HIV

Long acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early and late stage clinical trials. Strategies to manage toxicities and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations.

Unitaid and the Medicines Patent Pool have worked together to develop a brief overview of the intellectual property status of long-acting drugs, formulation processes and delivery devices for major infectious diseases that are in pre-clinical or later stages of development as of October 2018.

Poor adherence to oral antiretroviral therapy (ART) remains an important challenge in the treatment of HIV. Microneedles (MN) potentially could offer a non-invasive long-acting (LA) delivery approach, avoiding the need for daily dosing of ART. However, this claim has yet to be explored amongst its potential end-users. The aim of this mixed methods study was to investigate the perspectives from various end-users surrounding the translation of MN technology to general clinical practice, with a particular focus on delivery of ART. Quantitative postal questionnaires were distributed amongst healthcare professionals (HCPs) and the lay public (LP). A total of 208 responses were obtained (HCP, 69; LP, 139), with a completion rate of 34.7%. The consensus on MN technology was positive from both demographics (HCP, 97.1%; LP, 98.6%), with further strong support of postulated MN use within HIV (HCP, 97.1%; LP, 98.6%). 

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution.

Diverging physicochemical properties of HIV drug combinations are challenging to formulate as a single dosage form. We have found that 2-to-4 hydrophilic and hydrophobic HIV drugs in combination can be stabilized with lipid excipients under a controlled solvent removal process to form a novel pharmaceutical powder distinct from typical amorphous material. This discovery has enabled production of a drug combination nanoparticle (DcNP) powder composed of 3 HIV drugs-water-insoluble lopinavir (LogP = 4.7) and ritonavir (LogP = 5.6) and water-soluble tenofovir (LogP = -1.6). 

Long-Acting/Extended Release Antiretroviral Research Resource Program to add therapy development for tuberculosis and viral hepatitis

July 28, 2020—The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) today announced approval of a new NIH grant that allows for expansion of its charter to promote development of medications that are more manageable for patients. Going forward LEAP will include tuberculosis and viral hepatitis, which are comorbidities that complicate HIV treatment.

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection.

Although effective, some oral pre-exposure prophylaxis (PrEP) users face barriers to adherence using daily pills, which could be reduced by long-acting formulations. Long-acting cabotegravir (CAB LA) is a potential new injectable formulation for HIV PrEP being tested in Phase III trials.

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. 

The first long-acting formulations of HIV drugs are undergoing regulatory review for use in maintenance of viral suppression in people with HIV. Although these novel drug formulations could contribute greatly to HIV treatment and prevention efforts, their lack of activity against hepatitis B virus (HBV) could limit their global impact, particularly in populations with high burdens of both HIV and HBV.