CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

482 FAVOURABLE OUTCOME OF IN VITRO SELECTIONS WITH NOVEL NRTI PRODRUG GS-9131 Ruxandra-Ilinca Ibanescu 1 , Maureen Oliveira 1 , Bonnie Spira 1 , Jean-Pierre Routy 2 , Bluma G. Brenner 2 , for the Montreal Primary HIV (PHI) Cohort Study Group 1 Lady Davis Institute for Medical Research, Montreal, QC, Canada, 2 McGill University, Montreal, QC, Canada Background: GS-9131 is an NRTI candidate for treatment of patients with resistance to other NRTIs. HIV reverse transcription is inhibited by GS-9131 by chain termination. In this study, we employed cell culture models to shed light on the ability of escape mutants to emerge under increasing drug pressure. Methods: Cord blood mononuclear cells (CBMC) and MT-2 cells were infected with clinical isolates and passaged in increasing concentrations of GS-9131 and tenofovir (TFV). Virus growth was monitored by weekly determinations of reverse transcriptase (RT) activity. For MT-2 cells, supernatants were collected at the peak of infection by cytopathic effect scoring. In order to identify alterations in the RT region, viral RNA was extracted from tissue culture supernatants and sequenced. Results: After 40 weeks of sustained drug treatment, none of the CBMC viral cultures tested yielded major resistance mutations. Despite the lack of changes in the RT region, most of the isolates were able to endure moderate to very high concentrations of the drugs, 500-20,000 -fold increase for GS-9131 and 100- 20,000 -fold for TDF. Using 3TC as a control, the M184I or V mutations rapidly arose in most viruses. Previous studies with GS-9148, for which GS-9131 is a pro- drug, were done in MT-2 cells, and some resistance patterns were identified. In our experiment using MT-2 cells, no major resistance pathways emerged. One isolate did select for the L187Mmutation, which was also identified in the previous study. Conclusion: Two methods were employed in order to obtain a better picture of the ability of GS-9131, a drug in development, to put pressure on viruses to escape. The lack of emergent variants indicates that GS-9131 is a promising antiretroviral for HIV treatment, which has also been shown to be suitable for individuals harbouring NRTI mutations. Its versatility for use in combination with other drugs may provide more precise and potent options to patients with limitations due to NRTI resistance. 483 LONG-TERM SAFETY & EFFICACY OF FOSTEMSAVIR IN TREATMENT- EXPERIENCED HIV PARTICIPANTS Melanie Thompson 1 , Fernando Mendo Urbina 2 , Gulam Latiff 3 , Sandra Trevino Perez 4 , Edwin DeJesus 5 , Natalia Zakharova 6 , Marcelo Martins 7 , Johannes Bogner 8 , Li Yi 9 , Amy Pierce 10 , Shiven Chabria 11 , Peter Ackerman 11 , Cyril Llamoso 11 , Max Lataillade 11 , for the 205889 Investigative Study Team 1 AIDS Research Consortium of Atlanta, Atlanta, GA, USA, 2 Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, 3 KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa, 4 Mexico Centre for Clinical Research, Mexico City, Mexico, 5 Orlando Clinical Research Center, Orlando, FL, USA, 6 Center of AIDS and Infectious Diseases Prevention and Treatment, St Petersburg, Russian Federation, 7 Instituto Oulton, Cordoba, Argentina, 8 University of Munich, Munich, Germany, 9 GlaxoSmithKline, Collegeville, PA, USA, 10 ViiV Healthcare, Research Triangle Park, NC, USA, 11 ViiV Healthcare, Branford, CT, USA Background: Fostemsavir (FTR) is an investigational first-in-class attachment inhibitor prodrug of temsavir (TMR). TMR binds to HIV-1, locking gp120 in a conformational state that prevents initial attachment to and infection of host immune cells. Study 205889 (AI438011, NCT01384734) is a recently completed Phase 2b dose-ranging trial in treatment-experienced (TE) HIV-1-infected participants. Herein, we present efficacy results through Week 192 (latest visit achievable by all participants prior to study conclusion) and cumulative safety data. Methods: TE adults (≥1-week of prior ART and naïve to integrase inhibitors) were randomized to 1 of 4 FTR arms (400 or 800mg BID; 600 or 1200mg QD) or reference (REF; atazanavir/ritonavir [ATV/r] 300/100mg QD), each with raltegravir (RAL, 400mg BID) and tenofovir (TDF, 300mg QD). After the Week 48 interim analysis, those randomized to FTR switched to open-label FTR at 1200mg QD with RAL+TDF. REF participants remained on ATV/r+RAL+TDF. Results: 251 adults were treated: 200 FTR, 51 REF. Median time on FTR was 4.5 years (max 5.6); 2.9 years for REF. Rates of virologic suppression (HIV-1 RNA <50 c/mL, Table 1) and mean improvement in baseline CD4 count (+279.9 and +263.7 cells/µl) were comparable between FTR and REF through Week 192. Most adverse events (AEs) were low-grade (Grade 1-2) in intensity. A greater

percentage of REF than FTR participants experienced Grade 2-4 AEs related to study drug or Grade 3-4 AEs (39% vs. 12%; 33% vs. 18% respectively). Fewer participants in the FTR arm had an AE leading to discontinuation (4% vs. 12% for REF). No participant discontinued due to a FTR-related AE. There were 3 drug-related SAEs (overdose in FTR arm, and overdose and influenza on REF). The most common drug-related AEs for FTR were headache (6%) and nausea (5%), and for REF were nausea, dizziness (8% each), and AEs related to bilirubin elevation (e.g., jaundice, scleral icterus; 8-18%). Conclusion: Among HIV-1-infected TE participants, FTR with RAL+TDF demonstrated favorable safety compared to ATV/r with RAL+TDF with lower cumulative rates of Grade 2-4 related AEs, Grade 3 4 AEs, and AEs leading to discontinuation despite longer median exposure (4.5 vs. 2.9 years). FTR had comparable rates of virologic suppression to ATV/r throughout 192 weeks.These results support the ongoing Phase 3 evaluation of FTR in heavily TE adults with limited therapeutic options (≤2 classes of ARVs remaining) due to resistance, tolerability issues or contraindications (NCT02362503).

Poster Abstracts

484 ACTIVITY OF ECD4-IG AGAINST CCR5 ANTAGONIST-RESISTANT HIV-1 Zixin Hu 1 , Phillip Tomezsko 2 , Matthew Gardner 3 , Michael Farzan 3 , Athe Tsibris 1 , Daniel R. Kuritzkes 1 1 Brigham and Women’s Hospital, Boston, MA, USA, 2 Harvard Medical School, Boston, MA, USA, 3 The Scripps Research Institute, La Jolla, CA, USA Background: The anti-HIV molecule eCD4-Ig targets CD4 and chemokine coreceptor binding sites of HIV-1 gp120. eCD4-Ig neutralizes a broad range of HIV-1 isolates from various clades, and protects humanized mice and macaques from infection with HIV and SHIV, respectively. To investigate whether eCD4-Ig can neutralize HIV-1 isolates resistant to the CCR5 antagonists maraviroc (MVC) and vicriviroc (VCV) we determined the eCD4-Ig susceptibility of infectious HIV-1 recombinants expressing env fromMCV-susceptible and -resistant viruses. Methods: HIV-1 resistant to VCV and MVC was identified from 3 participants in ACTG protocol A5211, a phase 2 trial of VCV. Infectious recombinant viruses carrying env genes of the paired baseline and MVC-resistant viruses cloned from plasma HIV-1 RNA were generated by transfection into 293T cells together with the recombination vector pNL4-3ΔEnv. Susceptibility to eCD4-Ig, MVC and the CXCR4 antagonist AMD3100 was determined by a standardized drug susceptibility assay on TZM-bl cells. HIV-1 recombinants expressing env from HIV-1 Bal, Hxb2 and 89.6, respectively, served as controls. Susceptibility was expressed as the 50% inhibitory concentrations (IC50) or percent maximum inhibition (PMI). Results: As reported, VCV and MVC resistance emerged after 24, 103 and 138 weeks of VCV treatment (sub07, sub57 and sub85, respectively). At baseline, the IC50s for MVC ranged from 0.2 to 5.2 nM and IC50s to eCD4-Ig ranged from .07 to 4.3 μg/mL. The PMI for MVC of the paired resistant viruses ranged from 0% to approximately 45% (IC50s could not be calculated). By contrast, susceptibility to eCD4-Ig showed three distinct patterns: unchanged (sub57); increased susceptibility (0.4-fold change in IC50; sub85); and decreased (14.8-fold change in IC50; sub07). By comparison, recombinant viruses expressing env from Bal, Hxb2 or 89.6 ranged from 2-13 ng/mL. Conclusion: Recombinant HIV-1 resistant to MVC showed disparate patterns of susceptibility to eCD4-Ig, suggesting that mutations conferring resistance to small-molecule CCR5 antagonists affect interactions with the CCR5mim1 sulfonated peptide moiety of eCD4-Ig in different ways. Analysis of additional

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