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.

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.

• Authors: Quentin Le Hingrat, Gilles Collin, Minh Lê, Gilles Peytavin, Benoit Visseaux, Mélanie Bertine, Roland Tubiana, Marina Karmochkine, Nadia Valin, Fidéline Collin, Adrien Lemaignen, Louis Bernard, Florence Damond, Sophie Matheron, Diane Descamps, Charlotte Charpentier, French National Agency for Research on AIDS and Viral Hepatitis (ANRS) CO5 HIV-2 Cohort
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 69 Issue 4 Pg. 657-667 (08 01 2019) ISSN: 1537-6591 [Electronic] United States
• PMID: 30383215 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Amides
• Anti-Retroviral Agents
• HIV Integrase Inhibitors
• Heterocyclic Compounds, 3-Ring
• Heterocyclic Compounds, 4 or More Rings
• Piperazines
• Pyridones
• bictegravir
• HIV Integrase

Topics

• Adult
• Amides
• Anti-Retroviral Agents (therapeutic use)
• Drug Resistance, Viral
• Female
• HIV Infections (drug therapy, virology)
• HIV Integrase (chemistry, genetics)
• HIV Integrase Inhibitors (pharmacology)
• HIV-2 (drug effects, genetics)
• Heterocyclic Compounds, 3-Ring
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Male
• Middle Aged
• Phenotype
• Piperazines
• Pyridones
• Sequence Analysis, Protein