CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

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).

Oral Abstracts

Kaplan-Meier survival estimates according to time of starting ART Conclusions: We found little evidence that early ART was associated with higher mortality after CM than deferred ART, although confidence intervals were wide. Although we adjusted for potential confounding factors, confounding and selection bias may not be fully adjusted for; we aim to address this limitation by ascertaining additional information on treatment of CM after diagnosis. Mortality among patients cared for in high income settings was clearly lower than reported in the RCTs conducted in low-income countries. 838 Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis Joshua Rhein 1 ; Katherine H. Hullsiek 1 ; Bozena Morawski 1 ; Kyle Smith 1 ; Ali Al-Hadab 1 ; Abdu Musubire 2 ; DarlishaWilliams 2 ; Kristen Nielsen 1 ; David B. Meya 2 ; David R. Boulware 1 1 University of Minnesota, Minneapolis, MN, US; 2 Makerere University College of Health Sciences, Kampala, Uganda Background: Mortality from HIV-associated cryptococcal meningitis (CM) remains unacceptably high. Identifying new effective antifungals is of paramount importance. We evaluated the efficacy of adjunctive sertraline, previously demonstrated to be active against Cryptococcus neoformans both in vitro and in murine models. Methods: 144 HIV-infected persons with first episode of CM were prospectively enrolled in a phase IIb, open-label clinical trial in Kampala, Uganda between Aug 2013-2014. Sertraline at doses of 100-400 mg/day was added to standard therapy (amphotericin + fluconazole 800mg/day). Early fungicidal activity (EFA) was measured as the rate of cryptococcal clearance in serial quantitative CSF cultures and calculated by mixed effect model for all participants with at least 2 CSF cultures (N=122). Sertraline concentrations in plasma were measured using high performance chromatography–mass spectrometry in 77 subjects to evaluate how rapidly sertraline achieves steady state. In vitro susceptibility was assessed on a subset of C. neoformans isolates (N=95) to determine target 90%minimum inhibitory concentration (MIC90). Results: Those receiving any dose of sertraline had 28% faster rate of clearance compared with recent historical controls (Table): EFA -0.39 vs. -0.30 for those with vs. without sertraline (p=0.03). Sertraline reached steady state in plasma by day 7, with a median level of 215 (IQR, 126-305) ng/mL at 200mg/day and 400 (IQR, 281-556) ng/mL at 400mg/ day. Plasma levels were 68% of steady state levels by day 3. The projected steady state brain tissue concentration at 200mg/day was a median of 3.5 (IQR, 2.1-5.0) mcg/mL and at 400mg/day was 6.6 (4.6-9.2) mcg/mL. Among Cryptococcus isolates, the MIC90 was ≤ 1 mcg/mL for 9.5%, ≤ 2 mcg/mL for 30.5%, ≤ 4 mcg/mL for 84%, and ≤ 8 mcg/mL for 99% of isolates. In vitro synergy studies (n=9) found a median 2-fold reduction in the MIC90 with a combination of sertraline and fluconazole. For sertraline at doses 200-400mg/day, the incidence of paradoxical IRIS or relapse through 12 weeks was 1%.

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CROI 2015