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.
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
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
Sequential
Immediate ART Initiation
DrugAntiretroviral therapy will be initiated immediately at enrollment for participants randomized to immediate ART initiation. ART drug choice will be per clinical standard of care.
Delayed ART Initiation
DrugAntiretroviral 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.
10-Week Fluconazole
DrugParticipants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then stop fluconazole.
24-Week Fluconazole
DrugParticipants 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.
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Treatment groupsSee each treatment group below.
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.
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.
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.
24-week known survival
Known survival at 24 weeks will be assessed. Death and loss to follow-up will be considered therapeutic failures.
Incidence of cryptococcal meningitis
Incidence of cryptococcal meningitis will be assessed during study follow-up.
Incidence of hospitalization
Incidence of hospitalization, irrespective of cause, will be assessed during study follow-up.
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