A Nature Communications paper by Orris, Siddiqui, Tang and colleagues delineates evolutionary pathways HIV‑1 uses to escape lenacapavir, an extended‑release capsid inhibitor. The team identified both recurrent mutations and novel resistance trajectories that compromise drug binding, informing surveillance and next‑generation capsid inhibitor design. The work combines longitudinal sequencing from treated patients with in vitro selection experiments to chart predictable mutational patterns and occasionally unique adaptations. Findings highlight the need for resistance monitoring in patients on long‑acting antiretrovirals and may guide combination strategies to limit escape. Researchers recommend incorporating key resistance markers into diagnostic panels and re‑evaluating monotherapy or prolonged dosing strategies where resistance emergence risk is higher.