Bisson 2013.

Methods	Study design: open‐label RCT
Participants	Inclusion criteria: adults ≥ 21 years of age: HIV‐positive, (positive enzyme‐linked immunosorbent assay and/or a detectable (i.e. > 400 copies/mL) plasma viral load); India ink–positive cryptococcal meningitis; ART‐naive, no past use of ART besides for prevention of mother‐to‐child transmission ≥ 6 months previously; could provide written informed consent; to initiate or had initiated amphotericin B ≤ 72 hours prior to enrolment; no antifungal use within the prior 14 days; not pregnant, as determined by a negative urine β–human chorionic gonadotropin test, or were breastfeeding; not initiated antitubercular therapy ≤ 2 weeks prior to assessment; not have bacterial meningitis; unlikely to initiate immunomodulatory therapy (e.g. cancer chemotherapy) prior to the week 4 study visit; not prisoners; available CSF for determination of baseline CFUs; and would obtain outpatient care within the logistical reach of the study team. Informed consent. Exclusion criteria: patients not meeting the inclusion criteria Number randomized: 28 Descriptive baseline data: Age: median: 35 years (IQR 32 to 41) Sex: n = 14 (52%) male CD4 count: median: 29 (IQR 11 to 50) cells/μL Fungal burden: median: 5.7 log10 CFU (IQR 5.2 to 6.5) GCS: median: 15 (IQR not reported) Duration of antifungal therapy prior to randomization: 72 hrs Dropouts during study period: 1
Interventions	Antifungal therapy provided: amphotericin B 0.7 mg/kg × 14 days, followed by oral fluconazole 400 mg daily × 8 weeks, followed by oral fluconazole 200 mg daily until the CD4 count is > 200 cells/μL for 6 months Supportive care: not described CSF pressure management: not described ART regimen provided: 18 (82%) participants initiated combination TDF/FTC/EFV, whereas the remaining 4 participants initiated combination zidovudine/lamivudine plus NVP or EFV (2 participants) or TDF/FTC and NVP (2 participants). Early ART: 12 of 13 (92%) participants initiated ART at a median of 7 days (IQR 5 to 10) after randomization. Delayed ART: 10 of 14 (71%) participants in the control arm initiated ART at a median of 32 days (IQR 28 to 36) after randomization. Adherence: not reported
Outcomes	Primary outcomes All‐cause mortality Cryptococcal meningitis relapse Secondary outcomes Time to CSF fungal clearance: "fungal colony forming units (CFUs) were measured using a standard protocol on the initial CSF sample submitted for diagnosis, on CSF obtained at a study‐specific lumbar puncture performed 4 weeks after randomization, and on available CSF obtained from other lumbar punctures." Time to death (authors provided additional unpublished data ‐ HR for mortality) IRIS: defined by 2 research team physicians unblinded using Haddow 2010 definition Adverse events: incident adverse events were graded using the Division of AIDS Table for Grading Adult Adverse and Pediatric Adverse Events Virological suppressions Timing of outcome measurement Study‐specific visits, performed at entry and at days 7 and 14, week 4, and monthly thereafter, included medical history and physical examination. HIV load, CD4 count, and complete blood count were performed at randomization, at week 4, and then at weeks 12 and 24 after the planned date of ART initiation. Serum chemistries were performed as above and at days 7 and 14. Study‐specific lumbar puncture performed 4 weeks after randomization.
Notes	Country: Botswana Setting: hospital setting Dates: September 2009 and November 2011 Funding: Doris Duke Charitable Foundation via a Doris Duke Clinical Scientist Development Award (to GPB) and by the Penn Center for AIDS Research International Core Other: early study termination due to slow recruitment and funding (planned sample size = 25 per study arm)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The trial authors mention randomization, but do not describe how this was done.
Allocation concealment (selection bias)	Unclear risk	The trial authors do not describe the allocation concealment process.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label trial
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Outcome assessment was not reported as blinded. Immune reconstitution inflammatory syndrome assessment was unblinded. This is unlikely to bias results for mortality and laboratory tests, however bias could be introduced for adverse events and IRIS.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 1 participant dropped out after randomization.
Selective reporting (reporting bias)	Low risk	This trial was registered on ClinicalTrials.gov in 2009: clinicaltrials.gov/ct2/archive/NCT00976040 clinicaltrials.gov/ct2/show/NCT00976040 2 proposed outcomes were not reported: Clearance of Cryptococcus neoformans antigen from CSF and blood (time frame: 6 months) Change in the number of peripheral blood mononuclear cells responding to C neoformans (time frame: 4 weeks) We do not see these as introducing bias, as all main relevant outcomes were reported.
Other bias	Low risk	We did not identify any other potential sources of bias.