Abstract
Long-acting injectable HIV pre-exposure prophylaxis (LAI-PrEP) demonstrates superior efficacy and persistence compared to daily oral PrEP. However, real-world implementation reveals that only 52.9% of prescribed individuals initiate treatment with their first injection. This implementation barrier stems from a fundamental mismatch between the traditional PrEP cascade-designed for oral formulations allowing same-day initiation-and LAI-PrEP's unique requirements involving a 2-8 week "bridge period" between prescription and first injection to establish HIV-negative status. We synthesize data from major clinical trials (HPTN 083, HPTN 084, PURPOSE-1/2; >15,000 participants) with real-world implementation studies to characterize bridge period navigation as the critical implementation barrier. This review proposes a reconceptualized PrEP cascade explicitly recognizing the bridge period as a distinct, measurable step requiring dedicated management strategies. We examine pharmacological bases for conservative initiation protocols, quantify population-specific barriers to bridge period completion, and synthesize evidence on strategies to improve initiation success. This paradigm shift from individual behavioral adherence to structural factors within the healthcare system requires parallel innovations in cascade conceptualization, measurement frameworks, and implementation approaches. Addressing this structural barrier is essential to translate LAI-PrEP's extraordinary clinical efficacy (>96%) into meaningful public health impact, particularly for populations experiencing the highest HIV burden.