Abstract
Cryptococcal meningitis is the most common adult neuroinfection in sub-Saharan Africa and causes ~15%
of AIDS-related mortality globally. In the weeks prior to onset of meningitis, cryptococcal antigen (CrAg) is
detectable in the blood, and is a predictor of meningitis and death. CrAg screening in plasma is an effective
public health strategy to identify persons with CD4<200 cells/mcL at high risk of meningitis and death. In a
randomized trial of 2000 persons with HIV, CrAg screening and preemptive fluconazole treatment yielded a
28% survival benefit over standard-of-care. As a result, the World Health Organization and U.S. guidelines
recommend CrAg screening. Yet despite the survival benefit seen with CrAg screening and preemptive
therapy, 25% of initially asymptomatic CrAg+ persons treated with fluconazole still die, even with HIV therapy.
From 4 prospective cohort studies of CrAg+ persons in Africa, we have determined that as plasma CrAg
titer increases, mortality increases, despite fluconazole therapy. Among asymptomatic CrAg+ persons,
disseminated cryptococcosis is the most commonly identified cause of death. We posit that subclinical
disseminated early neuroinfection in the brain parenchyma accompanies high CrAg titers, and fluconazole is
inadequate therapy. More effective treatment is critically needed to reduce mortality in CrAg+ persons.
For symptomatic cryptococcal meningitis, amphotericin B is the most effective antifungal; fluconazole alone
is inadequate. Recent randomized trial data reported single dose of liposomal amphotericin (AmBisome) 10 mg
/kg with flucytosine (5FC) and fluconazole is as effective and less toxic than the traditional 7-day amphotericin
+ 5FC for meningitis. We hypothesize that AmBisome (10mg/kg x1), when combined with fluconazole, will be
more effective than fluconazole monotherapy for asymptomatic CrAg+ persons. We have enrolled 244 CrAg+
persons in the initial phase II of a phase II/III randomized trial to demonstrate safety and feasibility of this
enhanced regimen in Uganda, and now we seek to complete the phase III trial in order to test efficacy.
The objective of this application is to assess the efficacy of AmBisome plus fluconazole to prevent
cryptococcal meningitis and death. We will complete a randomized clinical trial of 600 CrAg+ persons (i.e. 356
more participants) to determine if preemptive therapy with AmBisome (10mg/kg x1) plus fluconazole for CrAg+
persons will improve cryptococcal meningitis-free 6-month survival compared with the current standard of
fluconazole monotherapy (Aim 1). In Aim 2, we will determine if neurocognitive outcomes in CrAg+ persons
preemptively treated with AmBisome with fluconazole are superior to outcomes with fluconazole monotherapy.
Finally, in Aim 3 we will evaluate the cost and cost-effectiveness of AmBisome with fluconazole preemptive
treatment in CrAg+ persons. Findings from this trial will impact U.S. and international HIV guidelines on the
optimal prevention of cryptococcal meningitis, in order to reduce mortality in persons living with HIV.
