CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results: 57 subjects were enrolled: 42 not taking ART, 8 on effective ART and 7 with virological failure on ART. Median CD4 count was 34 cells/ μ L and median CSF WCC 18/ μ L. CD8 T cells were the most frequent CSF cell followed by neutrophils, macrophages and CD4 T cells (median 50%, 12%, 6.7% and 6.2%WCC respectively). Compared to individuals not on ART, the CSF of those taking effective ART had significantly increased CD4 T cells, decreased CD8 T cells, increased CD4/CD8 ratio and increased CD206 expression on CD14+ and CD14- macrophages - suggesting M2 phenotype ( table 1 ). CD206 expression was inversely correlated with plasma viral load (even in persons not taking ART (r=-0.59, p=0.0001)) but was not associated with fungal burden (r=-0.02, p=0.893). Fungal burden was inversely correlated with CSF GCSF, IL6, CD4, CD8, CD4-CD8- and NK cells (r= -.49, -.41 -.61, -.55, -.49, -.40 respectively; all p <.05 and q<.1). Non-survivors had decreased CSF CD4-CD8- T cells and reduced CSF IFN γ but this was not significant when adjusted for multiple comparisons (p=.021 q=.92; p=.038, q=.97; respectively).

Table 1. Immune parameters that differed significantly between subjects taking effective ART and those who were not. Geometric means are displayed; parametric tests were performed on log2 transformed variables. Q values refer to the false discovery rate.“Large T cells”were a secondary population of T cells with increased forward scatter. WCC=white cell count; M=macrophage Conclusions: In CM, ART is associated with an increased CSF CD4/CD8 ratio and an increased M2 macrophage phenotype, likely mediated through effects on HIV viral load. In contrast to animal data the M2 phenotype was not associated with increased fungal load or fatal outcome. Instead, fungal burden was negatively correlated with CSF T cells (CD8, CD4 and CD4-CD8-) and concentrations of pro-inflammatory cytokines. This is supportive of the theory that a paucity of CSF inflammation is associated with severe disease in CM. 836 Detrimental Outcomes of Unmasking Cryptococcal Meningitis With Recent ART Initiation Background: Cryptococcal meningitis (CM) remains a major cause of HIV-related mortality in Africa. Increased antiretroviral therapy (ART) availability coupled with a lack of pre-ART cryptococcal antigen screening has led to a greater proportion of patients developing CM after initiating ART. Despite this changing epidemiology, data regarding CM in patients already receiving ART are lacking. We compared the clinical presentation and outcomes in ART-naïve and ART-experienced Ugandans. Methods: We enrolled a prospective cohort of 165 HIV-infected persons with cryptococcosis in Kampala, Uganda from Aug 2013 to Aug 2014. Subjects were classified by ART status, the timing of ART initiation, and previous CM history. The primary endpoint was 2-week mortality. Statistical comparisons were made with Kruskal-Wallis or Fisher’s Exact tests. Results: 87% (144/165) of subjects presented with their first episode of CM whereas 13% (21/165) had a previous history of CM. Of those with first CM episode, 40% (58/144) were receiving ART at presentation, having initiated ART a median of 110 (IQR, 20-519) days prior to CM diagnosis. Those receiving ART had higher CD4 (median 32 (IQR, 10-73) vs 12 (IQR, 6-39) cells/mcL; p =.02) and lower CSF fungal burdens (median 4.0 (IQR, 2.5-4.9) vs 4.8 (IQR, 3.9-5.6) log 10 CFU/mL CSF; p <.001). 55% (32/58) had initiated ART within the last 4 months, and 22% (13/58) initiated ART within the last 14 days. Persons starting ART <4 months prior were more likely to present with altered mental status (44% vs 19% with GCS<15, p =.05) despite having lower CSF fungal burdens (median 3.7 (2.3-4.3) vs 4.5 (3.4-5.1) log 10 CFU/mL; p =.04) compared to those initiating ART >4 months prior to CM diagnosis. CSF WBC did not differ. The 2-week mortality was significantly higher in those on ART for <14 days (54%) compared to those on ART for 15 days to 4 months (16%; p =.05), >4 months (12%; p =.01), or ART-naïve (24%). CM presenting after >4months on ART was an indication of virologic failure. Conclusions: The occurrence of CM after initiating ART is now common in Africa. Although these patients have higher CD4 counts and lower fungal burdens, outcomes do not appear to be improved. Patients developing CMwithin 14 days of initiating ART are at a higher risk of death. Immune recovery in the setting of a CNS infection is detrimental, and management of this population requires future study. Implementing pre-ART cryptococcal antigen screening would decrease CM occurring early after ART initiation. 837 Impact of ART on Mortality in Cryptococcal Meningitis Patients: High-Income Settings Suzanne M. Ingle 1 ; Jose M. Miro 2 ; Hansjakob Furrer 4 ; Amy Justice 5 ; Michael S. Saag 6 ; Christian Manzardo 2 ; Anna Esteve 7 ; Lauren E. Cain 3 ; Jonathan A. Sterne 1 ; MargaretT. May 1 1 University of Bristol, Bristol, United Kingdom; 2 Hospital Clínic–L’Institut D’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; 3 Harvard School of Public Health, Boston, MA, US; 4 Bern University Hospital and University of Bern, Bern, Switzerland; 5 Yale University School of Medicine, VA Connecticut Healthcare System, New Haven, CT, US; 6 University of Alabama at Birmingham, Birmingham, AL, US; 7 Centre d’Estudis Epidemiològics Sobre ITS/VIH/SIDA de Catalunya, Barcelona, Spain Background: Randomised trials (RCTs) from low-income countries have shown that early ART among antiretroviral-naïve HIV-1–infected patients presenting with cryptococcal meningitis (CM) is associated with higher mortality than delayed ART. There is limited information on the impact of timing of ART on short-termmortality in patients with CM cared for in high-income settings. Methods: Data on ART-naive patients diagnosed with CM between 1998 and 2009 were combined from cohorts contributing to the COHERE, NA-ACCORD and CNICS collaborations. Follow-up time was calculated from date of CM diagnosis to the first of death, last follow-up or 6 months post-diagnosis. We mimicked an RCT comparing regime A (“start ART within 14 days of CM diagnosis”) with regime B (“defer ART until 14 -56 days after CM diagnosis”). Marginal structural models were used to compare the effects of these regimes on all-cause mortality. Models were adjusted for gender, age, mode of transmission, CD4, viral load (VL), AIDS (other than CM), year of diagnosis and whether data were European/North American. Results: Of 235 patients (84%male) from 28 cohorts across Europe and N. America with full covariate data, 42 (18.0%) died within 6 months. Median age at CM diagnosis was 38 years (IQR 34-44). Of 150 patients (64%) who started ART, 18 (12%) died within 6 months. 7/62 (11%) patients died among those who started ART within 2 weeks of CM diagnosis, compared with 11/88 (12%) among those who started ART after 2 weeks. The graph shows crude survival over time, according to when the patient started ART. In data mimicking an RCT, there were 15 deaths (33.3 years follow-up) in regime A and 26 deaths (47.8 years) in regime B. The crude and adjusted hazard ratios comparing deferred with early treatment were 1.29 (95% CI 0.68-2.43) and 1.30 (0.66-2.55). Joshua Rhein 1 ; Katherine H. Hullsiek 1 ; Nathan C. Bahr 1 ; Reuben Kiggundu 3 ; DarlishaWilliams 3 ; HenryW. Nabeta 3 ; Abdu Musubire 3 ; David B. Meya 3 ; David R. Boulware 1 1 University of Minnesota, Minneapolis, MN, US; 2 University of Minnesota, Minneapolis, MN, US; 3 Makerere University College of Health Sciences, Kampala, Uganda

Poster Abstracts

507

CROI 2015