. Long-acting cabotegravir 
represented a transformative advancement in human immunodeficiency virus prevention with demonstrated 
superiority over oral regimens, though realizing global impact requires addressing substantial implementation, cost, 
and equity challenges to ensure access extends beyond high-income settings.