Abstract
Polypharmacy, the concurrent use of multiple medications, presents a growing challenge in HIV care as people living with HIV age and experience earlier onset of age-related co-morbidities. However, how polypharmacy is defined and assessed in HIV research remains inconsistent. The commonly used threshold of five or more medications, often derived from geriatric medicine, may not adequately reflect the clinical complexity of HIV care, where lifelong antiretroviral therapy (ART) forms the foundation of treatment. This review examines how polypharmacy has been defined and operationalized in HIV studies and compares this to approaches in geriatric research, where tools (e.g., STOPP/START and the Beers criteria) have been more systematically applied. We argue that HIV care can benefit from, but must also adapt, these frameworks to address the unique pharmacologic, psychosocial and adherence-related considerations faced by people with HIV. We also review emerging evidence linking polypharmacy in HIV with negative outcomes, including increased risk of drug-drug interactions, hospitalization, reduced quality of life, and associated healthcare costs. At the same time, polypharmacy is not inherently inappropriate, as many regimens may reflect guideline-concordant care. Rather than focusing on medication count alone, attention should shift toward evaluating appropriateness, safety and alignment with the individual's evolving health needs. Finally, we explore the role of deprescribing in HIV care, acknowledging both its promise and the challenges it presents, particularly in preserving ART stability and supporting shared decision-making. Reframing polypharmacy through an HIV-specific lens can support safer prescribing and improve outcomes as the HIV population continues to age.