HIV-1 resistance against dolutegravir fluctuates rapidly alongside erratic treatment adherence: a case report.

Autor: van Kampen JJA; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Pham HT; Department of Microbiology and Immunology, McGill University, Canada., Yoo S; Department of Microbiology and Immunology, McGill University, Canada., Overmars RJ; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Lungu C; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Mahmud R; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Schurink CAM; Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands., van Boheemen S; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Gruters RA; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Fraaij PLA; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Pediatrics, Subdivision Infectious Diseases and Immunology, Sophia's Children Hospital, Erasmus Medical Center, Rotterdam, The Netherlands., Burger DM; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Voermans JJC; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Rokx C; Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands., van de Vijver DAMC; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands., Mesplède T; Viroscience department, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: t.mesplede@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Journal of global antimicrobial resistance [J Glob Antimicrob Resist] 2022 Dec; Vol. 31, pp. 323-327. Date of Electronic Publication: 2022 Nov 05.
DOI: 10.1016/j.jgar.2022.11.001
Abstrakt: Objectives: We report a case of incomplete HIV-1 suppression on a dolutegravir, lamivudine, and abacavir single-tablet regimen with the emergence of the H51Y and G118R integrase resistance mutations.
Methods: Integrase sequencing was performed retrospectively by Sanger and next-generation sequencing. Rates of emergence and decline of resistance mutations were calculated using next-generation sequencing data. Dolutegravir plasma concentrations were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The effects of H51Y and G118R on infectivity, fitness, and susceptibility to dolutegravir were quantified using cell-based assays.
Results: During periods of non-adherence to treatment, mutations were retrospectively documented only by next-generation sequencing. Misdiagnosis by Sanger sequencing was caused by the rapid decline of mutant strains within the retroviral population. This observation was also true for a M184V lamivudine-resistant reverse transcriptase mutation found in association with integrase mutations on single HIV genomes. Resistance rebound upon treatment re-initiation was swift (>8000 copies per day). Next-generation sequencing indicated cumulative adherence to treatment. Compared to WT HIV-1, relative infectivity was 73%, 38%, and 43%; relative fitness was 100%, 35%, and 10% for H51Y, G118R, and H51Y+G118R viruses, respectively. H51Y did not change the susceptibility to dolutegravir, but G188R and H51Y+G118R conferred 7- and 28-fold resistance, respectively.
Conclusion: This case illustrates how poorly-fit drug-resistant viruses wax and wane alongside erratic treatment adherence and are easily misdiagnosed by Sanger sequencing. We recommend next-generation sequencing to improve the clinical management of incomplete virological suppression with dolutegravir.
Competing Interests: Competing interests None declared
(Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: