CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

in vitro and in vivo activity against Cryptococcus. We evaluated the efficacy of adjunctive sertraline for cryptococcal meningitis in a double-blind, randomized, placebo-controlled clinical trial. Methods: We assessed 18-week survival among HIV-infected adults with cryptococcal meningitis fromMarch 2015 to May 2017. Participants were recruited in Kampala and Mbarara, Uganda and randomly assigned to receive standard therapy (7-14 days of amphotericin + fluconazole starting at 800 mg daily) with either adjunctive sertraline or placebo. Sertraline was administered at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for an additional 10 weeks prior to tapering. Secondary outcomes included the rate of fungal clearance from cerebral spinal fluid (CSF), adverse events, incidence of relapse, quantitative neurocognitive performance and depression scores. Results: The trial was stopped for futility after enrolling 460 of a planned 550 patients. The 18-week mortality was 52% in the sertraline group and 46% in the placebo group (hazard ratio for sertraline, 1.21; 95% CI, 0.93-1.57; p=0.16) (Figure). The rate of fungal clearance from CSF was similar between groups (-0.33 (95% CI, -0.36 to -0.30) vs -0.32 (95% CI, -0.35 to -0.30) log 10 CFU/mL CSF/day; p=0.37), as was incidence of grade ≥ 4 adverse events (24% vs 26%; p=0.63). While there was no difference in overall neurocognitive performance between groups among survivors at day 14, there was a trend towards improved depression scores among those receiving sertraline (CES-D score of 14 (95% CI, 11-16) vs 17 (95% CI, 14-20) for those receiving placebo; p=0.06). Incidence of relapse (1% in each group) and re-hospitalizations (13% in each group) were similar. Despite the use of high dose sertraline, no cases of serotonin syndrome were observed in the trial. Mortality was similar among antiretroviral naïve and antiretroviral experienced patients. Conclusion: Sertraline did not reduce mortality among patients with HIV- associated cryptococcal meningitis at tested doses. Investigations are currently underway to better understand the reasons for sertraline inactivity, which may be multifactorial and possibly related to inadequate drug concentrations, drug- drug interactions, or unknown immune effects.

35 HIGHER HIGH DOSE FLUCONAZOLE FOR THE TREATMENT OF CRYPTOCOCCAL MENINGITIS Umesh G. Lalloo 1 , Richard Larsen 2 , Judith Aberg 3 , Evelyn Hogg 4 , Lauren Komarow 5 , David B. Clifford 6 , Sandy Pillay 1 , Deborah Langat 7 , Agrey Bukuru 8 , Vidya Mave 9 , Khuanchai Supparatpinyo 10 , Wadzanai Samaneka 11 1 Durban University of Technology, Durban, South Africa, 2 USDA, Davis, CA, USA, 3 Icahn School of Medicine at Mt Sinai, New York City, NY, USA, 4 Social &Scientific Systems, Silver Spring, MD, USA, 5 Harvard University, Cambridge, MA, USA, 6 Washington University St Louis, St Louis, MO, USA, 7 KEMRI/Walter Reed Proj, Kericho, Kenya, 8 Joint Clinical Research Centre, Kampala, Uganda, 9 BJGMC Clinical Trials Unit, Pune, India, 10 Chiang Mai University, Chiang Mai, Thailand, 11 University of Zimbabwe, Harare, Zimbabwe Background: The WHO recommends high dose 1200 mg fluconazole (FLU) if amphotericin B (AmB) is not available or not feasible to use in persons with AIDS associated cryptococcal meningitis (CM) in resource limited settings. We report the safety and efficacy of high dose (1200-2000mg/d) oral FLU for the initial treatment of AIDS-associated CM in an AmB-controlled 2-stage dose escalation study. Methods: HIV-infected adults (18years and older) with acute CM were randomized 3:1(Stage 1) or 2:1 (Stage 2) to high dose oral FLU or AmB. Stage 1 was a dose-finding escalation study of FLU (1200, 1600 and 2000 mg/d for up to 10 weeks) compared with AmB (0.7 mg/kg daily for 2 wks followed by low-dose fluconazole). Stage 2 enrolled simultaneous cohorts of the safe and effective FLU (1600 and 2000 mg/d) vs. AMB for safety and efficacy. Quantitative CSF cultures were evaluated every 2 wks until negative or wk 10 (therapeutic efficacy). After wk 10, all participants took 200 mg of FLU through wk 24 (protocol completion). Antiretroviral therapy (ART) was deferred for 4 wks if ART naïve and in Stage 2, ART was also permitted if initiated before enrollment. FLU dose adjustments were for weight and concomitant rifampin. The 1200mg FLU dose showed inferior efficacy and was excluded from Stage 2. The participants from Stage 1 and Stage 2 were combined in the analysis. Results: A total of 48, 22, 50 and 48 patients were in the safety analysis in the AmB, 1200mg FLU, 1600mg FLU and the 2000mg FLU groups respectively. There were 46, 20, 45 and 43 in the efficacy analysis. The groups were matched for demographic, clinical and laboratory characteristics. The clearance of crypto (KM prop: 90% CI) was 81%:71-90; 45%:29-65; 56%:45-69; and 60%:49-73. The mortality (KM% over 24 weeks) was 24, 41, 30 and 36% respectively. Log10 baseline CSF crypto CFUs and baseline GCS (below 15) were significant independent determinants of efficacy: p<0.009 and p<0.0043 respectively. In the safety population baseline log 10 HIV viral load, Log 10 baseline CFUs, and baseline GCS (less than 15) were significant independent determinants: p<0.020, p<0.003 and p<0.022 respectively. Conclusion: These results suggest that the WHO recommendation of FLU 1200 mg may be too low. It appears that weight based1600mg oral FLU is the most effective dose and safer than 2000mg and may be preferable to use over 1200 mg in conditions where AmB is unavailable. Overall, higher dose FLU was found to safe and well tolerated but less effective than AMB across all doses. 36 ADJUNCTIVE SERTRALINE IN HIV-ASSOCIATED CRYPTOCOCCAL MENINGITIS Joshua Rhein 1 , Kathy Huppler Hullsiek 1 , Lillian Tugume 2 , Edwin Nuwagira 3 , Edward Mpoza 2 , Reuben Kiggundu 2 , Kenneth Ssebambulidde 2 , Darlisha A. Williams 2 , Ananta Bangdiwala 1 , Mahsa Abassi 1 , Abdu Musubire 2 , Conrad Muzoora 3 , David Meya 2 , David R. Boulware 1 1 University of Minnesota, Minneapolis, MN, USA, 2 Infectious Disease Institute, Kampala, Uganda, 3 Mbarara University of Science and Technology, Mbarara, Uganda Background: Identifying new antifungals effective for cryptococcal meningitis (CM) remains a priority given the high costs, toxicity, and limited availability of current first line therapy. Sertraline has previously demonstrated

Oral Abstracts

37LB ONE MONTH OF RIFAPENTINE/ISONIAZID TO PREVENT TB IN PEOPLE WITH HIV: BRIEF-TB/A5279 Susan Swindells 1 , Ritesh Ramchandani 2 , Amita Gupta 3 , Constance A. Benson 4 , Jorge T. Leon-Cruz 2 , Ayotunde Omoz-Oarhe 5 , Marc Antoine Jean Juste 6 , Javier R. Lama 7 , Javier A. Valencia 7 , Sharlaa Badal-Faesen 8 , Laura E. Moran 9 , Courtney V. Fletcher 1 , Eric Nuermberger 10 , Richard E. Chaisson 10 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Harvard University, Boston, MA, USA, 3 Johns Hopkins Hospital, Baltimore, MD, USA, 4 University of California San Diego, San Diego, CA, USA, 5 Molepolole Clinical Research Site, Molepolole, Botswana, 6 GHESKIO, Port-au-Prince, Haiti, 7 Barranco Clinical Research Site, Lima, Peru, 8 University of the Witwatersrand, Johannesburg, South Africa, 9 Social & Scientific Systems, Silver Spring, MD, USA, 10 Johns Hopkins University, Baltimore, MD, USA Background: Tuberculosis (TB) is the leading killer of people with HIV infection. Preventive therapy is effective but current regimens are limited by toxicity and low completion rates. We hypothesized that an ultra-short course

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CROI 2018