Long-Acting Antiretroviral Therapies for HIV: From Approved Strategies to the Next Generation of Treatment and Prevention

Background/Objectives: Long-acting antiretroviral therapies (LA-ART) represent a major evolution in HIV treatment and prevention, addressing key limitations of lifelong daily oral medication. This narrative review summarizes current evidence on approved and investigational long-acting antiretroviral strategies, focusing on efficacy, pharmacology, resistance, clinical implementation and future perspectives. Methods: A structured narrative literature search was performed in PubMed/MEDLINE and the Cochrane Library for records published between January 2005 and October 2026, complemented by major conference proceedings (CROI, IAS, EACS) and regulatory and public-health sources (FDA, EMA, WHO, CDC, DHHS, IAS-USA). Findings were synthesized narratively and organized by drug class and clinical indication (treatment versus prevention), given substantial heterogeneity across study designs, agents and outcomes that precluded quantitative meta-analysis. Results: Injectable cabotegravir plus rilpivirine has become established as the first long-acting maintenance regimen for virologically suppressed individuals, with expanding evidence in adherence-challenged and adolescent populations. Long-acting cabotegravir has demonstrated superiority over oral tenofovir-based pre-exposure prophylaxis (PrEP) in the HPTN 083 and HPTN 084 trials. Lenacapavir, the first-in-class capsid inhibitor, has shown activity against multidrug-resistant HIV and, in the PURPOSE 1 and PURPOSE 2 trials, high efficacy as twice-yearly PrEP, with durable results on long-term follow-up. Investigational strategies, including islatravir plus lenacapavir and broadly neutralizing antibodies, may further extend dosing intervals, although resistance, implementation and equitable-access challenges remain across all approaches. Conclusions: Long-acting antiretroviral strategies have established a new therapeutic paradigm for HIV treatment and prevention. Their future impact will depend on resistance management, healthcare-delivery capacity and equitable global access, alongside continued clinical innovation.