CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Ifakara Hlth Inst, Morogoro, Tanzania, United Republic of, 2 Univ of Minnesota, Minneapolis, MN, USA, 3 Infectious Disease Inst, Kampala, Uganda Background: Cryptococcus neoformans is the leading cause of adult meningitis in sub-Saharan Africa. First-line antifungals are largely unavailable in this region. Sertraline has fungicidal activity against Cryptococcus, has synergy with fluconazole, and has shown promising results as an adjuvant for the treatment of cryptococcal meningitis. Methods: We prospectively enrolled 42 HIV-infected adults with cryptococcal meningitis at a regional referral hospital in the rural Kilombero district, Tanzania from October 2014 to September 2016. Participants received induction treatment with either: A) sertraline 400mg/day and fluconazole 1200mg/day for two weeks (n=28); or B) same regimen plus amphotericin B deoxycholate for 5 days (n=14). The consolidation phase for all participants consisted of sertraline 200mg/day and fluconazole 800mg/day for 12 weeks. Lumbar punctures were performed on day 1, 3, 7, 10 and 14. The primary outcome was early fungicidal activity (EFA) in cerebrospinal fluid (CSF) over the first 2 weeks calculated by linear regression. Secondary outcomes were 2 and 10-weeks survival. Results: The CSF Cryptococcus clearance EFA rate was 0.25 log10 CFU/day (95%CI: 0.12-0.39) with fluconazole plus sertraline and 0.44 log10 CFU/day (95%CI: 0.31-0.57) with amphotericin (5 days), fluconazole, and sertraline, (p=0.04). With fluconazole plus sertraline, 2 and 10-week survival were 64% (18/28) and 25% (7/28), respectively. With amphotericin, fluconazole, and sertraline, 2 and 10-week survival were 93% (13/14) and 36% (5/14), respectively. Severe hypokalemia (<2.5 mEq/L) occurred in 21% (3/14) of participants treated with amphotericin. Conclusion: Sertraline with fluconazole improved two-week CSF fungal clearance rate and clinical outcome as compared with fluconazole monotherapy (EFA=0.18) or short course amphotericin (EFA=0.30) in previously published data. Adding short course amphotericin B increased CSF clearance, reduced early mortality, and was safely implementable in this resource-limited setting. Further efforts are needed to improve outpatient survival in rural Africa. 745 MORTALITY DUE TO HIV-ASSOCIATED CRYPTOCOCCAL MENINGITIS IN BOTSWANA IN THE ART ERA Tshepo B. Leeme 1 , Raju K. Patel 1 , Caitlin Azzo 2 , Nametso Lekwape 1 , Katlego Tsholo 1 , Ephraim Tawanana 3 , Mooketsi Molefi 4 , Margaret Mokomane 3 , Mark W. Tenforde 5 , Joe N. Jarvis 6 1 Botswana–UPenn Partnership, Gaborone, Botswana, 2 Univ of Pennsylvania, Philadelphia, USA, 3 Botswana Ministry of Hlth, Gaborone, Botswana, 4 Univ of Botswana, Gaborone, Botswana, 5 Univ of Washington, Seattle, WA, USA, 6 US CDC, Gaborone, Botswana Background: Cryptococcal meningitis (CM) is a leading cause of death in HIV-infected individuals in Africa. Case fatality rates of 20-35%with amphotericin-B based treatment have been reported in clinical trials conducted in Africa. These are not representative of standard medical care. We evaluated CM outcomes in a routine care setting utilizing centralized electronic medical records and robust civil registration data unique in Africa. Methods: All laboratory-confirmed cases of CM at Princess Marina Hospital, Gaborone, from January 2012 to December 2014 were included in the study. Standard treatment for CM was amphotericin B 1mg/kg plus fluconazole 800mg for 14 days. Paper and electronic records were interrogated to retrieve demographic and clinical data and in-hospital mortality. Linkage with the National death registry allowed out of hospital deaths to be captured. The primary endpoint was mortality at 1 year. Results: During the study period there were 283 episodes of CM among 236 individuals (199 patients had a single episode, 37 patients had multiple episodes). 69% of patients were male and the median age was 36 (IQR 32-42) years. 80% of patients had a known HIV diagnosis prior to presentation with CM, and 51%were already on ART. At the time of death registry linkage in December 2015 vital status was available for 92% (216/236) of patients. Median duration of follow-up in the remaining 20 patients was 25 (IQR 16-153) days. Overall documented mortality was 62% (146/236), and was 68% (146/216) in those with complete data. Two-week mortality, 10-week mortality, and 1-year mortality were 26% (60/233), 50% (112/224), and 65% (142/219). In a sensitivity analysis assuming all those lost to follow-up had died, this increased to 27% (63/236), 53% (124/236), and 67% (159/236). Abnormal mental status at presentation (HR 1.63, 95%CI 1.1-2.5), low CD4 counts (HR 0.84 per 50 cells/μl increase, 95%CI 0.73-0.99), and CSF white cell counts <20 cells/ m l (HR 1.42, 95%CI 1.1-2.0) were associated with poor long-term survival. Conclusion: Long-term outcomes in patients with HIV-associated CM are extremely poor, with only 35% of patients surviving to one year even with amphotericin B based therapy and universal ART access in one of the best-resourced health-care services in Africa. Novel strategies are urgently needed for prevention of new cases and effective management of patients with cryptococcal meningitis. 746 CSF IMMUNE RESPONSES ASSOCIATED WITH DEPRESSION FOLLOWING CRYPTOCOCCAL MENINGITIS Sarah Lofgren 1 , Kathy Huppler Hullsiek 1 , Bozena M. Morawski 1 , Josh Rhein 1 , David Meya 2 , Mahsa Abassi 1 , Noeline Nakasujja 3 , Abdu Musubire 3 , David Boulware 1 , for the Adjunctive Sertraline for theTreatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM) 1 Univ of Minnesota, Minneapolis, MN, USA, 2 Infectious Disease Inst, Kampala, Uganda, 3 Makarere Univ, Kampala, Uganda Background: Depression is common after AIDS-related central nervous system infections. Immunologic factors are involved in the development of depression, but few studies have evaluated CSF immune profiles. Methods: We assessed risk factors for depression, defined by a Center for Epidemiological Studies-Depression (CES-D) score of >=16, among those with cryptococcal meningitis enrolled in two clinical trials in Kampala, Uganda from 2010-2014. We compared clinical factors and 19 CSF cytokines/chemokines (pg/mL) at screening with development and progression of depression at 4 and 12 weeks using descriptive statistics and t-tests. Results: 186 participants with cryptococcal meningitis were screened for depression at 4 and/or 12 weeks. At 4 weeks, 75% of 146 were depressed versus 36% of 163 at 12 weeks. We grouped the 123 screened at both time points into those never depressed and those depressed at one/both time points. CSF opening pressure >25cm H2O was non-significantly higher in those never depressed (81% vs 57%, p=0.06), and closing pressure was significantly higher in those never depressed (11 vs 9cm H2O, p=.04). CSF macrophage activation marker sCD14 was significantly higher in those never depressed (median 634 vs 202 ng/mL, p=.045). CSF cytokines TNFa (14 vs 6 pg/mL; p=.06), IL-4 (1.9 vs 0.9; p=.06), and MCP1 (748 vs 315; p=.06) all trended towards significantly higher in those never depressed. CSF WBC and quantitative cultures did not differ between groups (P=.94; P=.29, respectively). We further separated groups into those never depressed, those who were depressed but improved, and those who worsened. Opening pressure >25cmwas least frequent in the group that improved (81% vs. 47% vs, 88%, respectively; p=.03). Closing pressure was also lower in those who resolved their depression by 12 weeks (11 vs 8.8 vs 10.5cm, respectively; p=.03). Conclusion: Half of those with cryptococcal meningitis who were depressed at 4 weeks had resolved their depression by 12 weeks. Intracranial pressure was highest in the groups of those never depressed and those who worsened between 4 and 12 weeks. It is possible the elevated pressure of those never depressed had appropriate inflammation, with elevated intracranial pressure while those who worsened had dysfunctional inflammation, which raised intracranial pressure and potential risk for depression. Depression was possibly associated with lower levels of CSF inflammation of the innate immune system: sCD14, TNFa, and MCP1 (CCL2) as well as Th2 IL-4 response. 747 CLINICAL PERFORMANCE OF THE MP1P IMMUNOASSAY FOR RAPID DIAGNOSIS OF TALAROMYCOSIS Thu T. Nguyen 1 , Jasper F. Chan 2 , Hien T. Ha 1 , Nguyen Le Nhu Tung 3 , Jeremy Day 1 , Chau V. Nguyen 3 , Guy Thwaites 1 , Patrick C. Woo 2 , Kwok-Yung Yuen 2 , Thuy Le 1 1 Oxford Univ Clinical Rsr Unit, Ho Chi Minh, Vietnam, 2 Univ of Hong Kong, Hong Kong, 3 Hosp for Trop Diseases, Ho Chi Minh City, Vietnam, Ho Chi Minh, Vietnam Background: The gold standard to confirm Talaromyces marneffei infection (previously penicilliosis) is culture which can take up to 2 weeks. Diagnostic delay is associated with high mortality. Antigen detecting immunoassays offer rapid, specific and sensitive results, and have transformed management of other mycoses such as cryptococcosis. We describe the performance of the Mp1p immunoassay in a cohort of HIV-infected patients with talaromycosis and matched controls. Methods: We evaluated the performance of a novel monoclonal antibody-based immunoassay against Mp1p – an abundant mannoprotein in T. marneffei’s cell wall. We used plasma samples from a case-control study: HIV-infected patients with culture-confirmed talaromycosis (N = 284 cases) and HIV-infected patients with other opportunistic

Poster and Themed Discussion Abstracts

CROI 2017 324