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

Jeroen J.A. van Kampen, Hanh Thi Pham, Sunbin Yoo, Ronald J. Overmars, Cynthia Lungu, Rizwan Mahmud, Carolina A.M. Schurink, Sander van Boheemen, Rob A. Gruters, Pieter L.A. Fraaij, David M. Burger, Jolanda J.C. Voermans, Casper Rokx, David A.M.C. van de Vijver, Thibault Mesplède*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)323-327
Number of pages5
JournalJournal of Global Antimicrobial Resistance
Volume31
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by the Canadian Institutes for Health Research [grant number HB1 164063] and the National Institute of Allergy and Infectious Diseases [grant number R01AI147330]. The funding sources played no role in the collection and analysis of the data, writing of the report, or decision to publish.

Publisher Copyright:© 2022 The Author(s)

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