CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts


been due, in part, to histone complex gene downregulation. These data suggest that individual genetic responses may greatly influence the efficacy of immune therapies on HIV persistence. 401 NEUROTOXICITY WITH HIGH-DOSE DISULFIRAM AND VORINOSTAT USED FOR LATENCY REVERSAL James McMahon 1 , Vanessa Evns 2 , Jillian S. Lau 1 , Ajantha Solomon 2 , Surekha Tennakoon 2 , Ashanti Dantanarayana 2 , Michelle Hagenauer 1 , Sulggi Lee 3 , Sarah Palmer 4 , Katie Fisher 4 , Namandje Bumpus 5 , David M. Burger 6 , Bonnie J. Howell 7 , Thomas A. Rasmussen 2 , Sharon R. Lewin 2 1 Alfred Hospital, Melbourne, VIC, Australia, 2 Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia, 3 University of California San Francisco, San Francisco, CA, USA, 4 The Westmead Institute for Medical Research, Westmead, NSW, Australia, 5 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 6 Radboud University Medical Center, Nijmegen, Netherlands, 7 Merck & Co, Inc, Kenilworth, NJ, USA Background: The histone deacetylase inhibitor, vorinostat (VOR), and disulfiram (DSF), a drug used to treat alcohol dependence, reverse HIV latency in vivo by different pathways and have been safely administered to people with HIV. Three days of 2000mg DSF has been safely given as a latency reversal agent. This study aimed to determine if these two agents (i) reverse HIV latency more potently than a single agent and (ii) are safe and tolerable. Methods: HIV-infected adults on suppressive antiretroviral therapy (ART) were enrolled in a prospective single arm study of DSF 2000mg daily for 28 days and VOR 400mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline. We quantified cell associated (CA) unspliced (US) and multiply spliced (MS) RNA and HIV DNA in CD4+ T-cells from blood; HIV RNA in plasma using a single copy assay; and p24 expression by SiMoA and histone acetylation by flow cytometry from PBMCs. Plasma concentrations of ART, VOR and DSF were quantified. Results: The first two participants (P1 and P2) experienced grade 3 neurotoxicity (altered mental status possibly and probably related to DSF respectively), which led to trial suspension. P1 was a 67 year-old male on ABC/3TC/DTG with a CD4 count of 762 cells/L and VL <50 copies/mL for 16.7 years. On study day 24 (having missed DSF and VOR on day 10 and stopped DSF and all ART from day 17-24) he presented with confusion, lethargy, and ataxia. Neuroimaging revealed sagittal sinus thrombosis and chronic vertebral artery occlusion. He was admitted to hospital, anticoagulated and symptoms resolved by day 29. P2 was a 61 year-old male on TAF/FTC + RAL with a CD4 of 1085 cells/L and VL <50 copies/mL for 4.8 years. On day 11 he presented with paranoid ideation, emotional lability, lethargy and ataxia. He was admitted to hospital; brain CT scan was normal and his symptoms resolved by day 23. Both participants had increased CA-US RNA following study drugs, which persisted for weeks after drug cessation (Figure). P2 also had increased plasma viremia from day 8-37 (peak 81 copies/mL on day 21) with therapeutic ART drug levels. Low but detectable levels of VOR and histone acetylation were seen in both participants. Conclusion: The study drug combination was not safe with significant but reversible neurotoxicity, which we suspect was related to prolonged high dose DSF. There was evidence of latency reversal in both participants. Prolonged high dose DSF, with or without VOR, should not be further pursued.

Donn J. Colby 1 , Rapee Trichavaroj 2 , Suteeraporn Pinyakorn 3 , Siriwat Akapirat 2 , Trevor A. Crowell 3 , Eugène Kroon 1 , Khunthalee Benjapornpong 1 , Somporn Tipsuk 1 , Carlo Sacdalan 1 , Praphan Phanunphak 1 , Merlin L. Robb 4 , Nittaya Phanuphak 1 , Mark de Souza 1 , Jintanat Ananworanich 3 , for the RV254/ SEARCH010 Study Team 1 Thai Red Cross AIDS Research Center, Bangkok, Thailand, 2 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 3 US Military HIV Research Program, Bethesda, MD, USA, 4 US Military HIV Research Program, Silver Spring, MD, USA Background: Analytic treatment interruption (ATI) is a temporary and carefully monitored withdrawal of antiretroviral therapy (ART) often used to assess new interventions in early phase HIV remission trials. Rebound viremia during ATI presents a risk for HIV transmission to sexual partners. Methods: The SEARCH 010/RV254 cohort in Thailand enrolls participants who start ART during acute HIV infection (AHI). Participants in 3 substudies that included ATI opted to provide semen and anal (lavage or sponge) samples up to 4 times: AHI prior to ART, pre-ATI, viral rebound during ATI, and after ART re-initiation. HIV-1 RNA was extracted using modified High Pure Systemmethod and quantified by Roche COBAS TaqMan HIV-1 with lower limit of detection of 1.5 (all HIV RNA values reported as log10 copies/mL). Results: 47 male participants who underwent ATI provided anogenital samples at one or more time points. At AHI all had plasma viremia with median (range) HIV RNA 5.7 (3.3-7.2). HIV RNA was detected pre-ART in 63% of semen (median 3.3, range 1.9-5.0) and 67% of anal samples (median 2.6, range 1.7-4.1). Prior to ATI after median (range) ART duration of 136 (73-343) weeks, all participants were aviremic and all semen (n=34) and anal (n=39) samples were HIV RNA undetectable. During ATI, all but one participant experienced plasma viral rebound (median HIV RNA 3.7, range 1.7-5.4). HIV-RNA was detectable in 11% (2/19) of semen and 33% (5/15) anal samples at viral rebound; and at low level ranging from 2.1 to 2.4. HIV RNA in semen and/or the anus was predominantly detected when plasma HIV RNA was >4.0 (6/12 samples) and uncommon below this level (1/22 samples) (p=0.008 by Fisher exact). After ART re-initiation and subsequent viral suppression, at a median of 48 (range 9-52) weeks, all semen (n=14) and anal (n=16) samples were undetectable for HIV RNA. Conclusion: Viral rebound after ATI can be associated with detectable HIV RNA in the semen and anal secretions, but at low levels and predominantly when the plasma HIV viral load is above 4.0 log10 copies/mL. This is relevant to future HIV remission trials that require longer periods and higher levels of viremia to assess intervention efficacy. ART re-initiation and suppression of plasma viremia clears HIV RNA from the semen and anus. Study participants and their sexual partners should be counseled on potential risk for HIV transmission during ATI and should employ standard HIV prevention methods such as condom use and/ or preexposure prophylaxis.

Poster Abstracts

CROI 2019 145

Made with FlippingBook - Online Brochure Maker