4. Table of studies at serious risk of bias overall (ROBINS‐I): disease‐related outcomes.

Studies at serious risk of bias outcomes: death, relapse of histoplasmosis
Study	Review objective	Domain(s)	Comment
ACTG120, 1992	1 and 2	Confounding; participant selection; intervention classification	Severity of HIV; severity of PDH and comorbidities were not controlled for using appropriate statistical methodology. ART use at baseline of an earlier phase of the trial reported: those who responded to the intervention (ITRA) in the induction phase were selected for the intervention in the maintenance phase: participants started intervention at various doses and had reductions in dose made at variable intervals. While this was likely to have been informed by ITRA blood levels that were being monitored, detailed data were not provided per participant.
ACTG174, 1994	1 and 2	Confounding; participant selection	At 3 months, protocol was revised and treatment regimen amended. Analyses were performed on participants who received the revised protocol (higher doses of FCN). Severity and management of HIV was not reported or controlled with appropriate statistical methods: selection into the maintenance arm of the study was related to the effect of the intervention in the induction phase.
Luckett 2015	1	Intervention classification; outcome measurement	No information about dose, frequency, and timing of interventions. Information was collected retrospectively. Treatment failure outcome was based on clinician judgement only. This was likely to favour switch from azole to amphotericin.
ACTG084, 1992	2	Confounding	Severity of HIV infection and ART use were not controlled for with appropriate statistical methods.
Goldman 2004	2	Participant selection	Start of intervention varied – participants enrolled after a range of 14–81 months of antifungal therapy. Unclear how many eligible people were not enrolled.
Mootsikapun 2006	2	Confounding; participant selection	≥ 1 known important domain was not appropriately measured or controlled for: details of disease severity, comedications and comorbidities not provided for 27 participants discharged from hospital: maintenance therapy was commenced in those who responded to initial treatment on amphotericin B. Timing of start of maintenance therapy was not reported. Selection into this part of the study was related to the intervention.
Melzani 2020	3	Confounding	ART was discontinued in 2/22 participants at the physician's decision; 2/22 due to patient choice. In unmasking group (14 participants), 10/14 received lAmB and 4/14 received ITRA. Paradoxical group (8 participants) physicians continued ART and ITRA for 6/8. Rationale for treatment choices not reported. Appropriate statistical measures to control for confounding were not reported. ≥ 1 known important domain was not appropriately measured or controlled for.

For details of risk of bias assessment see Appendix 3.

ART: antiretroviral therapy; FCN: fluconazole; ITRA: itraconazole; lAmB: liposomal amphotericin B; PDH: progressive disseminated histoplasmosis.