CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

assay measuring fold-change (FC) values with respect to the NL4-3 virus. Patient demographics and laboratory data were described by median (Q1-Q3) or frequency (%). Statistical analysis included Mann-Whitney and Spearman correlation tests. Results: Overall, 18 (90%) patients were male, median age 51 years (43-53), time since HIV-1 diagnosis 22 years (18-26), time on ART 19 years (16-22), 11 (55%) with a previous AIDS diagnosis, median viral load (VL) 4.42 log 10 copies/ mL (3.36-5.15) and median CD4+ cell count 195 cells/µL (75-278); 11 patients (55%) were receiving NNRTI (ETR=10, RPV=1), while 7 (35%), 5 (25%), 8 (40%) patients had been exposed to 1, 2 and 3 NNRTI, respectively, with a median time of exposure to NNRTI of 1529 days (353-2169). Globally, median DOR FC was 9.8 (1.8-65.7), while FC were 17.9 (7.4-80.1) and 3.7 (0.7-53.5)(p=0.105) in patients with and without current NNRTI pressure, respectively. According to Stanford HIVdb algorithm, intermediate to high-level resistance to DOR was predicted in 13/20 (65%) cases. DOR FC values correlated with the number of NNRTI mutations (r = 0.548; p=0.010) and with the DOR resistance level by HIVdb algorithm (r = 0.754; p=0.0001) but not with the number of previously experienced NNRTI (r = -0.167; p=0.483), VL (r = -0.121; p=0.612), time of exposure to NNRTI (r = 0.044; p=0.855) or time elapsed since last exposure to NNRTI (r = -0.330; p=0.155). Median DOR FC values were significantly higher in viruses harbouring major DOR RAMs according to both HIVdb (FC 100 [41.9-100] vs. 6.2 [1.2-17.2], p=0.003) and IAS-USA lists (FC 100 [38.4-100] vs. 6.2 [1.2- 20.2], p=0.007). However, both Stanford low-level and intermediate resistance groups included FC values spanning >1 log. Conclusion: DOR activity decreases with increasing number of NNRTI mutations and is inferred with fair accuracy by HIVdb and the IAS list, independently from the extent and time of NNRTI exposure. 532 HIV A1 OR B DO NOT DIFFERENTIALLY IMPACT CABOTEGRAVIR IN VITRO POTENCY OR DURABILITY Jerry Jeffrey 1 , Marty St Clair 1 , Ping Wang 1 , Chunfu Wang 2 , Zhufang Li 2 , Robert Fridell 2 , Mark Krystal 2 , Jan Van Lunzen 3 , Sandy Griffith 1 , Ronald D’Amico 1 , David A. Margolis 1 , Kim Smith 1 , William Spreen 1 1 ViiV Healthcare, Research Triangle Park, NC, USA, 2 ViiV Healthcare, Branford, CT, USA, 3 ViiV Healthcare, London, UK Background: The Phase 3 FLAIR study evaluates monthly i.m. Long Acting (LA) cabotegravir (CAB) and rilpivirine (RPV) as maintenance therapy in suppressed HIV infected adults over 48 weeks and demonstrated non-inferiority to 3 drug daily oral ART. A total of 3/283 (1%) participants (PTS) who received CAB+RPV LA had confirmed virologic failure (CVF). All 3 CVFs occurred among 8 PTS in that study armwith subtype A1 virus and all 3 had baseline integrase (IN) substitution L74I, as did 2/5 PTS who maintained viral suppression. All 8 PTS with subtype A1 virus were sensitive to CAB at baseline. 174/283 (61%) PTS in the LA arm had subtype B, 7%with L74I without CVF. Given the apparent clustering of CVF among A1 and presence of L74I, we sought to determine the impact of L74I and subtype A1 compared to subtype B IN on CAB sensitivity. Methods: IN genotypes and phenotypic sensitivity to CAB were generated at Monogram Biosciences. Site directed mutants were generated in subtype B NL4-3 and a consensus A1 IN sequence derived from the 3 CVF baseline IN sequences. In vitro susceptibility to CAB was assayed and compared across virus subtypes. The in vitro durability of CAB was tested against bulk infected cultures at various CAB concentrations for 3 weeks. Results: All baseline, A1 IN sequences (8/283 subjects) were sensitive to CAB with IC 50 fold-change (FC) ranging from 0.7-1. The 3 CVF sequences at the failure timepoint had CAB FC IC 50 values of 5.22 – 9.36 and substitutions at L74I and G140R or Q148R. The site-directed mutants L74I/G140R (FC 0.87 A1 vs 0.58 B) or L74I/Q148R (FC 4.1 A1 vs 4.4 B) in the A1 background resulted in similar IC 50 FC compared to subtype B background. Across both subtypes, time to viral breakthrough was similar at the lowest CAB concentration (1nM) and no viral breakthrough was detected at 3 weeks for CAB concentrations of 5nM or 410nM (1xPAEC 90 ). The genotypes of the breakthrough viruses will be presented. Conclusion: The FLAIR study demonstrated CAB+RPV LA was noninferior to oral ART at Week 48 with 3 CVFs harboring HIV subtype A1 with baseline L74I. In vitro virologic assessments do not indicate a differential sensitivity to CAB between subtypes A1 or B in viruses containing IN mutations observed in the CVFs. However, our evaluations cannot determine if HIV subtype A1 with L74I has greater likelihood of selection of additional INSTI mutations under selection pressure. Other factors may contribute to the risk of CVF and require further investigation.

1 Assistance Publique – Hôpitaux de Paris, Paris, France, 2 INSERM, Paris, France Background: Management of HIV-2 infection is hampered by the limited number of active ARV drugs and the rapid acquisition of drug resistance- associated mutations (DRAMs). There is still a strong need for new ARV effective on HIV-2, especially for patients infected by multi-drug resistant viruses. GS-9131 is the prodrug of GS-9148, a new NRTI with low potential for mitochondrial toxicity and renal accumulation that previously demonstrated its in vitro efficacy against wild-type (WT) and NRTI-mutant HIV-1 isolates, except those harbouring the Q151M complex. Here, we report GS-9131 antiviral activity on HIV-2 clinical isolates. Methods: Phenotypic susceptibility to GS-9131 was assessed for 13 HIV-2 isolates, and references strains of HIV-1 (BRU) and HIV-2 (ROD), using the ANRS assay. Briefly, viruses were cultured without GS-9131 and with 6 dilutions of the drug, ranging from 6250 to 0.002 nM. At days 3 or 4, viral replication was assessed by RT-PCR on the supernatant. All but one of the 13 HIV-2 isolates exhibited major DRAMs in the reverse transcriptase gene (K65R, Q151M, M184V and/or S215Y/F), according to the ANRS list (Table). Results: GS-9131 exhibited a potent activity against WT HIV-2 isolates (IC 50 = 3.4 and 4.4 nM). The sole presence of K65R mutation or M184V mutation increased the IC 50 for GS-9131 (12.0 and 27.0 nM for K65R, and 16.6 nM for M184V). GS-9131 had a lower activity on 2 isolates displaying a combination of 2 DRAMs (K65R+M184V and M184V+S215Y, IC 50 = 108 and 134 nM, respectively). All isolates harbouring a Q151Mmutation were highly resistant to GS-9131 (with IC 50 ranging from 178 to >6250 nM), regardless of associated-NRTI mutations. Conclusion: GS-9131 exhibits potent in vitro activity against WT HIV-2 isolates. Regarding the 3 main resistance genotypic profiles described in HIV-2-infected patients failing NRTI-based regimens (K65R, Q151M and M184V), our data showed that isolates harbouring only K65R or M184V mutations presented moderate increases in IC 50 for GS-9131, while the presence of a Q151Mmutation rendered HIV-2 isolates highly resistant to GS-9131. These in vitro data suggest that GS-9131 might offer an attractive, new therapeutic opportunity for persons living with HIV-2, either at initiation of antiretroviral therapy or for second-line regimens, as it retained potential for some activity against K65R and M184V mutants.

Poster Abstracts

531 PHENOTYPIC DORAVIRINE SUSCEPTIBILITY AFTER NNRTI EXPOSURE IN THE PRESTIGIO REGISTRY Francesco Saladini 1 , Federica Giammarino 1 , Franco Maggiolo 2 , Micol Ferrara 3 , Giovanni Cenderello 4 , Benedetto Maurizio Celesia 5 , Ferdinando Martellotta 6 , Vincenzo Spagnuolo 7 , Giulio Maria Corbelli 6 , Nicola Gianotti 8 , Maria M. Santoro 9 , Stefano Rusconi 10 , Maurizio Zazzi 1 , Antonella Castagna 7 , for the PRESTIGIO STUDY GROUP 1 University of Siena, Siena, Italy, 2 Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy, 3 Amedeo di Savoia Hospital, Torino, Italy, 4 Galliera Hospital, Genoa, Italy, 5 Garibaldi Hospital, Catania, Italy, 6 Centro di Riferimento Oncologico di Aviano, Aviano, Italy, 7 San Raffaele Vita-Salute University, Milan, Italy, 8 San Raffaele Scientific Institute, Milan, Italy, 9 University of Rome Tor Vergata, Rome, Italy, 10 Luigi Sacco University Hospital, Milan, Italy Background: Doravirine (DOR) is an NNRTI recently licensed for first-line ART showing superior genetic barrier to resistance and partial cross-resistance with older NNRTI. We investigated susceptibility to DOR in patients with documented 4-class drug-resistance to NRTI, NNRTI, PI, INSTI (4CR), enrolled in the Italian PRESTIGIO Registry. Methods: Recombinant HIV-1 expressing patient derived PR-RT were generated from plasma samples from 20 4CR patients failing ART. In vitro susceptibility to DOR was assessed through a TZM-bl cell based phenotypic

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