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

Abstract

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 potential integrase mutations not currently classified as integrase strand transfer inhibitor (INSTI) resistance mutations (DRMs) in individuals with viremia on dolutegravir-based regimens. METHODS: We included integrase sequences from DTG RESIST study sites in African countries. These were interpreted using Stanford HIVdb v9.8. We used a viral genome-wide association study-like approach restricted to the integrase region (INT-WAS) to identify mutations not classified as major or accessory INSTI DRMs but occurring more frequently in sequences carrying major INSTI DRMs than in those without major INSTI DRMs. We performed the same INT-WAS analysis with drug-naïve sequences from the Los Alamos HIV-1 database to test whether these identified mutations were enriched among sequences from individuals with viraemia whilst receiving DTG-based treatment. RESULTS: Among 382 sequences, 104 (27.2%) showed at least intermediate dolutegravir resistance. Twelve integrase mutations not classified as major or accessory DRMs (S39R, L45I, I72L, L74I, V79I, I113V, S119R, K156N, I208M, T218M, A265V, and R284G) were significantly associated with predicted DTG resistance. Among them, V79I [adjusted odds ratio (aOR) 167.1, 95% credible interval (CrI) 17.9-2947.6] and I72L (aOR 65.6, 95% CrI 6.6-1273.7) were strongly associated. S39R, L45I, V79I, S119R, and K156N were linked to established INSTI resistance pathways, and I72L, L74I, V79I, K156N, I208M, and R284G were overrepresented in sequences from viraemic individuals on DTG-based treatment relative to drug-naïve sequences. CONCLUSIONS: We identified several amino acid substitutions outside the established DRMs that are strongly associated with predicted dolutegravir resistance. Dolutegravir resistance evolution is complex and likely involves mutations not currently classified as DRMs.