Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance

Isabelle Malet, Eloise Thierry, Marc Wirden, Samuel Lebourgeois, Frédéric Subra, Christine Katlama, Eric Deprez, Vincent Calvez, Anne-Geneviève Marcelin, Olivier Delelis
Journal of Antimicrobial Chemotherapy 2015, 70 (10): 2870-80

OBJECTIVES: HIV-1 integration can be efficiently inhibited by strand-transfer inhibitors such as raltegravir, elvitegravir or dolutegravir. Three pathways conferring raltegravir/elvitegravir cross-resistance (involving integrase residues Q148, N155 and Y143) were identified. Dolutegravir, belonging to the second generation of strand-transfer compounds, inhibits the Y143 and N155 pathways, but is less efficient at inhibiting the Q148 pathway. The aim of this study was to characterize the combination of two pathways involved in raltegravir resistance described in one patient failing a dolutegravir regimen for their propensity to confer dolutegravir resistance.

METHODS: In this study, a patient first failing a regimen including raltegravir was treated with dolutegravir and showed an increase in viruses carrying a combination of two pathways (N155 and Q148). Impacts of these mutations on integrase activity and resistance to strand-transfer inhibitors were characterized using both in vitro and virological assays.

RESULTS: Our data showed that the combination of N155H, G140S and Q148H mutations led to strong resistance to dolutegravir.

CONCLUSIONS: Combination of N155H, G140S and Q148H mutations originating from two distinct resistance pathways to raltegravir or elvitegravir led to a high level of dolutegravir resistance. Due to its high genetic barrier of resistance, it would be reasonable to use dolutegravir in first-line therapy before emergence of raltegravir or elvitegravir resistance.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"