Journal of Antivirals & Antiretrovirals
Open Access

Next-Generation Antiretrovirals Long-Acting Formulations and Injectable Therapies

Markus Riedl^{* *}Correspondence: Markus Riedl, Department of Clinical Pharmacology, Vienna Institute for HIV Therapeutics, Medical University of Austria, Vienna, Austria, Email:

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Description

In recent years, the landscape of HIV treatment has undergone significant evolution with the emergence of next-generation antiretrovirals (ARVs), particularly long-acting (LA) formulations and injectable therapies. These innovations have been developed to overcome limitations associated with daily oral regimens, such as pill fatigue, adherence challenges, and the psychological burden of daily reminders of illness. Long-acting therapies offer the potential to transform HIV care by enhancing adherence, improving virologic suppression, and reducing stigma associated with daily medication intake. Among the most notable advances in this field are the injectable formulations of cabotegravir (an integrase strand transfer inhibitor) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor), which are now being utilized in clinical settings as monthly or bi-monthly injections.

The rationale for LA therapies is rooted in their pharmacokinetic properties, which allow for sustained plasma drug concentrations above the inhibitory threshold over extended periods. This eliminates the need for daily dosing and offers greater flexibility for patients. Phase III clinical trials such as ATLAS and FLAIR have demonstrated that LA injectable cabotegravir-rilpivirine is non-inferior to traditional oral ART in maintaining viral suppression in treatment-experienced patients with undetectable viral loads. These results are encouraging and suggest that long-acting injectables may serve as a viable alternative for many patients, especially those with adherence issues or those seeking greater discretion in their treatment.

Moreover, long-acting ARVs present novel opportunities in HIV prevention. Cabotegravir LA has shown significant efficacy as a pre-exposure prophylaxis (PrEP) agent in the HPTN 083 and HPTN 084 trials, which evaluated its use among men who have sex with men (MSM), transgender women, and cisgender women at risk of HIV. The studies found cabotegravir LA to be superior to daily oral tenofovir/emtricitabine in preventing HIV acquisition, marking a pivotal moment in HIV prevention strategies. This paradigm shift could lead to increased uptake of PrEP in populations with poor adherence to daily regimens or in those facing social and structural barriers to consistent access.

Despite their promise, long-acting and injectable ARVs also present several clinical and logistical challenges. The requirement for intramuscular administration by healthcare professionals necessitates regular clinic visits, which may not be feasible for all patients, especially those in resource-limited settings. Injection site reactions, although generally mild, are common, and discontinuation of LA therapy poses a risk of sub-therapeutic drug levels, potentially leading to resistance. Therefore, careful patient selection, counseling, and monitoring are crucial for the successful implementation of long-acting therapies. Additionally, maintaining cold chain logistics and ensuring supply chain integrity for these injectable products can present hurdles for widespread implementation.

Further development is ongoing to refine LA formulations, including implants, oral long-acting drugs, and nanoparticles, aiming to extend dosing intervals and enhance drug delivery systems. For example, lenacapavir, a capsid inhibitor currently under investigation, provides the potential for twice yearly subcutaneous administration, which could significantly simplify HIV treatment and prevention. Such innovations are particularly promising for use in global HIV programs, especially in areas where healthcare infrastructure is limited.

In conclusion, long-acting and injectable antiretrovirals represent a transformative step in the treatment and prevention of HIV. They offer compelling advantages in terms of adherence, convenience, and stigma reduction, with the potential to improve clinical outcomes and quality of life for people living with HIV. However, their successful integration into clinical practice depends on addressing the logistical and clinical challenges associated with these therapies. With ongoing research, technological advancements, and global cooperation, next-generation ARVs may redefine the future of HIV management and bring us closer to achieving global treatment and prevention goals.