Which mutations cause resistance to integrase strand-transfer inhibitors in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Resistance mutations in the integrase gene have been characterized for raltegravir and elvitegravir. [75, 76, 77] Two primary resistance pathways associated with raltegravir treatment failures in the BENCHMRK-1 and BENCHMRK-2 studies have been described, as follows [78] :

  • Q148K/R/H (25-fold decrease in susceptibility)

  • N155H (10-fold decrease in susceptibility)

The most common mutational sequence (Q148H/G140S) results in a greater than 100-fold decrease in susceptibility to raltegravir. [44] A third resistance pathway involving mutations at Y143C/H/R has also been described for raltegravir but is uncommon. [79] Secondary mutations (L74M/R, E92Q, T97A, E138A/K, G140S/A, V151I, G163R, H183P, Y226D/F/H, S230R, D232N) confer additional resistance. [79]

High-level resistance to elvitegravir is associated with mutations at E92Q in combination with E138K, Q148K/R/H, or N155H, leading to a 150-fold loss of susceptibility. Resistance patterns involving Q148H/G140S and Q148R/G140S demonstrate resistance to both elvitegravir and raltegravir, suggesting cross-resistance is likely. [80]

Dolutegravir exhibits a higher genetic barrier to resistance, attributed to its prolonged dissociation half-life from HIV-1 integrase-DNA complexes, and is considered a second-generation INSTI.  The presence of Q148R with two or more of the following INSTI mutations (L74I/M, E138K/A/D/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, G193E/R) is associated with a substantially lower response to dolutegravir. [81]   Treatment-emergent resistance is uncommon with dolutegravir but has been associated with the development of INSTI mutations at R236K, N155H, and S230R. [82]

Limited information presently exists regarding the resistance profile of bictegravir.  Similar to dolutegravir, bictegravir has an extended dissociation half-life from HIV-1 integrase-DNA complexes and exhibits a higher barrier to resistance than first-generation INSTIs (raltegravir, elvitegravir). [83]   In vitro, site-directed mutagenesis studies demonstrate that M50I, S153F, R236K, and M50I + R236K resulted in 1.3-, 1.9-, 2.2-, and 2.9-fold reductions in susceptibility to bictegravir. [84]

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