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

NCT07743593 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: STUDY00024821
• Study Type: interventional
• Target: 505
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cryptococcal Antigenemia; HIV-1-infection; Cryptococcal Infection; Cryptococcal Meningitis

Keywords

Cryptococcal antigen; CrAg; Fluconazole; Fluconazole Short-course fluconazole; Low CrAg titer; Immediate ART; Advanced HIV disease; Cryptococcal meningitis-free survival; Hospitalization-free survival; Uganda; ART initiation; Antiretroviral therapy

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Incidence of grade 3 to 5 clinical adverse events or serious adverse events

  Up to 24 weeks

• 24-week known survival

  24 weeks

• Incidence of cryptococcal meningitis

  Up to 24 weeks

• Incidence of hospitalization

  Up to 24 weeks

• Incidence of death

  Up to 24 weeks

Study Arms (6)

Immediate ART + 10-Week Fluconazole Arm Type:

EXPERIMENTAL

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; Drug: 10-Week Fluconazole

Immediate ART + 24-Week Fluconazole

EXPERIMENTAL

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; Drug: 24-Week Fluconazole

Delayed ART + 10-Week Fluconazole

EXPERIMENTAL

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: Delayed ART Initiation; Drug: 10-Week Fluconazole

Delayed ART + 24-Week Fluconazole

ACTIVE COMPARATOR

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: Delayed ART Initiation; Drug: 24-Week Fluconazole

ART-Experienced + 10-Week Fluconazole

EXPERIMENTAL

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

ART-Experienced + 24-Week Fluconazole

ACTIVE COMPARATOR

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

Interventions

Immediate ART Initiation DRUG

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.

Immediate ART + 10-Week Fluconazole Arm Type:; Immediate ART + 24-Week Fluconazole

Delayed ART Initiation DRUG

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.

Delayed ART + 10-Week Fluconazole; Delayed ART + 24-Week Fluconazole

10-Week Fluconazole DRUG

Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then stop fluconazole.

ART-Experienced + 10-Week Fluconazole; Delayed ART + 10-Week Fluconazole; Immediate ART + 10-Week Fluconazole Arm Type:

24-Week Fluconazole DRUG

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.

ART-Experienced + 24-Week Fluconazole; Delayed ART + 24-Week Fluconazole; Immediate ART + 24-Week Fluconazole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (1)

Infectious Diseases Institute, Makerere University

Kampala, Uganda

Location

MeSH Terms

Conditions

Meningitis, Cryptococcal

Interventions

Fluconazole

Condition Hierarchy (Ancestors)

Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses; Infections; Cryptococcosis; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Radha Rajasingham, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Radha Rajasingham, MD

CONTACT

612-625-4680; radha@umn.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants with low-titer cryptococcal antigenemia will undergo sequential randomization. Participants eligible for antiretroviral therapy timing randomization will be randomized at enrollment to immediate antiretroviral therapy initiation or delayed antiretroviral therapy initiation after 14 days. At week 10, participants who are alive and have not developed cryptococcal meningitis will be randomized to stop fluconazole after 10 weeks or continue fluconazole through 24 weeks.

Study Record Dates

• First Submitted: July 30, 2026
• First Posted: August 4, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): August 30, 2031
• Study Completion (Estimated): August 30, 2031
• Last Updated: August 4, 2026

Record last verified: 2026-07

Locations

UG (1)