Abstract

Background: Integrase strand transfer inhibitors (INSTIs) are widely used in HIV treatment, yet few large-scale studies have examined acquired resistance (AR) at the population level. This study assessed the prevalence, patterns, and clinical implications of AR to INSTIs in Chile over a 12-year period. Methods: We analyzed 5266 genotypic sequences from ART-experienced individuals with confirmed virological failure and INSTI-based regimens between 2012 and 2023. Resistance-associated mutations were classified using the Stanford HIVdb algorithm. Resistance trends were compared between pre-pandemic (2012–2019) and post-pandemic (2020–2023) periods. Results: High AR rates were observed for first-generation INSTIs: raltegravir (28 %) and elvitegravir (27.7 %). Lower resistance levels were found for dolutegravir (8.3 %), bictegravir (8.3 %), and cabotegravir (18.7 %). Major resistance mutations included N155H (25.2 %), Q148 H/K/R (17.2 %), and Y143R (14.3 %). Notably, Q148 H/K/R mutations were always found in combination with other major mutations. Subtype-specific differences were observed, with higher first-generation INSTI resistance in subtype F (55.6 %) than in subtype B (23.9 %). Post-pandemic resistance increased significantly for first-generation INSTIs (25 % vs. 31 %, p < 0.05). The mutation N155H, while not impacting DTG or BIC significantly, conferred intermediate resistance to CAB. CAB resistance was detected despite its absence in treatment protocols, likely due to cross-resistance pathways. Conclusions: Acquired INSTIs resistance in Chile is high, especially for first-generation drugs. These findings highlight the need for nationwide molecular surveillance and pre-treatment genotyping, particularly before initiating long-acting regimens such as CAB-LA. Strategic monitoring will be critical to maintaining the efficacy of current and next-generation INSTIs. © 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/