A Nature Communications study by Orris, Siddiqui, Tang and colleagues delineated recurrent and novel evolutionary routes HIV‑1 takes to escape lenacapavir, a long‑acting capsid inhibitor used in antiretroviral regimens. The work characterizes both common and unique resistance mutations emerging under drug pressure. Researchers used longitudinal viral sequencing and phenotypic assays to show how compensatory changes restore fitness while conferring reduced drug susceptibility. The study highlights multiple mutational trajectories rather than a single predictable path, complicating resistance monitoring strategies for long‑acting agents. The findings matter for clinicians prescribing lenacapavir and for developers designing next‑generation capsid inhibitors and resistance surveillance assays. Regulators and treatment programs may need to refine resistance testing recommendations for long‑acting HIV therapeutics.