Boston, Massachusetts
March 4–7, 2018


Conference Dates and Location: 
February 13–16, 2017 | Seattle, Washington
Abstract Number: 



Joseph N. Jarvis1, Tshepo B. Leeme2, Awilly A. Chofle3, Gabriella Bidwell3, Mooketsi Molefi4, Katlego Tsholo2, Nametso Lekwape2, Charles Muthoga2, Síle Molloy5, Thomas S. Harrison5

1CDC Botswana, Gaborone, Botswana,2Botswana–UPenn Partnership, Gaborone, Botswana,3Natl Inst of Med Rsr, Mwanza, Tanzania, United Republic of,4Univ of Botswana, Gaborone, Botswana,5St. George's Univ of London, London, UK

Abstract Body: 

Cryptococcal meningitis (CM) is associated with 10-20% of deaths in HIV-programs in Africa. Current antifungal treatments are inadequate and new treatment strategies are urgently needed. Recent data suggest it may be possible to deliver highly effective induction therapy with very few large doses of liposomal amphotericin B (L-AmB). We performed a phase-II randomized controlled non-inferiority trial examining the Early Fungicidal Activity (EFA) of three alternative short-course high-dose L-AmB schedules for the treatment of HIV-associated CM in Tanzania and Botswana.

HIV-infected patients admitted with a first episode of cryptococcal meningitis were randomised to one of four treatment regimens: (i) L-AmB 10 mg/kg day 1 (single dose); (ii) L-AmB 10 mg/kg day 1, L-AmB 5 mg/kg day 3 (two doses); (iii) L-AmB 10 mg/kg day 1, L-AmB 5 mg/kg days 3, and 7 (three doses); (iv) standard 14-day L-AmB 3mg/kg/d (control arm). All were given with high dose fluconazole 1200mg/d. The primary endpoint was early fungicidal activity (EFA) over the initial 2 weeks of therapy, derived from serial quantitative CSF cultures. Linear regression analysis was used to compare EFA by treatment group.

80 participants were enrolled – median age 38 years, 54% male, 33% on ART, median CD4=34 cells/μL, 29% abnormal mental status at baseline. Rate of fungal clearance in all three short-course high-dose arms was non-inferior to the control arm at the predefined non-inferiority margin of 0.2 logCFU/ml/day (figure). Adjusting for baseline fungal burden, CD4 count, and mental status did not alter the strength of association. One-way ANOVA analysis comparing EFA between the three short-course treatment arms found no evidence for any significant difference. Overall mortality was 29% (23/80): 29% (6/ 21) in the control arm, 22% (4/18) in the single dose arm, 15% (3/20) in the two dose arm, and 48% (10 of 21) in the three dose arm. All treatment groups were well tolerated, with only three participants experiencing DAIDS grade 4 anemia (all in the control arm), and seven DAIDS grade 4 creatinine rises, with no participants requiring treatment interruptions.

Single doses of 10mg/kg L-AmB were well tolerated and led to non-inferior EFA compared to 14-day courses of 3mg/kg L-AmB in HIV-associated CM. Based on these results single dose 10mg/kg L-AmB is being taken forward to a phase 3 clinical endpoint trial.

Session Number: 
Session Title: 
Presenting Author: 
Joseph Jarvis
Presenter Institution: 
Center for Disease Control and Prevention