Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors

J Antimicrob Chemother. 2016 Jul;71(7):1948-53. doi: 10.1093/jac/dkw071. Epub 2016 Mar 29.

Abstract

Objectives: Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained.

Patient and methods: Genotypic analysis was performed on patients with virological failure (<1000 copies/mL) on dolutegravir-containing regimens. The Los Alamos database was queried for glycine codon 118 polymorphisms. Cell culture selections and phenotypic drug susceptibility assays assessed resistance via the G118R pathway.

Results: We report on two patients who developed viral failure while on dolutegravir monotherapy. Both patients had been on a current or previous regimen containing integrase inhibitors. Virological failure (<1000 copies/mL) emerged early within 2 months following the dolutegravir switch. The appearance of G118R in these two cases and subtype C and CRF02_AG in vitro selections were related to a rare GGA natural polymorphism at codon 118 (1.5% prevalence), facilitating a GGA to AGA transition. Cell culture selections were used to assess the in vitro progression of the G118R pathway leading to cross-resistance to all integrase inhibitors.

Conclusions: Although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Drug Resistance, Viral*
  • Genotyping Techniques
  • HIV Infections / drug therapy*
  • HIV Infections / virology*
  • HIV Integrase / genetics*
  • HIV Integrase Inhibitors / therapeutic use*
  • HIV-1 / drug effects
  • HIV-1 / genetics
  • HIV-1 / isolation & purification
  • Heterocyclic Compounds, 3-Ring / therapeutic use*
  • Humans
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Mutation, Missense*
  • Oxazines
  • Piperazines
  • Pyridones
  • Treatment Failure

Substances

  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Oxazines
  • Piperazines
  • Pyridones
  • dolutegravir
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1