High-level dolutegravir resistance can emerge rapidly from few variants and spread by recombination: implications for integrase strand transfer inhibitor salvage therapy.
Drug Resistance, Viral
/ genetics
HIV Infections
/ drug therapy
HIV Integrase
/ genetics
HIV Integrase Inhibitors
/ pharmacology
HIV-1
/ genetics
Heterocyclic Compounds, 3-Ring
/ pharmacology
Humans
Mutation
Oxazines
Piperazines
Pyridones
/ therapeutic use
Quinolones
/ pharmacology
Recombination, Genetic
Salvage Therapy
Journal
AIDS (London, England)
ISSN: 1473-5571
Titre abrégé: AIDS
Pays: England
ID NLM: 8710219
Informations de publication
Date de publication:
01 11 2022
01 11 2022
Historique:
pubmed:
19
7
2022
medline:
1
10
2022
entrez:
18
7
2022
Statut:
ppublish
Résumé
The integrase strand transfer inhibitor (INSTI) dolutegravir is commonly used in combination antiretroviral therapy regimens and retains strong potency even with primary resistance mutations to some other INSTIs. Acquisition of accessory mutations to primary mutations results in significant increases in dolutegravir resistance. Previously, we reported that addition of the secondary mutation T97A can result in rapid treatment failure in individuals with INSTI mutations at positions 140 and 148. Here, we conducted a detailed case study of one of these individuals and find that T97A-containing HIV emerged from a large replicating population from only a few (≤4) viral lineages. When combined with primary INSTI resistance mutations, T97A provides a strong selective advantage; the finding that T97A-containing variants spread by replication and recombination, and persisted for months after discontinuing dolutegravir, has important implications as dolutegravir is rolled out worldwide.
Identifiants
pubmed: 35848510
doi: 10.1097/QAD.0000000000003288
pii: 00002030-202211010-00011
pmc: PMC9594130
doi:
Substances chimiques
HIV Integrase Inhibitors
0
Heterocyclic Compounds, 3-Ring
0
Oxazines
0
Piperazines
0
Pyridones
0
Quinolones
0
dolutegravir
DKO1W9H7M1
HIV Integrase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1835-1840Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC010819
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
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