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J Antimicrob Chemother. 2016 Jul;71(7):1948-53. doi: 10.1093/jac/dkw071. Epub 2016 Mar 29.

Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors.

Author information

1
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
2
Clinique Médicale l'Actuel, Montreal, Quebec, Canada.
3
Infectious Disease and AIDS Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
4
Département de Microbiologie et d'Immunologie et Centre de Recherche du Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
5
Microbiology Department, Complejo Hospitalario Universitario Granada, Granada, Spain Hospital Universitario San Cecilio, Instituto de Investigación Ibs, Granada, Spain.
6
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada mark.wainberg@mcgill.ca.

Abstract

OBJECTIVES:

Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained.

PATIENT AND METHODS:

Genotypic analysis was performed on patients with virological failure (<1000 copies/mL) on dolutegravir-containing regimens. The Los Alamos database was queried for glycine codon 118 polymorphisms. Cell culture selections and phenotypic drug susceptibility assays assessed resistance via the G118R pathway.

RESULTS:

We report on two patients who developed viral failure while on dolutegravir monotherapy. Both patients had been on a current or previous regimen containing integrase inhibitors. Virological failure (<1000 copies/mL) emerged early within 2 months following the dolutegravir switch. The appearance of G118R in these two cases and subtype C and CRF02_AG in vitro selections were related to a rare GGA natural polymorphism at codon 118 (1.5% prevalence), facilitating a GGA to AGA transition. Cell culture selections were used to assess the in vitro progression of the G118R pathway leading to cross-resistance to all integrase inhibitors.

CONCLUSIONS:

Although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R.

PMID:
27029845
PMCID:
PMC4896408
DOI:
10.1093/jac/dkw071
[Indexed for MEDLINE]
Free PMC Article

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