TY - JOUR
T1 - Susceptibility to HIV-1 integrase strand transfer inhibitors (INSTIs) in highly treatment-experienced patients who failed an INSTI-based regimen
AU - for the PRESTIGIO Study Group
AU - Santoro, Maria M.
AU - Fornabaio, Chiara
AU - Malena, Marina
AU - Galli, Laura
AU - Poli, Andrea
AU - Menozzi, Marianna
AU - Zazzi, Maurizio
AU - White, Kirsten L.
AU - Castagna, Antonella
N1 - Funding Information:
Funding: The Monogram analyses were funded by Gilead Sciences, Inc. The PRESTIGIO registry is supported by ViiV Healthcare.
Publisher Copyright:
© 2020 Elsevier B.V. and International Society of Chemotherapy
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6–66], DTG 6.3 (IQR 0.8–>186), EVG >164 (IQR 2.6–>164) and RAL >188 (IQR 2.7–>197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.
AB - The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6–66], DTG 6.3 (IQR 0.8–>186), EVG >164 (IQR 2.6–>164) and RAL >188 (IQR 2.7–>197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.
KW - Antiretroviral therapy
KW - Drug resistance
KW - Drug susceptibility
KW - HIV
KW - Resistance phenotypes
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U2 - 10.1016/j.ijantimicag.2020.106027
DO - 10.1016/j.ijantimicag.2020.106027
M3 - Article
C2 - 32450199
AN - SCOPUS:85087208429
VL - 56
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
SN - 0924-8579
IS - 1
M1 - 106027
ER -