CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

goals of this study were to evaluate: 1) if delivery of ZFN using RNA-based transfection provides similar level of CCR5 disruption as the Ad5/35 vector 2) the safety and tolerability of a single dose of this product in HIV+ subjects 3) if a single dose of cyclophosphamide (CTX) increases engraftment 4) the persistence of the disrupted cells and their impact on viral rebound during an ATI and 5) if ∆32 CCR5 heterozygotes preferentially benefit from infusion of CCR5 ZFN treated T cells. Methods: We conducted a 3-arm open-label pilot study of the safety and antiviral activity of a single infusion of autologous CD4 T cells modified at the CCR5 gene by RNA encoding ZFN SB-728 with or without the prior administration of two different doses of CTX in well-controlled HIV+ individuals in which some were CCR5 Δ32 heterozygotes. We compared the AUC of the modified cells during the 16-week ATI between groups and time to viral rebound with ACTG historical controls. Results: We enrolled 14 participants; 93%male, 57% AA, 7% Hispanic, median age 44. Median baseline CD4 count was 831 c/mm3 (IQR 630-1030). SB-728mR-T was safe and well tolerated. No related grade 3 or higher adverse events were observed. CCR5 disruption in the product (MiSeq) was 24% vs 23%with Ad5 vector. The median CCR5-modified T cells was 7.4% at 1 week post infusion. The engraftment of the modified cells varied between groups during the 16-week ATI (KW p=0.04) with trend to greater early engraftment in the CTX groups (p=0.08) that was significant for the Δ32 group compared to the control (p=0.04). The rebound of HIV viremia (HIV RNA > 200 copies/ml) (Fig 1) was delayed when compared to ACTG historical controls (p=0.03). A subset of ∆32 CCR5 heterozygotes had low viral load in the absence of ART for up to 40 weeks. Conclusion: Introduction of CCR5 ZFNs via RNA transfection led to similar levels of disruption as Ad5/35 vectors. CTX led to an increase in engraftment and the administration of the product led to a modest, significant delay in viral rebound during the ATI and maintenance of low level viremia for up to 40 w in some, suggesting that a more efficient CCR5 modification could potentially benefit more individuals from this cure strategy.

1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Harvard University, Boston, MA, USA, 3 NIH, Bethesda, MD, USA, 4 The Ohio State University, Columbus, OH, USA, 5 University of California Los Angeles, Los Angeles, CA, USA, 6 Gilead Sciences, Inc, Foster City, CA, USA, 7 Case Western Reserve University, Cleveland, OH, USA, 8 University of Alabama at Birmingham, Birmingham, AL, USA, 9 Massachusetts General Hospital, Boston, MA, USA Background: Romidepsin (RMD) is a histone deacetylase inhibitor that has been reported to increase HIV-1 RNA expression in plasma and cells after single or multiple infusions of 5 mg/m2. We sought to determine if administering multiple doses of RMD would be safe and induce HIV-1 expression. Methods: HIV-1-infected participants were enrolled in a double-blind, randomized, placebo-controlled (3:1 RMD/placebo) cohort to receive RMD 5 mg/m2 x 4 doses (at days 0, 14, 28, 42). Enrollees were receiving RAL- or DTG- containing ART with plasma HIV-1 RNA <50 cps/mL. Viremia was measured by integrase single copy assay (iSCA) before and 24hr after each RMD/placebo infusion and 72hr after the 2nd infusion. Cell-associated HIV-1 DNA (CAD) and cellular unspliced RNA (CAR) were measured by qPCR in PBMC at the same time points, as well as changes in CD4%, histone-3/4 acetylation and methylation (H3-Ac/Me), P-TEFb, and NFκb by flow. Other measures included changes in T cell activation and apoptosis from baseline to 24 hrs post 1st and 4th infusion. RMD levels were measured at hr 4 post-infusions 3 and 4. Comparisons between arms used Wilcoxon tests. Results: 16 participants enrolled (13 RMD; 3 placebo); 11 male; median CD4 699 cells/mm3. All but two completed 4 infusions. One Grade 3 event (transient neutropenia) was deemed possibly treatment-related. Median RMD levels were 69 and 134 ng/mL, at hr 4 post-infusions 3 and 4, respectively. No significant increases in iSCA, CAR, or CAD were observed from baseline to post-baseline time points or from pre- to post-infusion for each infusion compared to placebo (Figure; all p>0.05). Evidence of host pharmacodynamic effects was demonstrated as significant decreases in CD4% at 24hr after infusions 2, 3, and 4 (median -3.5% to -4.5% vs. 1.5% to 1% in placebos, all p≤0.022). Significant increases were observed in H3-Ac/Me (pNFκB+)%, (pS175+)% on CD4+ T cells 24 and 72 hrs after 2nd infusion of RMD compared to placebo (Figure; all p≤0.02). No differences were detected in T cell activation/apoptosis changes between arms. Conclusion: Multiple RMD doses were safe but did not induce HIV-1 expression in individuals on suppressive ART despite pharmacodynamic effects on host cells including reductions in % CD4+T-cells, increases in histone acetylation, and PTEFb activation. More effective strategies will be needed to reverse HIV-1 latency.

Oral Abstracts


26 MULTIDOSE IV ROMIDEPSIN: NO INCREASED HIV-1 EXPRESSION IN PERSONS ON ART, ACTG A5315 Deborah McMahon 1 , Lu Zheng 2 , Joshua C. Cyktor 1 , Evgenia Aga 2 , Bernard J. Macatangay 1 , Catherine Godfrey 3 , Michael Para 4 , Ronald T. Mitsuyasu 5 , Joseph Hesselgesser 6 , Curtis Dobrowolski 7 , Jonathan Karn 7 , Edward P. Acosta 8 , Rajesh T. Gandhi 9 , John W. Mellors 1 , for the A5315 Team

Thomas S. Uldrick 1 , Steven Fling 1 , Scott V. Adams 1 , Ajantha Solomon 2 , Priscila H. Gonçalves 3 , Nicolas Chomont 4 , Rob Gorelick 5 , Jeffrey D. Lifson 5 , Robert Yarchoan 6 , Martin “Mac” A. Cheever 1 , Frank Maldarelli 7 , Steven G. Deeks 8 , Sharon R. Lewin 2 , for the DARE and CITN-12 Study Teams


CROI 2019

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