TY - JOUR
T1 - HIV-1 resistance against dolutegravir fluctuates rapidly alongside erratic treatment adherence
T2 - a case report
AU - van Kampen, Jeroen J.A.
AU - Pham, Hanh Thi
AU - Yoo, Sunbin
AU - Overmars, Ronald J.
AU - Lungu, Cynthia
AU - Mahmud, Rizwan
AU - Schurink, Carolina A.M.
AU - van Boheemen, Sander
AU - Gruters, Rob A.
AU - Fraaij, Pieter L.A.
AU - Burger, David M.
AU - Voermans, Jolanda J.C.
AU - Rokx, Casper
AU - van de Vijver, David A.M.C.
AU - Mesplède, Thibault
N1 - 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)
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85142189584&partnerID=8YFLogxK
U2 - 10.1016/j.jgar.2022.11.001
DO - 10.1016/j.jgar.2022.11.001
M3 - Article
C2 - 36347497
AN - SCOPUS:85142189584
SN - 2213-7165
VL - 31
SP - 323
EP - 327
JO - Journal of Global Antimicrobial Resistance
JF - Journal of Global Antimicrobial Resistance
ER -
