CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

72 SINGLE ROMIDEPSIN INFUSIONS DO NOT INCREASE HIV EXPRESSION IN PERSONS ON ART (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 , Evelyn Hogg 6 , Joseph Hesselgesser 7 , Edward P. Acosta 8 , Rajesh T. Gandhi 2 , John W. Mellors 1 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Harvard University, Cambridge, 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 Social & Scientific Systems, Silver Spring, MD, USA, 7 Gilead Sciences, Inc, Foster City, CA, USA, 8 University of Alabama at Birmingham, Birmingham, AL, USA Background: Romidepsin (RMD) is a potent histone deacetylase inhibitor reported to increase HIV RNA in plasma and cells after single or multiple infusions of 5 mg/m2. We sought to determine the safest, lowest effective dose of RMD for induction of HIV expression. Methods: Three single-dose cohorts (0.5 mg/m2, 2 mg/m2, 5 mg/m2) of HIV-infected participants were sequentially enrolled in a double-blind, randomized, placebo-controlled (3:1 active/placebo per cohort) study, target 15/cohort. Enrollees were virally suppressed on EFV, RAL, or DTG-containing ART with plasma HIV RNA ≥0.4 but <50 cps/mL. Viremia was measured by single copy assay (SCA) before and after RMD/placebo 4 hr infusion at hrs 6, 12, 24, 48 and days 7, 14, 28. Cell-associated HIV DNA (CAD) and unspliced RNA (CAR) were measured by qPCR in resting CD4+ cells pre- and post-infusion (hr 24; day 14). Histone-3 acetylation (H3-Ac) was measured by flow in total CD3+ T-cells pre-infusion and at hrs 12, 24, 48 and days 7, 14, 28. RMD was measured pre- and post-infusion at hrs 4, 6, 12, 24. Pre-specified primary comparisons were between the pooled RMD and pooled placebo groups using the Wilcoxon test. Results: 43 participants enrolled (36 RMD; 7 placebo); 40 male; 27 white, 14 black; median screening SCA 1.5 cps/mL; median CD4 667 cells/mm 3 . All completed the infusions; all but one completed 28-day follow-up. No Grade 3 events were deemed treatment-related. Median RMD levels at hr 4 were 12.0, 75.2, 89.0 ng/mL in the 0.5, 2.5 and 5 mg/m2 cohorts, respectively, and declined rapidly. The primary efficacy measure of SCA change from pre-infusion to the average of 24 and 48 hr post was similar between the pooled RMD and placebos (median: 0.12 vs. 0.12 log 10 cps/mL, p=0.88, [95% CI on difference: -0.48, 0.33]). There was no significant difference in change in CAR from pre-infusion to 24 hr post (-0.09 vs. 0 log 10 cps/106 resting CD4+ cells, p=0.37, [-0.54, 0.23]) or in CAD (-0.04 vs. 0.05 log 10 cps/106 resting CD4+ cells, p=0.73, [-0.33, 0.32]). No significant increases in any virologic measure or in H3-Ac were observed in any of the RMD dose arms compared to pooled placebos or from pre-infusion to other timepoints (all p > 0.05). Conclusion: In contrast to prior uncontrolled studies, in this placebo- controlled, dose-escalation study, single RMD doses that achieved a range (>5-fold) of systemic exposures were well-tolerated but did not increase HIV expression OR H3-Ac. Multiple or higher RMD doses may be needed to induce HIV expression.

Background: Previous studies have shown that broadly neutralizing antibodies (bNAbs) administered at the time of ART discontinuation can provide direct antiviral effects, but whether bNAbs can effectively target the viral reservoir during ART suppression remains to be determined. In this study, we assessed the impact of the V3 glycan-dependent bNAb PGT121 combined with the TLR7 agonist GS-9620 in ART suppressed, SHIV-infected rhesus monkeys. Methods: 44 rhesus monkeys were infected with SHIV-SF162P3 and initiated ART (TDF/FTC/DTG) on day 7 of infection. Following 96 weeks of continuous daily suppressive ART, animals received 10 mg/kg PGT121 by infusion (every 2 weeks x 5 doses), 0.15 mg/kg GS-9620 by oral gavage (every 2 weeks x 10 doses), both PGT121 and GS-9620, or sham controls (N=11/group). At week 130, which was 16 weeks after the final PGT121 and GS-9620 doses, ART was discontinued and viral rebound was monitored. Results: PGT121 administration resulted in 10 weeks of therapeutic antibody levels, followed by a decline to undetectable levels in peripheral blood, lymph nodes, and colorectal tissue for >8 weeks prior to ART discontinuation. Autologous cellular immune responses were minimal and were not increased by PGT121+GS-9620 administration. Viral DNA in lymph nodes was markedly lower in PGT121+GS-9620 treated animals as compared with sham controls (P=0.004, Mann-Whitney test). Following ART discontinuation, 100% (11 of 11) of sham controls exhibited rapid viral rebound with a median rebound time of 21 [IQR 21-42] days. In contrast, only 55% (6 of 11) of PGT121+GS-9620 treated animals rebounded by day 140 following ART discontinuation (P=0.03, Fisher’s exact test) and demonstrated a substantial delay in median rebound time of 112 [IQR 84-140+] days (P=0.0005, Mann-Whitney test) as well as a 2.64 log reduction of peak viral loads and a 1.52 log reduction of setpoint viral loads as compared with sham controls (P<0.0001, Mann-Whitney test). All PGT121+GS-9620 treated animals exhibited setpoint viral loads <400 RNA copies/ml. Intermediate outcomes were observed in the animals that received PGT121 alone. Conclusion: PGT121 combined with GS-9620 during ART suppression substantially delayed and controlled viral rebound following ART discontinuation in SHIV-infected rhesus monkeys that initiated ART during acute infection. These data suggest that bNAb administration together with innate immune stimulation during ART suppression may effectively target the viral reservoir. 74 IL-6, D-DIMER OR T-CELLS: WHICH BEST PREDICT EVENTS OR EXPLAIN BENEFITS OF EARLY ART? Jason V. Baker 1 , Birgit Grund 2 , Shweta Sharma 2 , Abdel Babiker 3 1 Hennepin County Medical Center, Minneapolis, MN, USA, 2 University of Minnesota, Minneapolis, MN, USA, 3 University College London, London, UK Background: In START, immediate ART led to immune recovery, reduced inflammation, and lower risk of AIDS and serious non-AIDS (SNA). We compare early measures of immunologic and inflammatory biomarkers for their ability to predict prognosis and/or explain the treatment effect in START. Methods: Plasma biomarkers studied included IL-6, D-dimer and CD4 and CD8 T-cells at baseline and month 8. Associations of latest biomarker levels (only baseline or month 8) with subsequent event risk were estimated with Cox regression adjusted for treatment group. Hazard ratios (HR) were calculated per 1 SD (standard deviation) of the biomarker at baseline, so that HRs are comparable. We calculated the percent of treatment effect (TE) explained by biomarkers as the reduction in the HR (immediate vs deferred ART) when adjusted for the latest biomarker levels, expressed as a percentage of the TE. Results: Analyses include 4273 (92%) START participants with IL-6, D-dimer and CD4 counts at baseline. Mean follow-up was 3.1 years; 129 participants had primary events (57 AIDS, 72 SNA events or non-AIDS deaths), with 23 occurring before month 8 and 106 after. Levels (assessed at baseline and month 8) of D-dimer, IL-6, CD8, and CD4:CD8, but not CD4, demonstrated strong associations with subsequent risk of AIDS and SNA (Table). IL-6 and D dimer levels were each significantly associated with event risk after adjusting for treatment group and CD8, adjusted HR (95%CI) per SD of IL-6 and D dimer: 1.33 (1.14, 1.57) and 1.57 (1.37, 1.80), respectively. D dimer also was significantly associated with risk after adjusting for treatment group, CD8 and IL-6 (adjusted HR 1.50 [1.30, 1.74]). The percent of TE explained in START by baseline and month 8 biomarker levels appeared similar for CD8 and D-dimer, but strongest for the CD4:CD8 ratio (20%). The effect of IL-6 and D-dimer (10%) for explaining the TE in START appeared additive when combined with the CD4:CD8 ratio (29% for all three; table).

Oral Abstracts

73LB PGT121 COMBINED WITH GS-9620 DELAYS VIRAL REBOUND IN SHIV- INFECTED RHESUS MONKEYS Erica Borducchi 1 , Peter Abbink 1 , Joseph Nkolola 1 , Mark G. Lewis 2 , Romas Geleziunas 3 , Dan Barouch 1 1 Beth Israel Deaconess Medical Center, Boston, MA, USA, 2 BIOQUAL, Inc, Rockville, MD, USA, 3 Gilead Sciences, Inc, Foster City, CA, USA

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CROI 2018