A New Mechanism of Resistance of Human Immunodeficiency Virus Type 2 to Integrase Inhibitors: A 5-Amino-Acid Insertion in the Integrase C-Terminal Domain

Clin Infect Dis. 2019 Aug 1;69(4):657-667. doi: 10.1093/cid/ciy940.

Abstract

Background: Integrase strand transfer inhibitors (INSTIs) are crucial for the treatment of human immunodeficiency virus (HIV) type 2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1, but no data are currently available for HIV-2.

Methods: We assessed the phenotypic susceptibility of 12 HIV-2 clinical isolates, obtained from 2 antiretroviral-naive and 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir) at the virological failure of an INSTI-based regimen. The 50% inhibitory concentrations (IC50s) were determined. Phenotypic inhibitory quotients were determined using trough INSTI plasma concentrations.

Results: Wild-type viruses were susceptible to the 5 INSTIs, with IC50s in the nanomolar range. Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance-associated mutations (codons 143, 148, and 155). We identified a new resistance profile-a 5-amino-acid insertion at codon 231 of the HIV-2 integrase (231INS)-in 6 patients at the virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations, but harbored multiresistant viruses with low genotypic susceptibility scores (median = 1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50 (3- to 5-fold change).

Conclusions: Our results confirm the potency of INSTI on HIV-2 clinical isolates with wild-type integrase. In addition, we identified a new resistance pathway, 231INS, selected in antiretroviral-experienced patients with multiresistant HIV-2 viruses. This highlights the need of close follow-up of those patients initiating an INSTI-based regimen.

Keywords: HIV-2; bictegravir; insertion; integrase inhibitor; phenotypic resistance.

MeSH terms

  • Adult
  • Anti-Retroviral Agents / therapeutic use
  • Drug Resistance, Viral*
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / virology*
  • HIV Integrase Inhibitors / pharmacology*
  • HIV Integrase* / chemistry
  • HIV Integrase* / genetics
  • HIV-2* / drug effects
  • HIV-2* / genetics
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Sequence Analysis, Protein

Substances

  • Anti-Retroviral Agents
  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 4 or More Rings
  • bictegravir
  • HIV Integrase