Cryptococcal Antigenemia, Cryptococcal Infection, Cryptococcal Meningitis, HIV-1-infection
Conditions
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
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.
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.
Interventions
DRUGImmediate 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.
DRUGDelayed 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.
DRUG10-Week Fluconazole
Participants will receive fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily through week 10, then stop fluconazole.
DRUG24-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.
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 24-week cryptococcal meningitis-free survival with retention in care | 24 weeks | 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 | 10 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade 3 to 5 clinical adverse events or serious adverse events | Up to 24 weeks | Incidence of grade 3 to 5 clinical adverse events or serious adverse events will be assessed among enrolled participants. |
| 24-week known survival | 24 weeks | Known survival at 24 weeks will be assessed. Death and loss to follow-up will be considered therapeutic failures. |
| Incidence of cryptococcal meningitis | Up to 24 weeks | Incidence of cryptococcal meningitis will be assessed during study follow-up. |
| Incidence of hospitalization | Up to 24 weeks | Incidence of hospitalization, irrespective of cause, will be assessed during study follow-up. |
| Incidence of death | Up to 24 weeks | Incidence of death, irrespective of cause, will be assessed during study follow-up. |
| Fluconazole adherence | Up to 24 weeks | Fluconazole adherence will be assessed using self-reported compliance, pharmacy records, and tablet counts when available. |
Countries
Uganda
Contacts
CONTACTRadha Rajasingham, MD
PRINCIPAL_INVESTIGATORRadha Rajasingham, MD
University of Minnesota
Outcome results
None listed