CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

561 IBALIZUMAB SUSCEPTIBILITY IN PATIENT HIV ISOLATES RESISTANT TO ANTIRETROVIRALS Steven Weinheimer 1 , Zvi Cohen 2 , Christian Marsolais 2 , Stanley Lewis 1 1 TaiMed Biologics USA, Irvine, CA, USA, 2 Theratechnologies, Inc, Montreal, QC, Canada Background: Ibalizumab (IBA) is a long-acting humanized IgG4 monoclonal antibody that blocks HIV entry into CD4 cells while preserving normal immunological function. IBA binds to domain 2 of the CD4 receptor, away from the MHC II binding site. IBA susceptibility of patient isolates was determined at Baseline for a 24-week, Phase 3 clinical trial (TMB-301) conducted in 40 heavily treatment-experienced patients with multi-drug resistant HIV-1. Susceptibility was compared for isolates that were sensitive and resistant to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), enfuvirtide (ENF) and maraviroc (MVC). Methods: Maximum Percent Inhibition (MPI) and ICHalfMax Fold Change (ICHMFC) from the dose-response curve were monitored as indicators of IBA susceptibility using the PhenoSense HIV Entry assay. MPI is the maximum level of inhibition achieved and ICHMFC occurs at the midpoint of the dose response curve. Results: IBA susceptibility at Baseline was determined for 38 of 40 patient isolates. The mean IBA MPI at Baseline was 91±14 (median of 97). Twenty-seven samples had MPI values of 90-100%, 6 had MPI values of 80-90%, and 5 had MPI values <80%. The mean ICHMFC was 1.2 ± 0.9 (median of 0.9). The mean IBA MPI for patient HIV isolates with wild-type susceptibility to NRTIs, NNRTIs, PIs, or INIs, was 81%, 98%, 89%, and 91%, respectively; the mean ICHMFC was 1.3, 0.9, 1.1, and 1.0, respectively. For isolates that were resistant to all NRTIs, NNRTIs, PIs, or INIs, the mean IBA MPI was 94%, 91%, 91%, and 92%, respectively; the mean ICHMFC was 1.2, 1.2, 1.3, and 1.1, respectively. 6 patients had HIV with reduced susceptibility to ENF at screening. 5 of these had IBA MPI values 84-99%with ICHMFC values 0.7-1.4, while 1 had HIV with reduced IBA susceptibility (MPI = 41%, ICHMFC = 6.2). Two patient isolates exhibited CCR5-dependent replication with reduced susceptibility to MVC – one was CCR5 tropic with MVC MPI = 58% and one was dual-mixed (DM) tropic with MVC MPI <0 . Both isolates were susceptible to inhibition by IBA with MPI = 94% and 100%, respectively. The mean MPI for CCR5, DM, and CXCR4 tropic isolates was 89%, 91%, and 92%, respectively. Conclusion: IBA is effective despite resistance to other antiretrovirals. The present in vitro IBA susceptibility results correlate with the efficacy observed in the Phase 3 trial 7 days after functional monotherapy. 562 RPV LA DOES NOT INHIBIT RESISTANT HIV TRANSMISSION OR SELECT SIGNIFICANT RESISTANCE Zandrea Ambrose 1 , Kevin Melody 1 , Chris Kline 1 , Mackenzie L. Cottrell 2 , Brandon Keele 3 , Angela Kashuba 2 , Moses Bility 1 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 University of North Carolina Chapel Hill, Chapel Hill, NC, USA, 3 Leidos Biomedical Research, Inc, Frederick, MD, USA Background: Long-acting rilpivirine (RPV LA) has been proposed for use as pre-exposure prophylaxis (PrEP) and the prevalence of transmitted RPV- resistant viruses can be relatively high in some populations. We studied how effectively RPV LA could inhibit vaginal transmission of WT HIV-1 as well as two RPV-resistant mutants. Methods: Plasma and female genital tract (FGT) RPV pharmacokinetics were determined after a single dose of RPV LA in female humanized BLT mice. Vaginal virus challenges of WT, Y181C, and Y181V HIV-1 were performed in untreated animals and after RPV PrEP when plasma and FGT concentrations were either at biologically relevant (low) or 7- to 9-fold higher (high) concentrations (n=6-10 per group). Quantitative RT-PCR was used measure plasma viremia in the mice until 10 weeks post-challenge. Single-genome sequencing of the reverse transcriptase coding region was performed on plasma HIV-1 RNA in mice infected during PrEP treatment. Results: Y181C HIV-1 conferred 2-fold resistance and Y181V HIV-1 conferred 30-fold resistance to RPV in vitro. High RPV concentrations delayed dissemination of a highly infectious WT HIV-1 clone (p>0.05) and completely inhibited Y181C HIV-1 (p=0.02). However, high RPV concentrations did not inhibit Y181V HIV-1. Biologically relevant RPV concentrations did not significantly inhibit vaginal transmission of WT or Y181C HIV-1. Newmutations

drug susceptibility to DRV, thus, demonstrating a direct linkage between Gag mutations and drug resistance to PIs. Conclusion: These data define a novel set of Gag signature mutations involved in PIs resistance and identify Gag as a direct contributor to PI resistance in the absence of mutations in the Protease. These findings are crucial for the optimization of genotypic tools to identify VF to PIs in the absence of Protease mutations. Additional studies in non-B clade virus would be essential to extend our findings to other HIV-1 subtypes. 560 ACTIVITY OF TENOFOVIR ALAFENAMIDE IN HIV-1 WITH THYMIDINE ANALOG MUTATIONS AND M184V Nicolas A. Margot , Renee R. Ram, Michael E. Abram, Richard Haubrich, Michael D. Miller, Christian Callebaut Gilead Sciences, Inc, Foster City, CA, USA Background: Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor tenofovir (TFV). In vivo, TAF achieves ~4-fold higher intracellular levels of TFV diphosphate (TFV-DP) compared to TDF. Thymidine analog mutations in HIV-1 (TAMs) confer incremental reduced susceptibility to TFV, and patients with TAM-containing HIV-1 may benefit from higher levels of TFV-DP delivered by TAF. Moreover, the presence of the M184V mutation increases susceptibility to TFV during TDF or TAF-based therapy. Virologic outcome of subjects harboring HIV with M184V/I are currently being studied clinically (GS-US-292-1824). Here, the in vitro activity of TAF was evaluated in a large set of TAM-containing HIV-1, with or without M184V. Methods: Site-directed mutants (SDM) containing combinations of TAMs (M41L, D67N, K70R, L210W, T215Y, and/or K219Q) with or without M184V were generated. Antiviral drug susceptibilities (fold change [FC] EC50 relative to wild- type) were determined in MT-2 cells using either a 2-day Single-Cycle (SC; n=96) or 5-day Multi-Cycle (MC; n=96) PR-RT HIV assay. Patient-derived (PD; n=14) mutants with TAMs were tested using the MC assay. Comparison of TAF and TFV resistance profiles were further assessed in viral breakthrough (VB) experiments mimicking clinically relevant drug concentrations using TAM-containing viruses (SDM and PD). Results: The presence of M184V in TAM-containing HIV-1 SDMs (n=48) significantly increased sensitivity to TAF in both SC and MC assays compared to TAM SDMs without M184V (n=48) (Table) (Mann-Whitney test: p-value of 0.005 and 0.003 for the SC and MC assays, respectively). The mean TAF FC for PD viruses (with or without M184V) was 3.8 (ranging from 1.4 to 14.6). FC resistance for TAF and TFV in MC assay showed a strong 1:1 correlation (r2=0.93). A total of 68 mutants (54 SDM and 14 PD) were assayed at physiological concentration in VB experiments, with 15 mutants breaking through under TFV treatment (average FC of 5.1; 3 to 6 TAMs ±M184V) and only 3 mutants breaking through under TAF treatment (average FC of 9.9; 5 TAMs without M184V). Conclusion: In the presence of M184V, the antiviral activity of TAF was increased in HIV-1 mutants harboring TAMs, similarly to TFV. However, in VB assay mimicking the 4-fold higher intracellular levels of TFV-DP delivered by TAF compared to TDF in vivo, TAF inhibited viral breakthrough of TAMs-containing HIV-1 that were not inhibited by TFV.

Poster Abstracts

CROI 2018 206