The Promise of Long-Acting Antiretroviral Therapies: From Need to Manufacture

Abstract

Antiretroviral therapy has transformed human immunodeficiency virus infections from certain death to a manageable chronic disease. Achieving strict adherence to drug regimens that limit toxicities and viral resistance are achievable goals. Success is defined by halting viral transmission and by continuous viral restriction. A step towards improving treatment outcomes is in long acting antiretrovirals. While early results remain encouraging there remain opportunities for improvement. These rest, in part, on the required large drug dosing volumes, local injection site reactions and frequency of injections. Thus, implantable devices and long acting parenteral prodrugs have emerged which may provide more effective clinical outcomes. The recent successes in transforming native antiretrovirals into lipophilic and hydrophobic prodrugs stabilized into biocompatible surfactants can positively affect both. Formulating antiretroviral prodrugs demonstrate improvements in cell and tissue targeting, in drug dosing intervals and in the administered volumes of nanosuspensions. As such the newer formulations also hold the potential to suppress viral loads beyond more conventional therapies with the ultimate goal of HIV-1 elimination when combined with other modalities. KeywordsLong acting slow effective release antiretroviral therapy; regimen adherence; human immunodeficiency virus type one; viral reservoirs; good manufacturing practices; implantable devices Current Long Acting (LA) Antiretroviral Drug (ARV) FormulationsOral administration of antiretroviral (ARV) drugs is the major delivery route for treatment and prevention of human immunodeficiency virus type one (HIV-1) infection.

A year-long extended release nanoformulated cabotegravir prodrug

“…However viral control is linked to regimen adherence affected by disease co-morbidity, stigma, behavior, illicit drug-use, and cost 1 . Such limitations were the impetus towards the development of long-acting (LA) injectables 2 , 3 , 4 , 5 , 6 . In April, 2019, ViiV Healthcare submitted a New Drug Application to the US Food and Drug Administration (FDA) for monthly cabotegravir and rilpivirine (CAB and RPV) injectables applied in HIV-1 treatments 7 .…”

Rod-shape theranostic nanoparticles facilitate antiretroviral drug biodistribution and activity in human immunodeficiency virus susceptible cells and tissues

“…The ability to sustain plasma and tissue drug levels beyond the plasma 90% inhibitory concentration (IC 90 ) for months would reduce pill burdens, increase regimen adherence and reduce adverse events that plague current medications. This would also lift the psychological stigma for strict daily regimens reminding patients of disease and impacting mental health 16, 39, 40. To simplify measurements of LA ARV efficacy by pharmacokinetic (PK) and biodistribution (BD) tests and optimize dosing, theranostics was introduced 16.…”

“…Nonetheless, a number of challenges exist to implement such regimens. These include, but are not limited to, required dosing volumes, frequencies of injection, untoward side effects, and maintenance of antiretroviral efficacy 16-18. Even more importantly, only two LA ARVs are currently in the pipeline 12.…”

Small Animal Models for Human Immunodeficiency Virus (HIV), Hepatitis B, and Tuberculosis: Proceedings of an NIAID Workshop

“…Therapeutics approved for HBV mainly include nucleos(t)ide analogues inhibitors of RT, two of which (tenofovir and lamivudine) also have anti-HIV activity. She reported that Long-Acting Slow Effective Release antiretroviral therapeutics (LASER ART) control HBV replication in the liver of humanized mice [11,12]. In rats, a single injection of 75 mg/kg nanoformulated lamivudine persisted for 28 days in the peripheral blood with significant accumulation in spleen, liver, and lymph nodes.…”