Drug-drug interactions in patients living with HIV and major depression

INTRODUCTION: Depression is common among people living with HIV and is often linked to poorer adherence, disease progression, and quality of life. The widespread use of lifelong antiretroviral therapy alongside antidepressants requires careful consideration of potential drug - drug interactions that may compromise treatment outcomes. AREAS COVERED: This review discusses current evidence on pharmacokinetic and pharmacodynamic interactions between antiretroviral agents and antidepressants. We examined key metabolic pathways, including cytochrome P450 enzymes and drug transporters, and their overlapping effects on the central nervous system and metabolism. A comprehensive literature search was performed using electronic databases, including PubMed, Embase, Google Scholar, and relevant regulatory body resources, covering studies from database inception through 2026. The literature was identified by evaluating clinical studies, pharmacokinetic analyses, systematic reviews, and major drug - drug interaction databases relevant to HIV and psychopharmacology. EXPERT OPINION: Although newer antiretroviral regimens have reduced many of the classic CYP-mediated interactions, clinically relevant risks remain through pharmacokinetic and pharmacodynamic overlap. Effectively managing HIV and depression together, therefore, requires mechanistically informed prescribing, personalized treatment strategies, and close collaboration among healthcare providers across disciplines.