High mortality despite high dose oral fluconazole (1600 mg) and flucytosine, and serial lumbar punctures, for HIV-associated cryptococcal meningitis :

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High mortality despite high dose oral fluconazole (1600 mg) and flucytosine, and serial lumbar punctures, for HIV-associated cryptococcal meningitis : ANRS 12257 study in Burundi and Côte d’Ivoire Poster WEPDB0103 IAS Paris 2017 A Chabrol (1) , A Doumbia (2) , R Landman (3) , A Fontanet (4) , S Eholie (2,3) , T Niyongabo (5) , L Nizigama (5) , D Laureillard (6) , B Sylla (3) , H Menan (2) , C Padoin (7) , S Brun (7) , C Alloui (7) , A Kakou (2) , O Bouchaud (7) And the ANRS 12257 Study Group (1) CH Corbeil, France (2) CHU Treichville, Côte d’Ivoire (3) IMEA, CHU Bichat, France (4) Epidémiologie, Institut Pasteur, France (5) CHU Kamenge, Burundi (6) CHU Nîmes, France (7) CHU Avicenne, France

Methods / characteristics of patients Cryptococcal meningitis in resource-limited countries High burden : 500 000 deaths per year in sub-Saharan Africa Amphotericin B + flucytosine + serial lombar punctures (LP) = gold standard treatment but often unavailable Treatment is usually fluconazole alone 800 to 1200 mg/day Prospective pilot study of « optimal real life treatment » for induction phase : 41 patients : oral fluconazole 1600 mg + oral flucytosine + serial LP (2 weeks) Excluded : children, relapse, comatose (Glasgow < 9)

Results : mortality rates Results of ANRS 12257 study In the litterature Study / Arm Mortality rate at 2 weeks Mortality rate at 10 weeks Mortality rate at 24 weeks Fluco 1200 (1) 55% Fluco 1200 (2) 37 % 48 % Fluco 1200 + flucytosine (2) 10 % 43 % AmB (3) 25% 44% 53% AmB + fluco 800 (3) 20% 33% 45% AmB + flucytosine (3) 15% 30% 34% Fluco 1200 + flucytosine (4) 18 % 35 % AmB-based 7 days (4) 22 % 36 % (1) Gaskell, PLoS One 2014 (2) Nussbaum, CID 2010 (Malawi) (3) Day, NEJM 2013 (Vietnam) (4) ACTA Trial, IAS 2017

Results : early fongicidal activity (EFA) EFA = -0.27 +/- 0.20 logCFU/ml/day In the litterature Study / Arm EFA (log CFU / ml / day) Fluco 1200 (1) - 0.11 Fluco 1200 + flucytosine (1) - 0.28 AmB (2) - 0.31 AmB + fluco 800 (2) - 0.32 AmB + flucytosine (2) - 0.42 Fluco 1200 + flucytosine (3) -0.26 AmB-based 7 days (3) -0.40 (1) Nussbaum, CID 2010 (Malawi) (2) Day, NEJM 2013 (Vietnam) (3) ACTA Trial, IAS 2017

Conclusion CAN WE DO BETTER ? YES WE SHOULD => Urgent need of Amphotericin B (short course 7 days) => Fluconazole –based preemptive strategies Acknowledgements : ANRS, IMEA, and every physician of the study in Côte d’Ivoire and Burundi