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.
Adult
Amides
Anti-Retroviral Agents
/ therapeutic use
Drug Resistance, Viral
Female
HIV Infections
/ drug therapy
HIV Integrase
/ chemistry
HIV Integrase Inhibitors
/ pharmacology
HIV-2
/ drug effects
Heterocyclic Compounds, 3-Ring
Heterocyclic Compounds, 4 or More Rings
/ pharmacology
Humans
Male
Middle Aged
Phenotype
Piperazines
Pyridones
Sequence Analysis, Protein
HIV-2
bictegravir
insertion
integrase inhibitor
phenotypic resistance
Journal
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
30
08
2018
accepted:
30
10
2018
pubmed:
2
11
2018
medline:
17
6
2020
entrez:
2
11
2018
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 30383215
pii: 5153362
doi: 10.1093/cid/ciy940
doi:
Substances chimiques
Amides
0
Anti-Retroviral Agents
0
HIV Integrase Inhibitors
0
Heterocyclic Compounds, 3-Ring
0
Heterocyclic Compounds, 4 or More Rings
0
Piperazines
0
Pyridones
0
bictegravir
8GB79LOJ07
HIV Integrase
EC 2.7.7.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
657-667Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.