Background <p>Many people living with HIV (human immunodeficiency virus) or their caregivers are challenged with consistent adherence to oral antiretroviral therapy (ART) and have a strong preference for long-acting injectable options. However, there are limited data describing the safety and efficacy of fully injectable regimens beyond long-acting cabotegravir-rilpivirine (CAB/RPV-LA) alone.</p> Methods <p>From January 1, 2023 to August 1, 2025, we identified fifteen patients who required completely injectable ART regimens but were ineligible for CAB/RPV-LA alone due to resistance. Data were collected from the electronic medical record, including baseline demographics and clinical characteristics, reason for difficulty taking oral ART, ART history, genotypic resistance profiles, and longitudinal viral load and CD4 cell count trends before and after initiation of an all-injectable ART regimen.</p> Results <p>Patients had diverse clinical indications for an all-injectable regimen, including poor adherence to daily oral ART, impaired gastrointestinal absorption, difficulty swallowing, and drug-drug interactions. Of the fifteen patients started on novel combinations of long-acting injectable ART agents, all fifteen patients had sustained viral loads less than 200 copies/ml at the time of final data collection, and many had improved CD4 counts. The injectable regimens were well tolerated with no serious adverse effects.</p> Conclusions <p>Novel long-acting injectable ART combinations, such as lenacapavir and long-acting cabotegravir, can be safe and effective in patients with HIV resistance and inability to take oral ART. Further study, such as a clinical trial, is needed to confirm safety and long-term efficacy of these regimens and broaden access to them.</p> Trial registration <p>Not applicable.</p>