The Role of Protease Inhibitors in HIV Treatment: Who Still Needs Them in 2025?

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INTRODUCTION: Protease inhibitors (PIs) remain an effective antiretroviral therapy (ART) option for people with human immunodeficiency virus (HIV) (PWH), particularly in complex clinical and virological scenarios. However, they are associated with greater metabolic toxicity and drug-drug interactions (DDI) compared with newer ART classes. This study aimed to characterize PWH currently receiving PI-based ART and to explore the reasons for maintaining these regimens. METHODS: We conducted a cross-sectional, observational study of all PWH on PI-based ART as of 30 June 2024 at the HIV Unit of Hospital Clínic de Barcelona. Demographic, clinical, laboratory, ART history, and genotypic resistance data were extracted from the institutional database and compared with the rest of the cohort. RESULTS: Among 6261 PWH on ART, 724 (11.6%) were receiving a regimen including a PI; their use progressively declined over the last two decades (p < 0.001). The most frequent reasons for PI prescription were prior virological failure (36%) and toxicity to previous ART (41%). Compared with other PWH, those on PIs were older (median 54 versus 48 years, p < 0.001), more frequently female patients (19% versus 13%, p < 0.001), and had higher rates of heterosexual (33% versus 21%, p < 0.001) and injection-drug-use transmission (15% versus 7%, p < 0.001). Virological suppression was significantly lower among PWH on PIs (88% versus 96%, p < 0.001). Genotypic resistance testing prior to PI prescription was available for 435 PWH; 74% had at least one major resistance substitution, and 70.4% had substitutions affecting two or more antiretroviral classes. In total, 299 PWH had experienced either virological failure or toxicity to non-nucleoside reverse transcriptase inhibitor (NNRTI)- or integrase strand transfer inhibitor (InSTI)-based regimens prior to initiating a PI-based regimen. Among them, 42 had documented failure of or toxicity to both drug classes. CONCLUSIONS: Although their use has declined, a substantial number of PWH remain on regimens including a PI. These PWH typically have long-standing infections, prior ART failures, and documented resistance substitutions, supporting the continued use of PIs when other therapeutic options are limited.

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