Study:ACTG120, 1992. Outcome: relapse of histoplasmosis –induction phase
Confounding domains	Measured variable(s)	Is there evidence that controlling for this variable was unnecessary?	Is the confounding domain measured validly and reliably?	OPTIONAL Is failure to adjust for this variable expected to favour intervention or comparator
Severity of PDH	Defined – severe disease excluded.	No	Yes	—
Severity of HIV	CD4	No	No. Only baseline reported	—
Comorbidities and comedications	Participants receiving concurrent treatment with drugs that interact with ITRA including rifampin were excluded.	No	No. Limited data reported	—
Cointerventions	Is there evidence that controlling for this cointervention was unnecessary?		Is presence of this cointervention likely to favour outcomes in the intervention or comparator?
ART at time of PDH diagnosis	No. Report 35/59 using ART at baseline. No further data provided on HIV management.		—
Supportive therapy	Those requiring intensive supportive therapy were excluded.		—
Bias domain	Signalling questions	Comments		Risk of bias judgement
Bias due to confounding	1.1–1.8	Severity of HIV; severity of PDH and comorbidities were not controlled for using appropriate statistical methodology.		Serious
Bias in participant selection	2.1–2.5	Selection into the study may have been related to the intervention and outcome as those with less severe histoplasmosis were more likely to be selected; however, start of follow‐up and intervention appear to coincide.		Moderate
Bias in classification of intervention	3.1–3.3	Data provided per participant for ITRA levels in non‐responders. Detailed data on ITRA levels not reported for remaining participants. ITRA levels determined dose of intervention.		Serious
Bias due to deviations from intended intervention	4.1–4.6	Deviations from intended intervention were consistent with usual practice. Data reported for toxicity and clinical reasons for discontinuation of intervention.		Low
Bias due to missing data	5.1–5.5	Data were reasonably complete.		Low
Bias in measurement of outcomes	6.1–6.4	Outcome measures were confirmed by laboratory assessments such as blood culture.		Low
Bias in selection of reported result	7.1–7.3	Reported results correspond to intended outcomes.		Low
Overall bias				Serious