Translational resilience in intravaginal HIV prevention and multipurpose prevention technologies: formulation, exposure, and implementation barriers

Intravaginal HIV prevention has progressed from early nonspecific microbicides to antiretroviral gels, films, inserts, and intravaginal rings, alongside emerging biologic agents and multipurpose prevention technologies (MPTs). Despite substantial advances in antiviral potency and formulation technology, translation from pharmaceutical development to consistent clinical protection has remained uneven, indicating that API activity or dosage-form performance alone is insufficient to explain clinical outcomes. This review critically examines the development of intravaginal HIV prevention and MPT products through a mechanistic pharmaceutical perspective, focusing on the relationships between controllable product attributes, drug release and transport, the cervicovaginal environment, compartment-specific pharmacokinetics/pharmacodynamics (PK/PD), and product use. Historical microbicide and antiretroviral programs are examined as translational case studies to identify how mucosal safety, local exposure and use-dependent drug delivery contributed to divergent clinical outcomes. The review further evaluates how cervicovaginal fluid, semen, mucus, epithelial barriers, hormonal state, microbiome composition, and inflammation can modify formulation behavior and drug transport; how API physicochemistry, solid state, drug loading, drug-polymer partitioning, and diffusivity constrain formulation architecture and release; and how these relationships differ among gels, films, inserts, sustained-release devices, MPTs, and biologic delivery systems. Particular attention is given to the distinction between drug incorporation, release, tissue transport, and pharmacologically relevant exposure, and to the additional challenges created when multiple APIs require different release rates, biological compartments, or durations of action. Platform characteristics are further considered in relation to the exposure patterns and product-use conditions they are intended to support. By integrating formulation science with cervicovaginal physiology, PK/PD, and clinical experience, this review provides a mechanistic basis for identifying where intravaginal prevention systems lose translational performance and which formulation-transport-exposure relationships require stronger evidence to support more reproducible clinical protection.