Cryptococcal Optimal ART Timing Trial

After 7-11 days of amphotericin B therapy, subjects will be randomized in a 1:1 allocation to:

* Early initiation of ART (Experimental Group) = ART initiated within 48 hours after study entry, OR
* Standard initiation of ART (Control Group) = ART at >=4 weeks after study entry

HIV therapy will be with efavirenz plus nucleoside backbone per national guidelines for first line therapy.

• efavirenz (Drug), also known as sustiva: Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
• nucleoside (Biological), also known as zidovudine or stavudine, lamivudine: Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

Primary outcomes

• Mortality [26 weeks from study entry]: Intention to treat analysis of 26 week survival of all subjects enrolled. Reported below are the numbers of participants who died by Week 26.

Secondary outcomes

• Incidence of Immune Reconstitution Inflammatory Syndrome [46 weeks]: Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
• Incidence of Cryptococcal-relapse [46 weeks]: Incidence of culture positive cryptococcal meningitis relapse
• Safety of ART Initiation [46 weeks]: Incidence of Adverse Events (Grade 3,4,5) through 46-weeks, as defined by the National Institute of Allergy and Infectious Diseases, Division of AIDS toxicity classification scale, version 2009.
• 46-week Survival [46 weeks]: 46-week survival by time-to-event analysis of all subjects enrolled
• HIV-1 Viral Suppression [26 weeks]: HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
• Antiretroviral Therapy Tolerability [26 weeks]: Incidence of antiretroviral therapy interruption by >=3 consecutive days
• Karnofsky Functional Status [46 weeks]: Functional status via Karnofsky performance status score at 4, 26, 46 weeks. Karnofsky Scale: 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of his personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead
• Microbiologic Clearance [4 weeks]: Microbiologic clearance of cryptococcus as measured by serial quantitative cryptococcal cultures collected at diagnosis through 14 days of amphotericin therapy. The early fungicidal activity (EFA) of the rate of clearance is expressed as log10 colony forming units (CFU) of Cryptococcus neoformans per mL of CSF per day.

Other outcomes

• Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 [26 weeks]: Percentage of Participants who died by week 26 based on CSF white blood cell (WBC) count at study entry (time of randomization at a median of 8 days of anti-fungal therapy).

Sex: All, ages: 14 Years to any

Inclusion Criteria:

* HIV-infection, documented by ELISA
* Antiretroviral medication naïve (excluding mother-to-child transmission therapy)
* Age >14 years
* Cryptococcal meningitis diagnosed by either culture or CSF cryptococcal antigen (CRAG)
* Ability and willingness of the participant or legal guardian/representative to give informed consent.
* Receiving amphotericin-based anti-fungal therapy

Exclusion Criteria:

* Study entry prior to receipt of <7 days or >11 days of amphotericin therapy
* History of prior, known cryptococcal meningitis
* Inability to take enteral medication
* Receiving chemotherapy or other immunosuppressant medications
* Cannot or unlikely to attend regular clinic visits
* Contraindication to immediate or delayed HIV therapy based on serious co-morbidities or co-infections, or laboratory values
* Pregnancy or Breastfeeding
* Female participants of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use two reliable methods of contraception

Participant flow

Outcome results

• Mortality (Primary), Number, participants: Earlier HIV Therapy 40; Deferred HIV Therapy 27 (p 0.03)
• Incidence of Immune Reconstitution Inflammatory Syndrome (Secondary), Number, participants: Earlier HIV Therapy 17; Deferred HIV Therapy 9 (p 0.32)
• Incidence of Cryptococcal-relapse (Secondary), Number, participants: Earlier HIV Therapy 2; Deferred HIV Therapy 8 (p 0.06)
• Safety of ART Initiation (Secondary), Number, participants: Earlier HIV Therapy 73; Deferred HIV Therapy 75 (p 0.98)
• 46-week Survival (Secondary), Number, participants: Earlier HIV Therapy 41; Deferred HIV Therapy 29 (p 0.04)
• HIV-1 Viral Suppression (Secondary), Number, participants: Earlier HIV Therapy 43; Deferred HIV Therapy 49 (p 0.26)
• Antiretroviral Therapy Tolerability (Secondary), Number, participants: Earlier HIV Therapy 5; Deferred HIV Therapy 1 (p 0.23)
• Karnofsky Functional Status (Secondary), Mean, Scores on a scale: Earlier HIV Therapy 70 +/- 19; Deferred HIV Therapy 70 +/- 19 (p 0.34)
• Microbiologic Clearance (Secondary), Mean, log10 CFU/mL/day: Earlier HIV Therapy -0.31 (-0.34 to -0.28); Deferred HIV Therapy -0.31 (-0.34 to -0.28) (p 0.44)
• Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 (Other pre specified), Number, percentage of participants: Earlier HIV Therapy 48.5; Deferred HIV Therapy 16.1 (p 0.02)

Adverse events

Time frame: 46 weeks

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The differences in mortality in the two arms were of sufficient magnitude that trial enrollment was stopped early by the Data and Safety Monitoring Board. Historically, trials stopped early routinely over-estimate the magnitude of benefit or harm.

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• Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, Musubire A, Rajasingham R, Williams DA, Thienemann F, Muzoora C, Meintjes G, Meya DB, Boulware DR. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014 Dec 1;59(11):1607-14. doi: 10.1093/cid/ciu596. Epub 2014 Jul 23. PMID 25057102
• Scriven JE, Rhein J, Hullsiek KH, von Hohenberg M, Linder G, Rolfes MA, Williams DA, Taseera K, Meya DB, Meintjes G, Boulware DR; COAT Team. Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial. J Infect Dis. 2015 Sep 1;212(5):769-78. doi: 10.1093/infdis/jiv067. Epub 2015 Feb 4. PMID 25651842
• Williams DA, Kiiza T, Kwizera R, Kiggundu R, Velamakanni S, Meya DB, Rhein J, Boulware DR. Evaluation of fingerstick cryptococcal antigen lateral flow assay in HIV-infected persons: a diagnostic accuracy study. Clin Infect Dis. 2015 Aug 1;61(3):464-7. doi: 10.1093/cid/civ263. Epub 2015 Apr 1. PMID 25838287
• Rajasingham R, Rhein J, Klammer K, Musubire A, Nabeta H, Akampurira A, Mossel EC, Williams DA, Boxrud DJ, Crabtree MB, Miller BR, Rolfes MA, Tengsupakul S, Andama AO, Meya DB, Boulware DR. Epidemiology of meningitis in an HIV-infected Ugandan cohort. Am J Trop Med Hyg. 2015 Feb;92(2):274-9. doi: 10.4269/ajtmh.14-0452. Epub 2014 Nov 10. PMID 25385864
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• Bahr NC, Rolfes MA, Musubire A, Nabeta H, Williams DA, Rhein J, Kambugu A, Meya DB, Boulware DR. Standardized electrolyte supplementation and fluid management improves survival during amphotericin therapy for cryptococcal meningitis in resource-limited settings. Open Forum Infect Dis. 2014 Aug 25;1(2):ofu070. doi: 10.1093/ofid/ofu070. eCollection 2014 Sep. PMID 25734140
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• Results publication: Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G; COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487-98. doi: 10.1056/NEJMoa1312884. PMID 24963568
• Results publication: Sadiq A, Kwizera R, Kiiza TK, Ayebare P, Ahimbisibwe C, Ndyetukira JF, Boulware DR, Meya DB. Experiences, challenges, gaps, and strategies for counselling persons presenting with advanced HIV-associated meningitis in Uganda. AIDS Res Ther. 2025 Feb 19;22(1):21. doi: 10.1186/s12981-025-00705-z. PMID 39972326
• Results publication: Kwizera R, Sadiq A, Ndyetukira JF, Nalintya E, Williams D, Rhein J, Boulware DR, Meya DB; COAT and ASTRO trial teams. Impact of community engagement and social support on the outcomes of HIV-related meningitis clinical trials in a resource-limited setting. Res Involv Engagem. 2020 Aug 20;6:49. doi: 10.1186/s40900-020-00228-z. eCollection 2020. PMID 32843994
• Results publication: Skipper C, Schleiss MR, Bangdiwala AS, Hernandez-Alvarado N, Taseera K, Nabeta HW, Musubire AK, Lofgren SM, Wiesner DL, Rhein J, Rajasingham R, Schutz C, Meintjes G, Muzoora C, Meya DB, Boulware DR. Cytomegalovirus Viremia Associated With Increased Mortality in Cryptococcal Meningitis in Sub-Saharan Africa. Clin Infect Dis. 2020 Jul 27;71(3):525-531. doi: 10.1093/cid/ciz864. PMID 31504335
• Results publication: Bayiyana A, Okurut S, Nabatanzi R, Zziwa G, Boulware DR, Lutwama F, Meya D. Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis. J Fungi (Basel). 2019 Jul 17;5(3):63. doi: 10.3390/jof5030063. PMID 31319498
• Results publication: Tugume L, Rhein J, Hullsiek KH, Mpoza E, Kiggundu R, Ssebambulidde K, Schutz C, Taseera K, Williams DA, Abassi M, Muzoora C, Musubire AK, Meintjes G, Meya DB, Boulware DR; COAT and ASTRO-CM teams. HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts. J Infect Dis. 2019 Feb 23;219(6):877-883. doi: 10.1093/infdis/jiy602. PMID 30325463

• David R Boulware, MD, MPH, Principal investigator, University of Minnesota

NIH grants: U01AI089244