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

BackgroundIntegrase mutations associated with dolutegravir resistance have been well characterized, but based on limited data from non-B subtypes. ObjectivesWe 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. MethodsMutations 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-naive sequences from the Los Alamos HIV-1 database to identify mutations associated with viraemia under DTG exposure. ResultsAmong 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, O177L, 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. ConclusionsWe identified several integrase mutations outside established DRM categories that are strongly associated with dolutegravir resistance. Dolutegravir resistance evolution is complex; likely involves mutations not currently classified as DRMs.