CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

a INI-based regimen, cumulative ART exposure, previous ART and reasons for switching, being naïve. Conclusion: Despite the low incidence of VF with INI-based regimen, DRMs, HIV subtype and zenith HIV-RNA still suggest caution in prescribing INI-based regimens. 548 GENOTYPIC AND PHENOTYPIC SUSCEPTIBILITY TO FOSTEMSAVIR IN MULTIDRUG-RESISTANT HIV-1 Francesco Saladini 1 , Alessia Giannini 1 , Franco Maggiolo 2 , Francesca Vichi 3 , Giulio M. Corbelli 4 , Andrea Galli 5 , Alba Bigoloni 5 , Maria M. Santoro 6 , Maurizio Zazzi 1 , Antonella Castagna 5 , for the PRESTIGIO Study Group 1 University of Siena, Siena, Italy, 2 Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy, 3 Santa Maria Annunziata Hospital, Florence, Italy, 4 Plus Onlus, Bologna, Italy, 5 San Raffaele Scientific Institute, Milan, Italy, 6 University of Rome Tor Vergata, Rome, Italy Background: Fostemsavir (FTR) is a prodrug of the investigational HIV-1 attachment inhibitor temsavir (TMR) currently under evaluation for the treatment of highly experienced patients with limited treatment options. This study aims to characterize the genotypic profile and the phenotypic susceptibility to TMR in a panel of samples collected from patients harboring multi resistant HIV-1 enrolled in the Italian PRESTIGIO cohort and potentially candidate for FTR treatment. Methods: Plasma samples from 24 patients included in the PRESTIGIO cohort were used for the sequencing of gp120 region, while viral tropism and susceptibility to TMR were assessed through a home-made phenotypic assay involving pseudotyped viruses expressing patient derived Env protein. Patient demographics and laboratory data are described as median (Q1-Q3), mean (±SD) or frequency (%). Results: Among 24 patients, 18 (75%) were male, median age 54 years (52-59), time since HIV-1 diagnosis 26 years (24-29), time on ART 25 years (22-26), 11 (46%) with a previous AIDS diagnosis, a median viral load at first sample collection of 3.87 log10 copies/mL (3.1-5.0) and a median CD4+ cell count of 242 cells/µl (137-387). At the time of sample collection, 12 (50%) were receiving entry inhibitors (MVC and/or T-20). Among 21/24 (88%) gp120 sequences obtained, all belonged to subtype B and TMR RAMs (L116P, A204D, S375M/H/N, M426L, M434I, M475I) were detected in only 3 cases (13%), two 426L and one 375N. Viral tropismwas X4, R5, and dual-mixed (DM) in 8, 9 and 7 out of 24 cases, respectively. Pseudotyped viruses were obtained from 23/24 samples and median IC50 to TMR was 0.5 nM (0.3-1.2). The reference wild-type viruses NL4-3 (X4), AD8 (R5) had mean IC50 of 1.1±0.6 nM and 1.3±0.7 nM, respectively, while the two samples harboring RAM 426L (both X4-tropic) had mean IC50 of 6.9±2.9 nM and 1110.6±798.2 nM, resulting in FC values of 6.2 and 1009, respectively. According to viral tropism, median IC50 values were 1.2 nM (0.4-4.2), 0.4 nM (0.3-1.2) and 0.6 nM (0.3-0.8) for X4, R5 and DM viruses, respectively. Concomitant use of MVC or T-20 also did not impact TMR IC50 values. Conclusion: In this study, TMR RAMs were detected in 3/21 samples and the polymorphic RAMM426L was associated with variable reduction of TMR susceptibility. Except for viruses harboring M426L, the susceptibility to TMR was comparable to wild-type strains in all the samples, irrespective of coreceptor usage or exposure to other entry inhibitors. 549 IN VITRO ACTIVITY OF DTG/BIC/E/CAB ON FIRST-GENERATION InSTI- RESISTANT HIV-1 Francesco Saladini , Alessia Giannini, Adele Boccuto, Filippo Dragoni, Alice Appendino, Edoardo Albanesi, Ilaria Vicenti, Maurizio Zazzi University of Siena, Siena, Italy Background: Exposure to INSTIs raltegravir (RAL) or elvitegravir (EVG) is frequently associated with the selection of RAMs at virological failure. This study aimed to assess cross-resistance to dolutegravir (DTG), bictegravir (BIC) and the investigational INSTI cabotegravir (CAB). Methods: Plasma samples from 19 patients harbouring major INSTI mutations (T66A/I/K, E92Q, G118R, E138A/K/T, G140A/C7S, Y143C/H/R, S147G, Q148H/K/R, N155H, R263K) were used for the generation of recombinant viruses containing the patient derived integrase coding region. In vitro susceptibility to DTG, BIC and CAB was determined in a phenotypic assay as fold change (FC) with respect to the reference isolate. Laboratory data are described as median (IQR1-IQR3). Results: Samples were collected from patients exposed to RAL only, EVG only, RAL and EVG, and RAL and DTG in 9, 4, 1 and 5 cases, respectively. Globally,

median FC for DTG, BIC and CAB were 3.5 (1.2-7.3), 2.4 (1.4-5.4) and 2.3 (1.3-21.7), respectively. Median DTG, BIC and CAB FC values from patients not exposed to DTG were 2.9 (1.0-4.4), 2.1 (1.3-3.3) and 2.3 (1.2-4.7), respectively, while exposure to RAL and then DTG resulted in FC >100 in three cases (Q148+2 INSTIs RAMs) and FC <3.5 in two cases (samples with E92Q and with R263K) for all drugs. Median DTG, BIC and CAB FC values were higher following exposure to RAL only vs. EVG only (3.5 [1.6-5.9], 2.4 [1.6-3.9], 2.3 [1.4-12.3] vs. 1.1 [0.8-3.6], 1.8 [0.3-3.3], 1.6 [0.8-8.0], respectively). According to the three major INSTI resistance pathways, median DTG, BIC and CAB FC values were 2.3 (1.0-3.5), 2.5 (2.4-2.5), 1.7 (1.2-2.2), respectively, with Y143R/C alone (n=2); 3.6 (2.6-4.4), 1.8 (1.7-2.7) and 2.3 (1.5-2.6) with N155H alone (n=6); 0.5, 0.8, and 1.2 with Q148R alone (n=1); 7.3 (1.0-8.0), 5.4 (3.2-8.0), 21.7 (9.9-66.3) with Q148R+1 additional INSTI RAM (n=3); and >100 for all the drugs with Q148H+2 additional INSTI RAMs (n=3). Among samples with other INSTIs RAMs (2 with E92Q, 1 with R263K and 1 with T66A+S147S/G), FC ≤3.5 were measured with all drugs. In particular, one sample from a failing DTG based regimen harboring 263K had DTG and CAB FC of 3.5, while BIC FC was 1.1. Conclusion: DTG, BIC and CAB retain comparable activity against major INSTIs RAMs, with the 148+1 or 2 additional INSTI RAMs resulting in substantially decreased susceptibility for all drugs. Consequent to selection of the 148 pathway, failing RAL appeared to compromise second generation INSTIs more than failing EVG in this dataset. 550 SUSCEPTIBILITY TO BICTEGRAVIR IN HIGHLY ARV-EXPERIENCED PATIENTS AFTER InSTI FAILURE Maria M. Santoro 1 , Chiara Fornabaio 2 , Marina Malena 3 , Laura Galli 4 , Andrea Poli 4 , Simone Marcotullio 5 , Marianna Menozzi 6 , Maurizio Zazzi 7 , Kirsten L. White 8 , Antonella Castagna 4 , for the PRESTIGIO Study Group 1 University of Rome Tor Vergata, Rome, Italy, 2 Istituti Ospedalieri di Cremona, Cremona, Italy, 3 Azienda ULSS 9 Scaligera, Verona, Italy, 4 San Raffaele Scientific Institute, Milan, Italy, 5 Associazione Nadir Onlus, Rome, Italy, 6 University of Modena and Reggio Emilia, Modena, Italy, 7 University of Siena, Siena, Italy, 8 Gilead Sciences, Inc, Foster City, CA, USA Background: Integrase strand transfer inhibitors (INSTIs) are a potent drug class. Bictegravir (BIC) has a favorable in vitro resistance profile with improved activity compared to all other INSTIs. Non-inferior efficacy with no resistance development was shown for BIC/emtricitabine/tenofovir alafenamide (B/F/TAF) in two studies in treatment naïve patients through Week 96 and in two switch studies in virologically suppressed patients through Week 48. The goal of this study was to characterize the genotypic and phenotypic resistance profile to BIC and other INSTIs in patients who have failed twice daily raltegravir (RAL)- or DTG-based regimens. Methods: This analysis used samples collected after failure on an INSTI-based regimen in 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 with individual INSTI resistance cutoffs defined separately by the assay. Patients’ demographics are described as median (Q1,Q3) or frequency (%). Results: Twenty-two samples from 17 patients were evaluated: 12 (71%) were male, median age 49 years (45, 53), time since HIV-1 diagnosis 20 years (Q1,Q3; 16, 25), time on ART 20 years (Q1,Q3; 16, 18), 10 (59%) with a previous AIDS diagnosis, median viral load at first sample collection of 4.5 log10 copies/ mL (4.1, 5.3) and median CD4+ cell count of 168 cells/µl (68, 439). The primary INSTI-resistance substitutions E138A/K, Y143C/H/R, Q148H, and N155H were found 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 resistance to EVG and RAL and two were resistant to BIC and DTG. The two isolates with resistance to BIC and DTG contained L74M, E138K, G140S, and Q148H or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H. 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 fold-change (range) values were: BIC 3.1 (0.6, 66), DTG 6.1 (0.8, >186), EVG >164 (2.6, >164), and RAL >188 (2.7, >197). Conclusion: In vitro, BIC retained activity against most isolates derived from patients failing INSTI regimens. These data support the study of BIC once-daily in patients with INSTI-resistance.

Poster Abstracts

CROI 2019 206