Abstract

Antiretroviral therapy has transformed HIV from a fatal disease into a manageable chronic condition. However, 
metabolic complications, including insulin resistance, dyslipidemia, and type 2 diabetes mellitus (T2DM) have 
emerged as major concerns in long-term management of people living with HIV (PLWH). Global prevalence 
estimates suggest that up to 15–20% of PLWH develop T2DM during chronic therapy, a rate significantly higher 
than in HIV-uninfected populations. This review examined the mechanisms, risk factors, and clinical consequences 
of antiretroviral therapy–associated metabolic alterations contributing to T2DM in PLWH. This review 
synthesized peer-reviewed studies from PubMed, Scopus, and Web of Science, focusing on clinical, molecular, and 
pharmacokinetic reports published between 2010 and 2025. Protease inhibitors and certain nucleoside reverse 
transcriptase inhibitors alter glucose transporter function, mitochondrial energetics, and adipokine signaling, 
producing insulin resistance. Chronic immune activation and adipose tissue inflammation further amplify metabolic 
risk. Host factors, including age, sex, ethnicity, and pre-existing obesity, interact with therapy-specific 
pharmacokinetics to increase susceptibility. Quantitative data indicate that protease inhibitor exposure increases 
diabetes incidence by approximately 1.5–2.0-fold, while integrase inhibitor regimens confer a lower but significant 
risk. Antiretroviral therapy remains essential but carries a measurable risk of T2DM mediated by drug-specific and 
host-related mechanisms. Integrative management strategies, including risk stratification, lifestyle modification, and 
pharmacovigilance, are needed.