CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

428LB Short-Term Disulfiram to Reverse Latent HIV Infection: A Dose Escalation Study Julian H. Elliott 1 ; James H. McMahon 1 ;Wendy Hartogensis 2 ; Namandje Bumpus 3 ; Christina Chang 4 ; Sulggi A. Lee 2 ; Jeff Lifson 5 ; Peter Bacchetti 2 ; Steven Deeks 2 ; Sharon R. Lewin 4 on behalf of the Disulfiram Study investigators 1 Monash University/Alfred Hospital, Melbourne, Australia; 2 University of California San Francisco, San Francisco, CA, US; 3 Johns Hopkins University, Baltimore, MD, US; 4 University of Melbourne, Melbourne, Australia; 5 National Cancer Institute, Frederick, MD, US Background: Disulfiram (DSF) is a licensed oral agent, dosed daily and well tolerated in the absence of alcohol. DSF reactivates HIV in a primary T-cell model of HIV latency and had a variable effect on plasma HIV RNA in a pilot clinical study. Methods: We conducted a prospective dose escalation study. Three cohorts of participants on suppressive antiretroviral therapy (n=10 each) were sequentially enrolled and received DSF daily for three days at doses of 500mg (licensed dose), 1000mg or 2000mg. Baseline samples were obtained at three pre-dosing timepoints (B1-B3); 2, 6 and 24 hours after the first and third doses; and at days 8 and 31. The primary endpoint was cell-associated unspliced HIV RNA (CA-US RNA) in CD4 T-cells. Random intercept negative binomial regression models were used to estimate changes from pre-DSF baseline to timepoints during DSF dosing (days 1-3) and post-DSF. Standard non-compartmental methods were used to estimate pharmacokinetic parameters. Results: DSF was well-tolerated at all doses. Compared to the mean of three pre-DSF time points, the estimated fold-increases in CA-US RNA during and post-DSF for each cohort were: 500mg: 1.7 (95% confidence interval 1.3 – 2.2) and 2.1 (1.5 – 2.9); 1000mg: 1.9 (1.6 – 2.4) and 2.5 (1.9 – 3.3); and 2000mg: 1.6 (1.2 – 2.1) and 2.1 (1.5 – 3.1) (p<0.01 for all). Of the three baseline samples, the third (B3) was collected earlier in the day, prior to first dose. CA-US RNA (but not DNA or plasma RNA) at this timepoint was substantially higher (p<0.0001). Using B3 only as the baseline, increases in CA-US RNA during and post-DSF were still observed, but were modest (fold change range 1.0 – 1.6). Compared to the pre-DSF time points, no consistent changes in plasma HIV RNA were noted during dosing, but an increase was seen post-dosing in the cohort receiving 2000mg/day (fold change 1.9 [95% CI 1.3 – 2.7], p=0.001). In a post-hoc analysis of the subgroup of participants with high baseline CA-US RNA and high exposure to DSF or its metabolites, there were significant increases in plasma HIV RNA at days 8 and 31 (fold-change ranged from 1.6 – 2.0 ; all p<0.032). Conclusions: Short-term administration of disulfiram resulted in increased CA-US RNA during dosing and up to 4 weeks after the last dose. Possible diurnal variation in baseline CA-US RNA levels was noted, complicating the analysis. The late post-DSF increases in both CA-US RNA and plasma HIV RNA remain unexplained, but are consistent with trends observed with other latency reversing agents. 2:30 pm– 4:00 pm Stem Cell Transplantation 429 Impact of Combination of Chemotherapy and Autologous Hematopoietic Stem-Cell Transplantation for Lymphoma on HIV Reservoir Persistence Heloise Delagreverie ; laurence Gerard; Marie Laure Chaix; Marie Laure Nere; Lionel Galicier; Francois Simon; Eric Oksendenhendler; Constance Delaugerre Hôpital Saint-Louis, APHP, Université Paris Diderot, Paris, France Background: Myeloablation and autologous stem cell transplantation (ASCT) lead to significant depletion of circulating CD4+ T cells and could impact the HIV-1 reservoir. We studied the longitudinal effect of combination chemotherapy and ASCT for HIV-related lymphoma on cellular HIV-1 DNA quantification in patients on suppressive antiretroviral therapy. Methods: Between 2012 and 2014, we analyzed antiretroviral successfully treated-HIV-infected patients who received intensive myeloablative chemotherapy and ASCT for relapsed or refractory lymphoma. HIV-DNA was quantified longitudinally using sensitive real-time PCR assay (HIV DNA CELL, Biocentric, threshold 5 copies/10 6 PBMC) on frozen whole blood samples at different time points before, during, and after ASCT (D0). Results: Thirteen patients received a combination of myeloablative chemotherapy and ASCT for lymphoma therapy (Hodgkin = 5, non-Hodgkin = 8). We obtained a total of 84 samples from 18 months before ASCT to more than 6 months after ASCT. Median (IQR) HIV-DNA (n=84) was 2.72 (2.39-3.07) log copies/10 6 PBMC. Median plasma HIV-RNA (n=64) was 1.3 (1.3-1.7) log 10 copies/ml and median CD4 cell counts (n=35) was 339 (215-476) cell/mm3. During the follow up, median HIV-DNA was 2.94 (2.44-3.31) log 10 copies/ml from -18 to -6 months pre-ASCT, 2.89 (2.66-3.36) from -6 months to ASCT, 2.68 (2.32-2.98) from ASCT to +6 months, and 2.56 (2.30-2.73) after 6 months post ASCT. Evolution of HIV-DNA is shown in the figure. HIV-DNA decreased during chemotherapy and ASCT according to cellular depletion. However, no significant differences in median HIV-DNA for each patient before and after ASCT were observed (Wilcoxon signed rank sum test, p=ns). In some patients, the proportion of infected cell decreased slightly after 6 months post ASCT. Strong correlation between HIV-DNA and HIV-RNA (p<10 4 ) and no correlation with the CD4 cell count were found. WEDNESDAY, FEBRUARY 25, 2015 Session P-F9 Poster Session Poster Hall

Poster Abstracts

301

CROI 2015