In spite of introduction of combination antiretroviral therapy (cART) against 
human immunodeficiency virus (HIV) infection; inaccessibility and poor adherence 
to oral cART costs 10 in 100,000 death worldwide. Failure in adherence leads to 
viral rebound, emergence of drug resistance and anticipated HIV infection in 
high risk individuals. Various Long-acting antiretroviral (LA ARV) 
nanoformulations including nano-prodrug, solid drug nanoparticles (SDN), 
nanocrystals, aspherical nanoparticles, polymeric and lipidic nanoparticles have 
shown plasma/tissue drug concentration in the therapeutic range for several 
weeks during pre-clinical evaluation. LA ARV nanoformulations therefore have 
replaced cART as better alternative for the treatment of HIV infection. 
Cabenuva™ is recently approved by Health Canada containing LA cabotegravir+LA 
rilpivirine nanocrystals (ViiV healthcare) for once monthly administration by 
intramuscular route. The LA nanoformulation due to its nanosize insist on better 
stability, delivery to lymphatic, slow release into systemic circulation via 
lymphatic-circulatory system conjoint and secondary drug depot within infiltered 
immune cells at site of administration and systemic circulation in contrast to 
conventional drugs. However, the pharmacokinetic, biodistribution and efficacy 
of LA nanoformulations hinge onto physicochemical properties of the drugs and 
route of administration. Therefore, current review emphasizes on these 
contradistinctive factors that affects the reproducibility, safety, efficacy and 
toxicity of LA anti-HIV nanoformulations. Moreover, it expatiates on application 
of profuse nanoformulations for long-acting effect with promising preclinical 
discoveries and two clinical leads. To add on, utilization of physiology-based 
and mechanism-based pharmacokinetic modelling and in vivo animal models which 
could lead to enhanced safety and efficacy of LA ARV nanoformulations in humans 
have been included.