title: Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome.
abstract: T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.4%; 47 of 3367 integrase sequences); most often among non-B (5.3%) than B (0.9%) HIV-1 subtypes. During INSTI-based therapy, few patients experienced virologic failure with emergent INSTI RAMs (3%; 122 of 3881 patients), among whom T97A emerged infrequently in the presence (n = 6) or absence (n = 8) of primary INSTI RAMs. A comparison between pre-existing and emergent T97A patient populations (i.e., in the absence of primary INSTI RAMs) showed no significant differences in EVG or RAL susceptibility in vitro. Furthermore, among all T97A-containing viruses tested, only 38-44% exhibited reduced susceptibility to EVG and/or RAL (all of low magnitude; <11-fold), while all maintained susceptibility to dolutegravir. Of the patients with pre-existing T97A, 17 had available clinical follow-up: 16 achieved virologic suppression and 1 maintained T97A and INSTI sensitivity without further resistance development. Overall, T97A is an infrequent integrase polymorphism that is enriched among non-B HIV-1 subtypes and can confer low-level reduced susceptibility to EVG and/or RAL. However, detection of T97A does not affect response to INSTI-based therapy with EVG or RAL. These results suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing T97A.
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Michael E
authors.identifier: http://orcid.org/0000-0002-2341-5319
authors.initials: ME
authors.lastname: Abram
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Renee R
authors.initials: RR
authors.lastname: Ram
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Margot
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Barnes
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: White
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
mesh_terms: D003062:Codon / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D009154:Mutation; D010641:Phenotype; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D000068898:Raltegravir Potassium / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D003062:Codon; D019428:HIV Integrase Inhibitors; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1