Long-acting slow effective release antiretroviral therapy

Abstract

Introduction Advances in the development of long acting antiretroviral therapy (ART) can revolutionize current treatments for HIV/AIDS. We have coined the term long active slow effective release ART (LASER ART) based on properties of slow drug dissolution, poor water-solubility, excellent bioavailability, limited off target systemic toxicities, and excellent patient treatment adherence. Drug carrier technologies characterized by high payload of antiretroviral drugs (ARVs) in a single carrier are being developed to improve the pharmacokinetics and pharmacodynamics of the nanoformulated ART (nanoART). Additionally, surface modification of slow release antiretroviral carriers with targeting ligands has facilitated receptor-mediated transport across physiological barriers serves to improve therapeutic outcomes. Areas covered This review highlights current developments of reservoir targeted LASER ART delivery platforms that have the potential to improve HIV/AIDS therapeutic outcomes. Such nanoART delivery platforms include decorated multifunctional nano- and micro- particles, prodrugs and polymer conjugates. Therapeutic strategies such as anti-inflammatory and neuroprotective agents and CRISPR/Cas 9 based gene-editing technologies that affect drug depots, boost ART effectiveness and facilitate viral clearance are discussed. Expert opinion The persistence of HIV-1 in its lymphoid, gut and nervous system reservoirs poses a major challenge to viral eradication. Emerging innovative strategies for effective medicines and slow release products to target intracellular pathogens, immune based interventions, genome-editing technologies, compounds that sustain drug depots and combinations of nanoART and image contrast agents have the potential to meet the unmet clinical needs of HIV patients. Such efforts will bring the medicines to sites of active viral replication and accelerate viral clearance.

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

“…LASER ART rests on four pillars; creation hydrophobic prodrug nanocrystals, the enhanced drug lipophilicity associated with improved cell membrane drug penetration, slow drug release and hydrolysis, and facilitated viral reservoir drug penetrance. These transformative technologies created ARVs that best penetrate viral reservoirs and increase the drug’s apparent half-life creating medicines that maximally restrict viral growth [20]. However, to realize the potential of long acting tissue viral reservoir penetrating ARVs, the drugs’ pharmacokinetic (PK) and pharmacodynamic (PD) profiles must be optimized to minimize on and off-target effects.…”

Lessons Learned From Failures and Success Stories of HIV Breakthroughs: Are We Getting Closer to an HIV Cure?

“…However, the LA ARVs can be rapidly metabolized and is not distributed extensively biologically. To counter such limitations, the LASER ART allows high drug loading capacities, extended circulation times, active targeting capabilities, enhanced drug dissolution rates and bioavailability, as well as reduced rapid plasma clearance (Edagwa et al, 2017). Most importantly, LASER ART potentially delivers the drugs to intracellular and tissue reservoir such as GALT, lymph nodes, genitourinary tract and the brain; while maintaining the therapeutic concentration over a long period of time.…”

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

“…Recently, an interesting strategy was developed comprising a "long-acting-, slow-effective release antiretroviral therapy" strategy (Laser ART) that enabled delivery of ARVs such as dolutegravir, lamivudine, abacavir and rilpivirine encapsulated in lipid nanoparticles via myristoylation. The result was hydrophobic, lipophilic "nanocrystals", which were non-specifically internalized into monocytes and macrophages, and slowly released to the surrounding extracellular space [102][103][104][105]. Interestingly, two out of seven humanized HIV-infected mice were cured when Laser ART was combined with CRISPR/Cas9-mediated excision of HIV DNA [106].…”