Major role of dolutegravir in the emergence of the S147G integrase resistance mutation.

Background: The S147G mutation is associated with high-level resistance to the integrase strand transfer inhibitor (INSTI) elvitegravir. In several poorly documented cases, it was also selected in patients on dolutegravir. Given the widespread use of dolutegravir, further studies of S147G are required.

Methods: We consulted the HIV-1 resistance databases of French laboratories to identify all cases of S147G emergence. We collected immunological and virological parameters, history of treatment and INSTI resistance mutations. Mann-Whitney and Fisher's exact tests were performed.

Results: We retrospectively identified 88 cases of S147G selection, from 2015 to 2022, in 22 laboratories. The most frequent HIV-1 subtypes were Clade B (55.7%) and CRF02_AG (21.6%). At the time of resistance genotyping, the median viral load was 5860 copies/mL (IQR 1011-24  525) and the median CD4 cell count was 412 cells/mm3 (228-560). S147G emerged on dolutegravir (48%), elvitegravir (36%) and raltegravir (10%) treatments. S147G was associated with a larger median number of other INSTI mutations on dolutegravir than on elvitegravir [3.0 (2.0-4.0) versus 2.0 (1.0-2.0); P = 0.0002] and was never observed with G148H or G118R. On dolutegravir, S147G was associated principally with T97A (62%), N155H (59%), E138K (50%), L74I/M (38%) and Q148R (33%).

Conclusions: In this French study, S147G emerged principally in patients on dolutegravir regimens, in association with up to five other INSTI resistance mutations. This accumulation of mutations suggests a replicative advantage on HIV strains under dolutegravir selection pressure, suggesting that caution is required when interpreting dolutegravir resistance in the presence of such S147G resistance patterns, even in patients prescribed dolutegravir twice daily.