Novel integrase mutations linked to genotypic DTG resistance in non-B HIV-1 strains from African participants: The DTG RESIST study

作者：Nuri Han, Tom Loosli, Mamatha Sauermann, İpek Çelikağ, Nanina Anderegg, Bertha Cinthia Baye, Carolyn Bolton‐Moore, Lydia Buzaalirwa, Helen Byakwaga, Cleophas Chimbetete, P V Ebasone, Suzanne Goodrich, Jacqueline Huwa, Charles Kasozi, Adolphe Mafoua, A C Massamba, Eugène Messou, Albert Minga, Gad Murenzi, Guy Muula, Winnie Muyindike, Shirelle Janine Naidoo, Dominique Nsonde, Armel Poda, Richard Ramdé, Aggrey Semeere, Lavanya Singh, Huldrych F. Günthard, Matthias Egger, Jennifer Giandhari, Richard Lessells, Roger D. Kouyos · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.10.23.25338481 · 被引用次数：1 · 研究领域：HIV/AIDS drug development and treatment、HIV/AIDS Research and Interventions、Biochemical and Molecular Research

Background: Integrase mutations associated with dolutegravir resistance have been well characterized, but based on limited data from non-B subtypes. Objectives: We aim to identify integrase mutations not currently classified as integrase strand transfer inhibitor (INSTI) resistance mutations (DRMs) in individuals with viremia on dolutegravir-based regimens. Methods: Mutations in integrase sequences in the DTG RESIST study from African countries were detected using Stanford HIVdb v9.8. We used a viral genome-wide association study (GWAS) approach to identify mutations not classified as major or accessory INSTI DRMs but associated with dolutegravir resistance. We performed the same GWAS on drug-naïve sequences from the Los Alamos HIV-1 database to identify mutations associated with viraemia under DTG exposure. Results: Among 387 sequences, 107 (27.6%) showed at least intermediate dolutegravir resistance. Fourteen integrase mutations not classified as major or accessory DRMs (S39R, L45I, I72L, L74I, V79I, F100Y, I113V, S119R, V126A, K156N, Q177L, I208M, A265V, and R284G) were significantly associated with resistance. V79I (adjusted odds ratio [aOR] 169.2, 95% credible interval [CrI] 18.2-2871.4) and I72L (aOR 67.7, 95% CrI 7.1-1326.2) were strongly associated with resistance. S39R, L45I, I72L, L74I, V79I, F100Y, S119R, and K156N were linked to established INSTI resistance pathways, and I72L, L74I, V79I, V126A, and K156N were associated with viraemia under DTG exposure. Conclusio...