Susceptibility to HIV-1 integrase strand transfer inhibitors (INSTIs) in highly treatment-experienced patients failing an INSTI-based regimen

Abstract The goal 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 have failed twice daily raltegravir (RAL)- or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced HIV-1 infected patients with multi-drug resistant virus and recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, South San Francisco, CA). The primary INSTI-resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H, and N155H were detected in 14/22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11/22 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 8/14 isolates for BIC and 9/14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median (range) fold-change in phenotypic susceptibility was: BIC 3.2 (0.6, 66), DTG 6.3 (0.8, >186), EVG >164 (2.6, >164), and RAL >188 (2.7, >197). In conclusion, our findings supported the in vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients failing INSTI regimens.