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

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 de-cline 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 sin-gle HIV genomes. Resistance rebound upon treatment re-initiation was swift ( > 80 0 0 copies per day). Next-generation sequencing indicated cumulative adherence to treatment. Compared to WT HIV-1, rel-ative 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.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Automated summary

This study reports a case of incomplete HIV-1 suppression and emergence of integrase resistance mutations in a patient on a dolutegravir-based regimen. Next-generation sequencing revealed the dynamics of resistance mutations and cumulative treatment adherence. Next-generation sequencing is recommended for clinical management of incomplete virological suppression.