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Antimicrob Agents Chemother. 2015 May;59(5):2596-606. doi: 10.1128/AAC.04844-14. Epub 2015 Feb 17.

Effects of raltegravir or elvitegravir resistance signature mutations on the barrier to dolutegravir resistance in vitro.

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Discovery Research Laboratories for Core Therapeutic Areas, Shionogi & Co., Ltd., Osaka, Japan.
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Global Development, Shionogi & Co., Ltd., Osaka, Japan.
Discovery Research Laboratories for Core Therapeutic Areas, Shionogi & Co., Ltd., Osaka, Japan


The recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) (S/GSK1349572) has overall advantageous activity when tested in vitro against HIV-1 with raltegravir (RAL) and elvitegravir (EVG) resistance signature mutations. We conducted an in vitro resistance selection study using wild-type HIV-1 and mutants with the E92Q, Y143C, Y143R, Q148H, Q148K, Q148R, and N155H substitutions to assess the DTG in vitro barrier to resistance. No viral replication was observed at concentrations of ≥ 32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in the mutants. In the Q148H, Q148K, or Q148R mutants, G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R secondary mutations were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K and G140S, as secondary substitutions to Q148H, Q148K, or Q148R, were associated with partial recovery in viral infectivity and/or INSTI resistance. In the E92Q, Y143C, Y143R, and N155H mutants, no secondary substitutions were associated with DTG. These in vitro results suggest that DTG has a high barrier to the development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution of E92Q, Y143C, Y143R, or N155H simultaneously increased the fold change in 50% effective concentration (EC50) to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate the development of DTG resistance in this pathway in vitro.

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