Long-Acting Injectable Antiretrovirals for HIV Prevention

Since the advent of oral antiretroviral therapy, adherence to daily dosing remains a major barrier to sustained HIV prevention. Long-acting injectable formulations offer the promise of prolonged drug exposure, reducing the need for frequent administration and maintaining therapeutic concentrations that minimise resistance. Key agents under investigation include integrase inhibitors and capsid inhibitors formulated as intramuscular or subcutaneous depots that release active drug over weeks to months. Cabotegravir and lenacapavir have advanced from preclinical models to large-scale trials, demonstrating high efficacy and acceptable tolerability across diverse populations. Implementation challenges such as injection site reactions, clinic visit logistics, cold-chain storage and cost–effectiveness in resource-limited settings are being addressed. Broad adoption of injectable pre-exposure prophylaxis could transform global HIV prevention strategies, particularly for individuals who struggle with daily oral regimens.

Research from Nature Portfolio

Recent studies have advanced ultra-long-acting delivery platforms capable of sustaining protective drug levels for six months or longer. A novel biodegradable in situ forming implant releases cabotegravir above established prevention benchmarks for over half a year. In murine and macaque models, this subcutaneous depot was well tolerated and achieved rapid attainment of therapeutic plasma concentrations. Female macaques subjected to repeated rectal viral challenges remained fully protected, and simple surgical removal of the implant enabled rapid decline of drug levels, demonstrating controllability. Pharmacokinetic modelling indicates that a single multi-millilitre implant could maintain protective cabotegravir concentrations in humans for more than five months. These findings support the clinical translation of ultra-long-acting implants for extended HIV prevention.

Long-Acting Injectable Antiretrovirals for HIV Prevention publication trend

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

Technical terms

Pre-exposure prophylaxis (PrEP): Administration of antiretroviral drugs to HIV-negative individuals to prevent infection.

In situ forming implant (ISFI): A liquid formulation that solidifies upon injection to create a drug-releasing depot in tissue.

Integrase inhibitor: A class of antiretroviral agents that block the HIV enzyme responsible for integrating viral DNA into host cells.

Capsid inhibitor: An antiretroviral compound that disrupts the viral protein shell, preventing proper virus assembly and infection.

References

1. Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection. Nature Communications (2023).
2. Long-acting lenacapavir acts as an effective pre-exposure prophylaxis in a rectal SHIV challenge macaque model. Journal of Clinical Investigation (2023).
3. Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial. The Lancet HIV (2023).