Optimizing Care for Cryptococcal Antigenemia: Evaluation of Short Course Fluconazole and ART Timing Among CrAg+ Persons With Low Titers
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 505
- 试验地点
- 1
- 主要终点
- 24-week cryptococcal meningitis-free survival with retention in care
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Immediate ART Initiation (Drug)
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.
干预措施: Immediate ART Initiation (Drug)
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.
干预措施: 24-Week Fluconazole (Drug)
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.
干预措施: Delayed ART Initiation (Drug)
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.
干预措施: 10-Week Fluconazole (Drug)
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.
干预措施: 10-Week Fluconazole (Drug)
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.
干预措施: Delayed ART Initiation (Drug)
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.
干预措施: 10-Week Fluconazole (Drug)
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.
干预措施: 24-Week Fluconazole (Drug)
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.
干预措施: 24-Week Fluconazole (Drug)
结局指标
主要结局
24-week cryptococcal meningitis-free survival with retention in care
时间窗: 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
时间窗: 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.
次要结局
- 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)
- Fluconazole adherence(Up to 24 weeks)