Makadzange 2010.

Methods	Study design: RCT
Participants	Inclusion criteria: eligible participants were aged 18 years and HIV‐positive. All participants had cryptococcal meningitis confirmed by positive results of India ink identification of Cryptococcus neoformans in the CSF or a CSF cryptococcal polysaccharide antigen (CrAg) test (CALAS; Meridian Diagnostics), or both. Participants residing in a 50‐kilometre radius of Harare. Informed consent Exclusion criteria: previous diagnosis of or treatment for cryptococcal meningitis, currently receiving ART, receiving medications that affect the metabolism of fluconazole (especially rifampicin), pregnant or lactating, or a history of hepatic or renal dysfunction Number randomized: 54 Descriptive baseline data Age (mean (SD) years): early ART ‐36.6 (±8.5); delayed ART ‐37.5 (±6.9) Sex (% male): early ART 50%; delayed ART 54% CD4 count (median (IQR) cells/μL): early ART 27 (17 to 69); delayed ART 51.5 (25 to 69.5) Fungal burden (CSF CrAg titre > 1:128 (n;%)): early ART 15 (65.2); delayed ART 21 (87.5) Level of consciousness at baseline: not reported Dropouts during study period: 8 (some numerical discrepancy in flow diagram, which suggests 6)
Interventions	Duration of antifungal therapy prior to randomization: 0 days ‐ randomized at time of diagnosis and treatment initiation Antifungal therapy provided: fluconazole (800 mg once per day; Diflucan (Pfizer)), after 10 weeks reduced to a prophylactic dosage of 200 mg once per day. Where treatment failure was suspected (positive culture, positive India ink or persistently elevated CrAg titres), dosage was increased once again to 800 mg daily until CSF clear. Supportive care: not described CSF pressure management: CSF hypertension reduced if clinically indicated or CSF pressure high at study visits where LPs were conducted. ART regimen: fixed‐dose combination of stavudine (30 mg twice per day) and lamivudine (150 mg twice per day), and nevirapine (200 mg twice per day, with a 200 mg once‐daily 2‐week lead‐in dose) Early ART: started within 72 hours of randomization Delayed ART: started after 10 weeks of antifungal therapy Adherence: adherence to fluconazole and ART: self reports and pill counts at each visit (not reported in outcomes)
Outcomes	Primary outcomes All‐cause mortality Secondary outcomes Time to death Adverse events Timing of outcome assessment: observed at outpatient clinic at 2, 4, 8, and 10 weeks, then monthly. Liver function tests conducted 6 monthly up to 2 years. Cerebrospinal fluid sampled at weeks 2, 4, and 10.
Notes	Country: Zimbabwe Setting: a tertiary referral teaching hospital in Harare Dates: October 2006 through April 2008 Funding: The AIDS Care Research in Africa (ACRiA) programme and the small grants funding programme from the Infectious Diseases Society of America Other: Study was terminated early by the data safety monitoring committee, and the optimal sample size was not achieved. Safety concerns with regard to administration of fluconazole in high dose and nevirapine and lack of regular LFT monitoring. Concerns about censoring. Participants were discharged from hospital within 1 week Numerical inconsistencies in results
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated randomization schedule was used to assign participants to the early ART and delayed ART arms of the trial.
Allocation concealment (selection bias)	Low risk	The randomization sequence was concealed to the trial nurse who was responsible for participant enrolment using sealed envelopes.
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. Trial did not report on IRIS. This is unlikely to bias results for mortality and laboratory tests, however bias could be introduced for adverse events.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses to follow‐up low and similar in both arms (3 out of 28 and 3/5 out of 26 in early ART and delayed ART arms)
Selective reporting (reporting bias)	Unclear risk	Protocol not available for review; outcomes not listed on ClinicalTrials.gov (protocol registered after trial was completed) clinicaltrials.gov/ct2/show/NCT00830856
Other bias	High risk	Some reported results were not arithmetically correct, which could have had an impact on effect estimates. In addition, the authors were not consistent with the intention‐to‐treat approach, which could have affected the time‐to‐event analysis. Concerns about the results of this trial are echoed in comments from other trial authors in the same field (Boulware 2010; Bicanic 2010; Grant 2010).