Optimizing Care for Cryptococcal Antigenemia: Evaluation of Short Course Fluconazole and ART Timing Among CrAg+ Persons With Low Titers

Cryptococcal antigenemia can be detected in the blood before the development of symptomatic cryptococcal meningitis and is associated with increased risk of meningitis and death among persons with advanced HIV disease. Current guidelines recommend cryptococcal antigen screening and preemptive fluconazole therapy for persons with asymptomatic cryptococcal antigenemia, but the optimal duration of fluconazole therapy and the optimal timing of antiretroviral therapy initiation remain uncertain.

This randomized clinical trial will enroll HIV-infected persons with asymptomatic cryptococcal antigenemia and low cryptococcal antigen titers in Uganda. The study is designed to answer two main questions. First, it will evaluate whether a shorter 10-week course of fluconazole is non-inferior to the standard 24-week fluconazole regimen for 24-week cryptococcal meningitis-free survival. Second, among participants eligible for antiretroviral therapy timing randomization, it will evaluate whether immediate antiretroviral therapy initiation is non-inferior to delayed initiation after 14 days for 10-week hospitalization-free survival.

At enrollment, eligible participants who meet criteria for antiretroviral therapy timing randomization will be randomized to immediate antiretroviral therapy initiation or delayed antiretroviral therapy initiation after 14 days. All participants will receive fluconazole 800 mg daily beginning at enrollment and continuing for 14 days, followed by fluconazole 400 mg daily through week 10. At week 10, participants who are alive and have not developed cryptococcal meningitis will be randomized to stop fluconazole or to continue fluconazole 200 mg daily for an additional 14 weeks, for a total fluconazole duration of 24 weeks.

Participants will be followed at weeks 2, 4, 6, 8, 10, 16, 20, and 24. Study assessments will include interval history, vital status, assessment for signs and symptoms of cryptococcal meningitis, medication review and adherence assessment, physical examination or symptom-directed examination as appropriate, and adverse event monitoring. Participants who miss visits or cannot attend scheduled clinic visits may be contacted by phone or through home visits to assess vital status and meningitis events.

The primary fluconazole-duration endpoint is 24-week cryptococcal meningitis-free survival with retention in care. The primary antiretroviral therapy timing endpoint is 10-week hospitalization-free survival with retention in care. Secondary endpoints include survival, incidence of cryptococcal meningitis, grade 3 to 5 clinical adverse events or serious adverse events, hospitalization, death, and fluconazole adherence.

Inclusion criteria

• HIV-1 infection
• Age greater than 18 years
• Ability and willingness to give informed consent
• Plasma or serum cryptococcal antigen positive with titer less than 1:160

Exclusion criteria

• Cannot or unlikely to attend regular clinic visits
• History of cryptococcal infection
• Symptomatic meningitis confirmed by cerebrospinal fluid cryptococcal antigen positivity
• More than 10 weeks of fluconazole therapy
• Pregnancy confirmed by urinary or serum pregnancy test
• Current breastfeeding