HIV

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.

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.

Long-acting (LA) administration using a subcutaneous (SC) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological (PK) profile and overcome sub-optimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV pre-exposure prophylaxis (PrEP). Daily drug-release requirements were then ascertained by averaging across the dosing interval.

The HIV Prevention Trials Network (HPTN) announced today results from HPTN 083, a global randomized, controlled, double-blind study that compared the safety and efficacy of long-acting injectable cabotegravir (CAB LA) to daily oral tenofovir/emtricitabine (TDF/FTC) (Truvada) for pre-exposure prophylaxis (PrEP). The study showed that CAB LA lowered HIV incidence among cisgender men and transgender women who have sex with men. During a planned review of study data, an independent Data and Safety Monitoring Board (DSMB) recommended that the study results be announced as soon as possible. The study sponsor, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, agreed with this recommendation.

Adherence to antiretroviral therapy (ART) is imperative for viral suppression and reducing HIV transmission, but many people living with HIV report difficultly sustaining long-term adherence. Long-acting injectable (LAI) ART has the potential to transform HIV treatment and prevention. However, little LAI ART-related behavioral research has occurred among women, particularly outside of clinical trials.

As a long-acting formulation of the non-nucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as pre-exposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice.