Abstract

Human immunodeficiency virus (HIV) remained a global public health challenge despite advances in antiretroviral 
therapy. Oral pre-exposure prophylaxis with tenofovir-based regimens has demonstrated efficacy but faces 
adherence barriers that limit real-world effectiveness. Long-acting cabotegravir, an integrase strand transfer 
inhibitor formulated for intramuscular injection, represents a paradigm shift in biomedical HIV prevention by 
eliminating daily adherence requirements. This review critically evaluated the biochemical properties, clinical 
efficacy, and implementation challenges of long-acting cabotegravir injectable pre-exposure prophylaxis in high
risk populations. A comprehensive literature search identified peer-reviewed clinical trials, pharmacokinetic studies, 
implementation science research, and policy documents published between 2015 and 2025. Cabotegravir exhibited 
sustained plasma concentrations following bimonthly intramuscular administration, achieving four-fold higher 
protective efficacy than oral tenofovir disoproxil fumarate/emtricitabine in clinical trials among men who have sex 
with men, transgender women, and cisgender women. Phase 3 trials demonstrated 66 to 89 percent relative risk 
reduction compared to daily oral prophylaxis. However, implementation barriers included injection site reactions in 
30 to 40 percent of recipients, prolonged pharmacokinetic tail necessitating oral bridging therapy, healthcare 
infrastructure requirements for injectable delivery, and substantial cost differentials compared to generic oral 
formulations. Emerging resistance patterns and inequitable global access remained critical concerns. Long-acting 
cabotegravir represented a highly efficacious prevention modality that addressed adherence challenges but required 
comprehensive implementation strategies addressing logistical, economic, and equity considerations to realize 
population-level impact.