Choosing between dual and three-drug antiretroviral therapy in aging and comorbid people with HIV: a narrative review

The widespread use of combination antiretroviral therapy has transformed HIV infection into a chronic condition, with life expectancy of people with HIV (PWH) approaching that of the general population when treatment is initiated early and virological suppression is maintained. As survival has improved, the demographic profile of the HIV population has shifted substantially, with a growing proportion of PWH in high-income countries now aged 50 years and older. In this context, the goals of HIV care extend beyond durable virological suppression to include long-term tolerability, management of multimorbidity, reduction of polypharmacy-related risks, and preservation of functional status and quality of life. Three-drug antiretroviral regimens (3DR) have long represented the standard of care due to their robust efficacy and high genetic barrier to resistance. However, in aging and comorbid PWH, lifelong exposure to multiple antiretroviral agents may increase the risk of cumulative organ toxicity-including renal, bone, and cardiovascular adverse effects-as well as clinically relevant drug-drug interactions with medications used to manage concomitant conditions. These considerations have driven interest in treatment simplification strategies, with dual antiretroviral therapy (2DR) emerging as the most clinically investigated approach. Current international guidelines endorse specific 2DR strategies on the basis of randomized controlled trials demonstrating non-inferior virological efficacy compared with 3DR in carefully selected populations. This narrative review integrates evidence from randomized trials and real-world observational studies to critically appraise the role of guideline-endorsed 2DR vs. 3DR in aging and comorbid PWH. We highlight clinical scenarios in which simplification may be advantageous, identify factors associated with reduced durability, and propose a patient-centred framework to support individualized antiretroviral therapy selection, one that extends beyond virological endpoints to incorporate the geriatric dimensions of contemporary HIV care.