Long-Acting Antiviral Therapeutics for HIV Prevention and Treatment

Long-acting antiviral therapeutics represent a transformative approach to HIV prevention and treatment by extending drug exposure beyond daily dosing and thereby improving adherence, reducing viral transmission and minimising resistance. These formulations encompass injectable nanosuspensions, subcutaneous implants, oral depot systems and in situ-forming hydrogels, each engineered to maintain therapeutic concentrations for weeks to months following a single administration. Such modalities address barriers associated with pill fatigue and variable adherence, particularly in populations facing structural challenges to daily therapy. The global significance of long-acting regimens is underscored by recent regulatory approvals of injectable cabotegravir and rilpivirine for both treatment and pre-exposure prophylaxis (PrEP), while ongoing research seeks to diversify delivery platforms, optimise pharmacokinetics and ensure suitability across ages, genders and risk groups. Technological developments focus on polymer selection, prodrug design and device tunability to achieve predictable release profiles, minimise local toxicity and enable safe removal or replacement. By uniting medicinal chemistry, biomaterials science and clinical pharmacology, the field aims to broaden access to efficacious, patient-centred interventions that advance efforts to end the HIV epidemic.

Research from Nature Portfolio

Innovative nanoformulations of the integrase inhibitor dolutegravir have been developed to extend systemic exposure for up to eight weeks in preclinical models. A hydrophobic prodrug encapsulated within poloxamer nanoparticles achieved sustained plasma and tissue levels above the inhibitory threshold, demonstrated intracellular drug retention in macrophages and provided prophylactic protection in humanised mice. Complementary work introduced an ultra-long-acting removable implant delivering the same agent over nine months in non-human primates and humanised mice, with the implant retrievable to halt drug delivery in cases of adverse events. In parallel, studies in a macaque model of SHIV infection have characterised the risk of resistance emergence during cabotegravir pre-exposure prophylaxis when administered during undiagnosed acute infection. Key integrase mutations were detected in plasma and mucosal fluids, highlighting the necessity for rigorous HIV testing strategies before and shortly after initiation of long-acting PrEP.

Long-Acting Antiviral Therapeutics for HIV Prevention and Treatment publication trend

The graph below shows the total number of articles in long-acting antiviral therapeutics for hiv prevention and treatment across all publications each year (not limited to Nature Index journals).

Technical terms

Antiretroviral therapy (ART): Treatment regimen using drugs that inhibit HIV replication and prevent disease progression.

Long-acting formulation: A drug delivery system engineered to release medication over an extended period, reducing dosing frequency.

Pre-exposure prophylaxis (PrEP): Preventive use of antiretroviral drugs by HIV-negative individuals to avert infection upon exposure.

Integrase strand transfer inhibitor: A class of antiretroviral drugs that block the integration of viral DNA into the host genome.

Nanoformulation: Encapsulation or conjugation of a drug within nanoscale carriers to modify release kinetics, stability and tissue distribution.

Subcutaneous implant: A device placed beneath the skin designed to deliver a predetermined drug dose over weeks or months.

References

1. Enzyme‐Triggered l‐α/d‐Peptide Hydrogels as a Long‐Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs. Advanced Healthcare Materials (2023).
2. Creation of a long-acting nanoformulated dolutegravir. Nature Communications (2018).
3. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nature Communications (2018).
4. Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection. Nature Communications (2019).
5. Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP). Pharmaceutics (2019).
6. A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques. Antimicrobial Agents and Chemotherapy (2020).