Journal of Global Antimicrobial Resistance (Dec 2022)

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

Journal volume & issue
Vol. 31
pp. 323 – 327

Abstract

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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.

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