FDA-Approved HIV-1 Capsid Inhibition With Lenacapavir: A Paradigm Shift in Pre-exposure Prophylaxis.

Human immunodeficiency virus type 1 (HIV-1) remains a major global health challenge, with over 40 million people currently living with the infection. While daily oral antiretroviral therapy and pre-exposure prophylaxis (PrEP) are highly effective, adherence barriers limit their impact. Lenacapavir, a first-in-class HIV-1 capsid inhibitor with a unique multistage mechanism of action, offers potent antiviral activity and sustained plasma concentrations that enable twice-yearly subcutaneous dosing. In two phase 3 randomized controlled trials, lenacapavir demonstrated superior efficacy to oral PrEP regimens, with near-complete prevention of HIV acquisition across diverse populations, including cisgender women, men, and gender-diverse individuals. The safety profile was acceptable, though injection site reactions were common, and the drug's prolonged pharmacokinetic tail necessitates strict HIV testing before each dose to prevent resistance. Implementation challenges include programmatic training, drug-drug interaction considerations, and disparities in PrEP uptake, particularly among women, Black and Hispanic/Latino populations, and individuals in the US South. While currently approved for PrEP only in the US, broader global access will depend on regulatory decisions, WHO guidance, and procurement strategies. Lenacapavir represents a significant advance in HIV prevention, with the potential to expand protection options and reduce new infections if integrated into equitable and robust public health programs.