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

This randomized clinical trial will evaluate the optimal duration of fluconazole therapy and timing of antiretroviral therapy initiation among HIV-infected persons with asymptomatic cryptococcal antigenemia and low cryptococcal antigen titers in Uganda.

Participants with low-titer cryptococcal antigenemia will be followed to assess 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. Among participants eligible for antiretroviral therapy timing randomization, the study will also compare immediate antiretroviral therapy initiation with delayed initiation after 14 days to evaluate 10-week hospitalization-free survival.

Participants will be followed for up to 24 weeks, with study visits and contacts to assess survival, cryptococcal meningitis, hospitalizations, adverse events, and fluconazole adherence.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV-1-infection; Cryptococcal Meningitis; Cryptococcal Infection; Cryptococcal Antigenemia
• Intervention / Treatment: Drug: Immediate ART Initiation; Drug: 10-Week Fluconazole; Drug: 24-Week Fluconazole; Drug: Delayed ART Initiation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 505
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Radha Rajasingham, MD; Phone Number: 612-625-4680; Email: radha@umn.edu

Study Locations

• Uganda
  • Kampala, Uganda
    • Infectious Diseases Institute, Makerere University
    • Contact: Radha Rajasingham, MD; Phone Number: 612-625-4680; Email: radha@umn.edu
    • Principal Investigator: Radha Rajasingham, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Immediate ART + 10-Week Fluconazole Arm Type: Participants eligible for ART timing randomization will initiate antiretroviral therapy immediately at enrollment. Participants who are alive and have not developed cryptococcal meningitis at week 10 will stop fluconazole after completing 10 weeks of preemptive fluconazole therapy.	Drug: Immediate ART Initiation; Antiretroviral therapy will be initiated immediately at enrollment for participants randomized to immediate ART initiation. ART drug choice will be per clinical standard of care.; Drug: 10-Week Fluconazole; Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then stop fluconazole.
Experimental: Immediate ART + 24-Week Fluconazole; Participants eligible for ART timing randomization will initiate antiretroviral therapy immediately at enrollment. Participants who are alive and have not developed cryptococcal meningitis at week 10 will continue fluconazole through 24 weeks of preemptive fluconazole therapy.	Drug: Immediate ART Initiation; Antiretroviral therapy will be initiated immediately at enrollment for participants randomized to immediate ART initiation. ART drug choice will be per clinical standard of care.; Drug: 24-Week Fluconazole; Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then fluconazole 200 mg daily for an additional 14 weeks, for a total fluconazole duration of 24 weeks.
Experimental: Delayed ART + 10-Week Fluconazole; Participants eligible for ART timing randomization will delay antiretroviral therapy initiation until 14 days after enrollment. Participants who are alive and have not developed cryptococcal meningitis at week 10 will stop fluconazole after completing 10 weeks of preemptive fluconazole therapy.	Drug: 10-Week Fluconazole; Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then stop fluconazole.; Drug: Delayed ART Initiation; Antiretroviral therapy will be initiated 14 days after enrollment for participants randomized to delayed ART initiation. ART drug choice will be per clinical standard of care.
Active Comparator: Delayed ART + 24-Week Fluconazole; Participants eligible for ART timing randomization will delay antiretroviral therapy initiation until 14 days after enrollment. Participants who are alive and have not developed cryptococcal meningitis at week 10 will continue fluconazole through 24 weeks of preemptive fluconazole therapy.	Drug: 24-Week Fluconazole; Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then fluconazole 200 mg daily for an additional 14 weeks, for a total fluconazole duration of 24 weeks.; Drug: Delayed ART Initiation; Antiretroviral therapy will be initiated 14 days after enrollment for participants randomized to delayed ART initiation. ART drug choice will be per clinical standard of care.
Experimental: ART-Experienced + 10-Week Fluconazole; Participants who are already receiving ART or are not eligible for ART timing randomization will continue ART per standard clinical care. Participants who are alive and have not developed cryptococcal meningitis at week 10 will stop fluconazole after completing 10 weeks of preemptive fluconazole therapy.	Drug: 10-Week Fluconazole; Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then stop fluconazole.
Active Comparator: ART-Experienced + 24-Week Fluconazole; Participants who are already receiving ART or are not eligible for ART timing randomization will continue ART per standard clinical care. Participants who are alive and have not developed cryptococcal meningitis at week 10 will continue fluconazole through 24 weeks of preemptive fluconazole therapy.	Drug: 24-Week Fluconazole; Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then fluconazole 200 mg daily for an additional 14 weeks, for a total fluconazole duration of 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-week cryptococcal meningitis-free survival with retention in care	Cryptococcal meningitis-free survival with retention in care at 24 weeks will be compared between participants randomized to 10 weeks of fluconazole and participants randomized to 24 weeks of fluconazole. Participants who develop cryptococcal meningitis, die, or are not retained in care will be considered treatment failures.	24 weeks
10-week hospitalization-free survival with retention in care	Hospitalization-free survival with retention in care at 10 weeks will be compared between participants randomized to immediate antiretroviral therapy initiation and participants randomized to delayed antiretroviral therapy initiation. Hospitalization-free survival will include assessment of events such as meningitis, serious opportunistic infections, immune reconstitution inflammatory syndrome events, hospitalization, death, and retention in care.	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grade 3 to 5 clinical adverse events or serious adverse events	Incidence of grade 3 to 5 clinical adverse events or serious adverse events will be assessed among enrolled participants.	Up to 24 weeks
24-week known survival	Known survival at 24 weeks will be assessed. Death and loss to follow-up will be considered therapeutic failures.	24 weeks
Incidence of cryptococcal meningitis	Incidence of cryptococcal meningitis will be assessed during study follow-up.	Up to 24 weeks
Incidence of hospitalization	Incidence of hospitalization, irrespective of cause, will be assessed during study follow-up.	Up to 24 weeks
Incidence of death	Incidence of death, irrespective of cause, will be assessed during study follow-up.	Up to 24 weeks
Fluconazole adherence	Fluconazole adherence will be assessed using self-reported compliance, pharmacy records, and tablet counts when available.	Up to 24 weeks

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Radha Rajasingham, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Estimated): January 5, 2027
• Primary Completion (Estimated): August 30, 2031
• Study Completion (Estimated): August 30, 2031

Study Registration Dates

• First Submitted: July 30, 2026
• First Submitted That Met QC Criteria: July 30, 2026
• First Posted (Actual): August 4, 2026

Study Record Updates

• Last Update Posted (Actual): September 3, 2026
• Last Update Submitted That Met QC Criteria: September 2, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Fluconazole; Antiretroviral therapy; Uganda; ART initiation; Advanced HIV disease; Cryptococcal antigen; CrAg; Fluconazole Short-course fluconazole; Low CrAg titer; Immediate ART; Cryptococcal meningitis-free survival; Hospitalization-free survival
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Bacterial Infections and Mycoses; Central Nervous System Infections; Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Cryptococcosis; Meningitis; Meningitis, Cryptococcal; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Triazoles; Fluconazole
• Other Study ID Numbers: STUDY00024821

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No