Natural occurrence of drug resistance mutations to the HIV‐1 capsid inhibitor lenacapavir

Aims Lenacapavir (LEN) is a first‐in‐class HIV‐1 capsid inhibitor. We investigated the natural occurrence of LEN drug resistance mutations (DRM) in HIV‐1 sequences from LEN treatment‐naïve individuals. Methods We analysed all available HIV‐1 capsid sequences ( n = 21 646) from individuals never exposed to LEN from the Los Alamos National Laboratory database. Results LEN DRMs were identified at all LEN DRM‐associated positions, including the highly resistant M66I variant, which was found in 9 sequences across multiple subtypes. In total, 56 sequences (0.26%) contained LEN DRMs. The most prevalent mutation was Q67H ( n = 22), and this mutation was more common in CRF01_AE (17/3053, 0.56%). Conclusions All known LEN DRMs can be found in viral populations without drug pressure. This finding may reflect immunological pressure on capsid epitopes containing DRMs. Our findings are of potential clinical relevance for LEN use in both therapeutic and prophylactic applications.