Treatment for HIV‐associated cryptococcal meningitis

Mark W Tenforde; Adrienne E Shapiro; Benjamin Rouse; Joseph N Jarvis; Tianjing Li; Ingrid Eshun‐Wilson; Nathan Ford

doi:10.1002/14651858.CD005647.pub3

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Figure 1

Study flow diagram.

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Figure 2

‘Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

‘Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, outcome: 7.1 Mortality.

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Figure 5

Forest plot of comparison: 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, outcome: 7.2 Early fungicidal activity.

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Figure 6

Forest plot of comparison: 8 Two weeks of AmBd + FLU versus two weeks of AmBd, outcome: 8.1 Mortality.

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Figure 7

Forest plot of comparison: 8 Two weeks of AmBd + FLU versus two weeks of AmBd, outcome: 8.2 Early fungicidal activity.

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Figure 8

Forest plot of comparison: 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, outcome: 9.1 Mortality.

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Figure 9

Forest plot of comparison: 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, outcome: 9.2 Early fungicidal activity.

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Figure 10

Network plot for 10‐week mortality.

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Figure 11

Ten‐week mortality treatment effect estimates. Values in the table are risk ratios (RRs) with 95% confidence intervals. Bolded values represent statistically significant effects. The bottom half of the table represents network meta‐analysis‐derived treatment effects, while the top half represents results from direct comparisons alone. For network meta‐analysis‐derived effects, RR < 1 favours the treatment combination in the column. For effects derived from pairwise meta‐analysis, RR < 1 favours the treatment combination in the row. Treatment combinations are ordered by surface under the cumulative ranking curve (SUCRA) rankings.

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Figure 12

Ten‐week mortality risk for each treatment combination compared to reference of two weeks of AmBd and FLU.

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Figure 13

Cumulative ranking probabilities for each treatment combination for 10‐week mortality. The SUCRA value represents the surface underneath the cumulative ranking curve and is the probabilities for each treatment combination to be among the n‐best options. The larger the SUCRA value, the higher the ranking probability for the treatment combination in the network. The SUCRA values for each treatment combination are as follows: AmBd (19%), AmBd + 5FC (59%), AmBd + 5FC + IFNg (59%), AmBd + FLU (45%), AmBd + FLU + 5FC (74%), AmBd + FLU + St (26%), FLU (27%), FLU + 5FC (67%), L‐Amb (67%), shortAmBd + 5FC (88%), shortAmBd + FLU (26%), shortAmBd + FLU + 5FC (45%).

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Figure 14

Modified GRADE for network meta‐analysis

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Analysis 1.1

Comparison 1 One week of AmBd + 5FC versus two weeks of AmBd + 5FC, Outcome 1 Mortality.

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Analysis 1.2

Comparison 1 One week of AmBd + 5FC versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.

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Analysis 1.3

Comparison 1 One week of AmBd + 5FC versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 2.1

Comparison 2 One week of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 1 Mortality.

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Analysis 2.2

Comparison 2 One week of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 2.3

Comparison 2 One week of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 3.1

Comparison 3 One week of AmBd + 5FC versus one week of AmBd + FLU, Outcome 1 Mortality.

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Analysis 3.2

Comparison 3 One week of AmBd + 5FC versus one week of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 3.3

Comparison 3 One week of AmBd + 5FC versus one week of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 4.1

Comparison 4 One week of AmBd + 5FC versus two weeks of 5FC + FLU, Outcome 1 Mortality.

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Analysis 4.2

Comparison 4 One week of AmBd + 5FC versus two weeks of 5FC + FLU, Outcome 2 Early fungicidal activity.

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Analysis 4.3

Comparison 4 One week of AmBd + 5FC versus two weeks of 5FC + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 5.1

Comparison 5 Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 1 Mortality.

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Analysis 5.2

Comparison 5 Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.

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Analysis 5.3

Comparison 5 Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 6.1

Comparison 6 Two weeks of 5FC + FLU versus two weeks of AmBd + FLU, Outcome 1 Mortality.

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Analysis 6.2

Comparison 6 Two weeks of 5FC + FLU versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 6.3

Comparison 6 Two weeks of 5FC + FLU versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 7.1

Comparison 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, Outcome 1 Mortality.

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Analysis 7.2

Comparison 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, Outcome 2 Early fungicidal activity.

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Analysis 7.3

Comparison 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 8.1

Comparison 8 Two weeks of AmBd + FLU versus two weeks of AmBd, Outcome 1 Mortality.

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Analysis 8.2

Comparison 8 Two weeks of AmBd + FLU versus two weeks of AmBd, Outcome 2 Early fungicidal activity.

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Analysis 8.3

Comparison 8 Two weeks of AmBd + FLU versus two weeks of AmBd, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 9.1

Comparison 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 1 Mortality.

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Analysis 9.2

Comparison 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 9.3

Comparison 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 10.1

Comparison 10 Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU, Outcome 1 Mortality.

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Analysis 10.2

Comparison 10 Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 10.3

Comparison 10 Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 11.1

Comparison 11 One week of AmBd + FLU versus two weeks of AmBd + FLU, Outcome 1 Mortality.

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Analysis 11.2

Comparison 11 One week of AmBd + FLU versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 11.3

Comparison 11 One week of AmBd + FLU versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 12.1

Comparison 12 One week of AmBd + FLU versus two weeks of AmBd + 5FC, Outcome 1 Mortality.

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Analysis 12.2

Comparison 12 One week of AmBd + FLU versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.

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Analysis 12.3

Comparison 12 One week of AmBd + FLU versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 13.1

Comparison 13 One week of AmBd + FLU versus two weeks of 5FC + FLU, Outcome 1 Mortality.

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Analysis 13.2

Comparison 13 One week of AmBd + FLU versus two weeks of 5FC + FLU, Outcome 2 Early fungicidal activity.

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Analysis 13.3

Comparison 13 One week of AmBd + FLU versus two weeks of 5FC + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 14.1

Comparison 14 Two weeks of FLU versus two weeks of 5FC + FLU, Outcome 1 Mortality.

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Analysis 14.2

Comparison 14 Two weeks of FLU versus two weeks of 5FC + FLU, Outcome 2 Early fungicidal activity.

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Analysis 14.3

Comparison 14 Two weeks of FLU versus two weeks of 5FC + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 15.1

Comparison 15 Two weeks of L‐AmB versus two weeks of AmBd, Outcome 1 Mortality.

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Analysis 16.1

Comparison 16 Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU, Outcome 1 Mortality.

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Analysis 16.2

Comparison 16 Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU, Outcome 2 Early fungicidal activity.

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Analysis 16.3

Comparison 16 Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 17.1

Comparison 17 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 1 Mortality.

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Analysis 17.2

Comparison 17 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.

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Analysis 18.1

Comparison 18 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + FLU, Outcome 1 Mortality.

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Analysis 18.2

Comparison 18 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 19.1

Comparison 19 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd, Outcome 1 Mortality.

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Analysis 19.2

Comparison 19 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd, Outcome 2 Early fungicidal activity.

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Analysis 20.1

Comparison 20 One week of AmBd + 5FC + FLU versus one week of AmBd + FLU, Outcome 1 Mortality.

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Analysis 20.2

Comparison 20 One week of AmBd + 5FC + FLU versus one week of AmBd + FLU, Outcome 2 Early fungicidal activity.

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Analysis 20.3

Comparison 20 One week of AmBd + 5FC + FLU versus one week of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.

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Analysis 21.1

Comparison 21 Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC, Outcome 1 Mortality.

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Analysis 21.2

Comparison 21 Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.

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Analysis 21.3

Comparison 21 Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.

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Summary of findings for the main comparison. One week of AmBd + 5FC compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

One week of AmBd + 5FC compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + 5FC Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 1 week of AmBd + 5FC
Mortality: 10 weeks	383 per 1000	237 per 1000 (161 to 356)	RR 0.62 (0.42 to 0.93)	228 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings for the main comparison. One week of AmBd + 5FC compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

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Summary of findings 2. One week of AmBd + 5FC compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

One week of AmBd + 5FC compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + 5FC Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 1 week of AmBd + 5FC
Mortality: 10 weeks	412 per 1000	239 per 1000 (161 to 355)	RR 0.58 (0.39 to 0.86)	227 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 2. One week of AmBd + 5FC compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 3. One week of AmBd + 5FC compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis

One week of AmBd + 5FC compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + 5FC Comparison: 1 week of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 1 week of AmBd + FLU	Risk with 1 week of AmBd + 5FC
Mortality: 10 weeks	486 per 1000	238 per 1000 (165 to 350)	RR 0.49 (0.34 to 0.72)	224 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 3. One week of AmBd + 5FC compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 4. One week of AmBd + 5FC compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis

One week of AmBd + 5FC compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: Randomized controlled trial Intervention: 1 week of AmBd + 5 FC Comparison: 2 weeks of 5FC + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of 5FC + FLU	Risk with 1 week of AmBd + 5FC
Mortality: 10 weeks	351 per 1000	239 per 1000 (165 to 348)	RR 0.68 (0.47 to 0.99)	338 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 4. One week of AmBd + 5FC compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 5. Two weeks of 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

Two weeks of 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of 5FC + FLU Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 2 weeks of 5FC + FLU
Mortality: 10 weeks	383 per 1000	352 per 1000 (264 to 471)	RR 0.92 (0.69 to 1.23)	340 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 5. Two weeks of 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

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Summary of findings 6. Two weeks of 5FC + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

Two weeks of 5FC + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of 5FC + FLU Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 2 weeks of 5FC + FLU
Mortality: 10 weeks	412 per 1000	350 per 1000 (264 to 466)	RR 0.85 (0.64 to 1.13)	339 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 6. Two weeks of 5FC + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 7. Two weeks of AmBd + 5FC compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + 5FC compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + 5FC Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of AmBd + 5FC
Mortality: 10 weeks	409 per 1000	270 per 1000 (188 to 388)	RR 0.66 (0.46 to 0.95)	231 (2 RCTs)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from two studies with few events.

Summary of findings 7. Two weeks of AmBd + 5FC compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

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Summary of findings 8. Two weeks of AmBd + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + FLU Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of AmBd + FLU
Mortality: 10 weeks	338 per 1000	317 per 1000 (186 to 547)	RR 0.94 (0.55 to 1.62)	371 (3 RCTs)	⊕⊕⊝⊝ LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for indirectness. Some participants received a lower dose of fluconazole than currently recommended in combination with AmBd. Pappas 2009 excluded from enrolment patients who were not expected to survive two weeks, so the study population may not be representative of general patients with cryptococcal meningitis. ²Downgraded one level for imprecision. Few events with broad CI including appreciable benefit and appreciable harm.

Summary of findings 8. Two weeks of AmBd + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

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Summary of findings 9. Two weeks of AmBd + 5FC compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + 5FC compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + 5FC Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 2 weeks of AmBd + 5FC
Mortality: 10 weeks	355 per 1000	320 per 1000 (245 to 423)	RR 0.90 (0.69 to 1.19)	538 (4 RCTs)	⊕⊕⊝⊝ LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for indirectness. Some participants received a lower dose of fluconazole than is currently recommended in combination with AmBd. A few participants in one study also received a different azole drug, voriconazole. ²Downgraded one level for imprecision. Few overall events.

Summary of findings 9. Two weeks of AmBd + 5FC compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 10. Two weeks of AmBd + FLU + steroids compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + FLU + steroids compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + FLU + steroids Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 2 weeks of AmBd + FLU + steroids
Mortality: 10 weeks	412 per 1000	473 per 1000 (383 to 584)	RR 1.15 (0.93 to 1.42)	450 (1 RCT)	⊕⊕⊕⊕ HIGH
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Summary of findings 10. Two weeks of AmBd + FLU + steroids compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 11. One week of AmBd + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

One week of AmBd + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + FLU Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 1 week of AmBd + FLU
Mortality: 10 weeks	412 per 1000	486 per 1000 (363 to 651)	RR 1.18 (0.88 to 1.58)	225 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 11. One week of AmBd + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 12. One week of AmBd + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

One week of AmBd + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + FLU Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 1 week of AmBd + FLU
Mortality: 10 weeks	383 per 1000	486 per 1000 (360 to 658)	RR 1.27 (0.94 to 1.72)	226 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 12. One week of AmBd + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

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Summary of findings 13. One week of AmBd + FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis

One week of AmBd + FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + FLU Comparison: 2 weeks of 5FC + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of 5FC + FLU	Risk with 1 week of AmBd + FLU
Mortality: 10 weeks	351 per 1000	488 per 1000 (376 to 632)	RR 1.39 (1.07 to 1.80)	336 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for imprecision. Data from a single study with few events.

Summary of findings 13. One week of AmBd + FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 14. Two weeks of FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis

Two weeks of FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of FLU Comparison: 2 weeks of 5FC + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of 5FC + FLU	Risk with 2 weeks of FLU
Mortality: 10 weeks	392 per 1000	573 per 1000 (376 to 875)	RR 1.46 (0.96 to 2.23)	98 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^1,2,3
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for risk of bias. High loss to follow‐up by 10 weeks. ²Downgraded one level for indirectness. Participants in one study received a lower dose of fluconazole than is recommended and a higher dose of flucytosine. ³Downgraded two levels for imprecision. Data from two small studies with few events.

Summary of findings 14. Two weeks of FLU compared to two weeks of 5FC + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 15. Two weeks of L‐AmB compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

Two weeks of L‐AmB compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of L‐AmB Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of L‐AmB
Mortality: 10 weeks	154 per 1000	66 per 1000 (6 to 654)	RR 0.43 (0.04 to 4.25)	28 (1 RCT)	⊕⊝⊝⊝ VERY LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: AmBd: amphotericin B deoxycholate; CI: confidence interval; L‐AmB: liposomal amphotericin B; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for risk of bias. Study sponsored by study drug manufacturer, and role of funder not stated. Mortality also not stated as primary outcome of interest. ²Downgraded two levels for imprecision. Data from single small study with few events and broad CI including appreciable benefit and appreciable harm.

Summary of findings 15. Two weeks of L‐AmB compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

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Summary of findings 16. Short‐course L‐AmB + FLU compared to two weeks of L‐AmB + FLU for HIV‐associated cryptococcal meningitis

Short‐course L‐AmB + FLU compared to two weeks of L‐AmB + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: short‐course L‐AmB + FLU Comparison: 2 weeks of L‐AmB + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of L‐AmB + FLU	Risk with short‐course L‐AmB + FLU
Mortality: 10 weeks	286 per 1000	294 per 1000 (134 to 643)	RR 1.03 (0.47 to 2.25)	79 (1 RCT)	⊕⊕⊝⊝ LOW¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; FLU: fluconazole; L‐AmB: liposomal amphotericin B; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded two levels for imprecision. Data from a single small study with few events and broad CI including appreciable benefit and appreciable harm.

Summary of findings 16. Short‐course L‐AmB + FLU compared to two weeks of L‐AmB + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 17. Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + 5FC + FLU Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 2 weeks of AmBd + 5FC + FLU
Mortality: 10 weeks	67 per 1000	187 per 1000 (22 to 1000)	RR 2.81 (0.33 to 24.16)	31 (1 RCT)	⊕⊝⊝⊝ VERY LOW^{1 2}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for indirectness. Data generated from a single study that used a low dose of fluconazole. ²Downgraded two levels for imprecision. Data from a single small study with few events and broad CI including appreciable benefit and appreciable harm.

Summary of findings 17. Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

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Summary of findings 18. Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + 5FC + FLU Comparison: 2 weeks of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + FLU	Risk with 2 weeks of AmBd + 5FC + FLU
Mortality: 10 weeks	438 per 1000	188 per 1000 (57 to 599)	RR 0.43 (0.13 to 1.37)	32 (1 RCT)	⊕⊝⊝⊝ VERY LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for indirectness. Data generated from a single small study that used a lower dose of fluconazole than is currently recommended. ²Downgraded two levels for imprecision. Data generated from a single small study with very few events.

Summary of findings 18. Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 19. Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + 5FC + FLU Comparison: 2 weeks of AmBd
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd	Risk with 2 weeks of AmBd + 5FC + FLU
Mortality: 10 weeks	188 per 1000	188 per 1000 (45 to 793)	RR 1.00 (0.24 to 4.23)	32 (1 RCT)	⊕⊝⊝⊝ VERY LOW^1,2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded one level for indirectness. Data generated from a single study that used a low dose of fluconazole. ²Downgraded two levels for imprecision. Data from a single small study with few events and broad CI including appreciable benefit and appreciable harm.

Summary of findings 19. Two weeks of AmBd + 5FC + FLU compared to two weeks of AmBd for HIV‐associated cryptococcal meningitis

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Summary of findings 20. One week of AmBd + 5FC + FLU compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis

One week of AmBd + 5FC + FLU compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 1 week of AmBd + 5FC + FLU Comparison: 1 week of AmBd + FLU
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 1 week of AmBd + FLU	Risk with 1 week of AmBd + 5FC + FLU
Mortality: 10 weeks	350 per 1000	301 per 1000 (122 to 735)	RR 0.86 (0.35 to 2.10)	40 (1 RCT)	⊕⊕⊝⊝ LOW¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; FLU: fluconazole; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded two levels for imprecision. Data from a single small study with few events and broad CI including appreciable benefit and appreciable harm.

Summary of findings 20. One week of AmBd + 5FC + FLU compared to one week of AmBd + FLU for HIV‐associated cryptococcal meningitis

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Summary of findings 21. Two weeks of AmBd + 5FC + IFNg compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

Two weeks of AmBd + 5FC + IFNg compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis
Patient or population: HIV‐infected individual with first episode of cryptococcal meningitis Setting: randomized controlled trial Intervention: 2 weeks of AmBd + 5FC + IFNg Comparison: 2 weeks of AmBd + 5FC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Risk with 2 weeks of AmBd + 5FC	Risk with 2 weeks of AmBd + 5FC + IFNg
Mortality: 10 weeks	323 per 1000	297 per 1000 (155 to 571)	RR 0.92 (0.48 to 1.77)	88 (1 RCT)	⊕⊕⊝⊝ LOW¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: 5FC: flucytosine; AmBd: amphotericin B deoxycholate; CI: confidence interval; IFNg: interferon gamma 1b; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded two levels for imprecision. Data generated from a single study with few events and broad CI that included appreciable benefit and appreciable harm.

Summary of findings 21. Two weeks of AmBd + 5FC + IFNg compared to two weeks of AmBd + 5FC for HIV‐associated cryptococcal meningitis

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Table 1. Overview of drugs evaluated for the treatment of HIV‐associated cryptococcal meningitis

Class	Mechanism of action	Drug examples for cryptococcal meningitis therapy	Major class side effects
Polyenes	Disrupt cell membranes	Amphotericin B (liposomal or non‐liposomal formulations)	Nephrotoxicity, electrolyte abnormalities, anaemia
Azoles	Inhibit ergosterol biosynthesis	Fluconazole, voriconazole, itraconazole	Hepatotoxicity, drug‐drug interactions, GI symptoms, rash
Pyrimidine analogue	Inhibit fungal RNA and protein biosynthesis	Flucytosine	Bone marrow suppression, hepatotoxicity, GI symptoms
Glucocorticoids	Various anti‐inflammatory effects	Dexamethasone	Hyperglycaemia, bleeding, psychiatric effects, secondary hypoaldosteronism, immunosuppression
Selective serotonin reuptake inhibitor (SSRI)	5‐hydroxytryptamine transporter inhibitor, antifungal mechanism of action unclear	Sertraline	Neurocognitive effects, GI symptoms
Carbonic anhydrase inhibitor	Reduces intracranial pressure by reducing cerebrospinal fluid production, likely through multiple mechanisms	Acetazolamide	Metabolic acidosis, nephrolithiasis, aplastic anaemia, GI symptoms, paraesthesias
Abbreviations: GI: gastrointestinal; RNA: ribonucleic acid

Table 1. Overview of drugs evaluated for the treatment of HIV‐associated cryptococcal meningitis

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Comparison 1. One week of AmBd + 5FC versus two weeks of AmBd + 5FC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.30, 1.03]
1.2 10 weeks	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.42, 0.93]
2 Early fungicidal activity Show forest plot	1	186	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.02, 0.12]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.16, 0.60]
3.2 Renal dysfunction	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.18, 1.93]
3.3 Neutropenia	1	228	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.43, 2.03]
3.4 Hypokalaemia	1	228	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.50, 3.39]
3.5 ALT abnormality	1	228	Risk Ratio (M‐H, Random, 95% CI)	3.05 [0.63, 14.81]

Comparison 1. One week of AmBd + 5FC versus two weeks of AmBd + 5FC

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Comparison 2. One week of AmBd + 5FC versus two weeks of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	227	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.28, 0.97]
1.2 10 weeks	1	227	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.39, 0.86]
2 Early fungicidal activity Show forest plot	1	192	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.14, ‐0.00]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	227	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.18, 0.71]
3.2 Renal dysfunction	1	227	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.10, 0.85]
3.3 Neutropenia	1	227	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.49, 2.51]
3.4 Hypokalaemia	1	227	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.42, 2.45]
3.5 LFT abnormality	1	227	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.34, 3.03]

Comparison 2. One week of AmBd + 5FC versus two weeks of AmBd + FLU

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Comparison 3. One week of AmBd + 5FC versus one week of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	224	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.20, 0.63]
1.2 10 weeks	1	224	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.34, 0.72]
2 Early fungicidal activity Show forest plot	1	179	Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.15, ‐0.01]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	224	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.21, 0.82]
3.2 Renal dysfunction	1	224	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.12, 1.09]
3.3 Neutropenia	1	224	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.62, 3.84]
3.4 Hypokalaemia	1	224	Risk Ratio (M‐H, Random, 95% CI)	1.77 [0.61, 5.11]
3.5 ALT abnormality	1	224	Risk Ratio (M‐H, Random, 95% CI)	2.95 [0.61, 14.29]

Comparison 3. One week of AmBd + 5FC versus one week of AmBd + FLU

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Comparison 4. One week of AmBd + 5FC versus two weeks of 5FC + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	338	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.35, 1.13]
1.2 10 weeks	1	338	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.47, 0.99]
2 Early fungicidal activity Show forest plot	1	280	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.24, ‐0.12]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	338	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.79, 4.13]
3.2 Renal dysfunction	1	338	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.24, 2.22]
3.3 Neutropenia	1	338	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.48, 1.88]
3.4 Hypokalaemia	1	338	Risk Ratio (M‐H, Random, 95% CI)	5.97 [1.65, 21.63]
3.5 ALT abnormality	1	338	Risk Ratio (M‐H, Random, 95% CI)	1.99 [0.66, 6.03]

Comparison 4. One week of AmBd + 5FC versus two weeks of 5FC + FLU

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Comparison 5. Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	340	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.56, 1.37]
1.2 10 weeks	1	340	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.69, 1.23]
2 Early fungicidal activity Show forest plot	1	270	Mean Difference (IV, Random, 95% CI)	0.23 [0.17, 0.29]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	340	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.09, 0.32]
3.2 Renal dysfunction	1	340	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.32, 2.02]
3.3 Neutropenia	1	340	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.51, 1.90]
3.4 Hypokalaemia	1	340	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.06, 0.83]
3.5 ALT abnormality	1	340	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.31, 7.48]

Comparison 5. Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC

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Comparison 6. Two weeks of 5FC + FLU versus two weeks of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	339	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.53, 1.29]
1.2 10 weeks	1	339	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.64, 1.13]
2 Early fungicidal activity Show forest plot	1	276	Mean Difference (IV, Random, 95% CI)	0.11 [0.05, 0.17]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	339	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.10, 0.39]
3.2 Renal dysfunction	1	339	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.19, 0.85]
3.3 Neutropenia	1	339	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.57, 2.36]
3.4 Hypokalaemia	1	339	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.05, 0.61]
3.5 ALT abnormality	1	339	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.17, 1.54]

Comparison 6. Two weeks of 5FC + FLU versus two weeks of AmBd + FLU

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Comparison 7. Two weeks of AmBd + 5FC versus two weeks of AmBd

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	3	612	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.44, 1.11]
1.2 10 weeks	2	231	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.46, 0.95]
1.3 6 months	1	199	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.46, 0.88]
2 Early fungicidal activity Show forest plot	2	225	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.26, ‐0.04]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	199	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.54, 1.06]
3.2 Renal dysfunction	1	199	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.14, 6.89]
3.3 Neutropenia	1	199	Risk Ratio (M‐H, Random, 95% CI)	4.46 [0.99, 20.10]
3.4 Hypokalaemia	1	199	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.64, 1.87]

Comparison 7. Two weeks of AmBd + 5FC versus two weeks of AmBd

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Comparison 8. Two weeks of AmBd + FLU versus two weeks of AmBd

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	3	371	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.45, 1.77]
1.2 10 weeks	3	371	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.55, 1.62]
1.3 6 months	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.64, 1.13]
2 Early fungicidal activity Show forest plot	2	223	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.06, 0.02]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.43, 0.91]
3.2 Renal dysfunction	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.14, 6.96]
3.3 Neutropenia	1	198	Risk Ratio (M‐H, Random, 95% CI)	4.5 [1.00, 20.30]
3.4 Hypokalaemia	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.34, 1.23]

Comparison 8. Two weeks of AmBd + FLU versus two weeks of AmBd

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Comparison 9. Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	4	538	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.55, 1.16]
1.2 10 weeks	4	538	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.69, 1.17]
1.3 6 months	1	199	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.53, 1.06]
2 Early fungicidal activity Show forest plot	4	474	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.14, ‐0.05]

3 DAIDS grade 3/4 toxicities Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	3	507	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.89, 1.55]
3.2 Renal dysfunction	3	507	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.31, 1.37]
3.3 Neutropenia	3	507	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.61, 1.98]
3.4 Hypokalaemia	3	507	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.63, 2.27]
3.5 ALT abnormality	2	308	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.07, 1.60]

Comparison 9. Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU

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Comparison 10. Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	450	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.57, 1.23]
1.2 10 weeks	1	450	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.93, 1.42]
1.3 6 months	1	450	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.99, 1.41]
2 Early fungicidal activity Show forest plot	1	450	Mean Difference (IV, Random, 95% CI)	0.1 [0.06, 0.14]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	450	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.90, 1.29]
3.2 Renal dysfunction	1	450	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.18, 2.16]
3.3 Neutropenia	1	450	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.51, 1.02]
3.4 Hypokalaemia	1	450	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.69, 0.98]
3.5 ALT abnormality	1	450	Risk Ratio (M‐H, Random, 95% CI)	3.36 [0.94, 12.06]

Comparison 10. Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU

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Comparison 11. One week of AmBd + FLU versus two weeks of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	225	Risk Ratio (M‐H, Random, 95% CI)	1.48 [0.95, 2.29]
1.2 10 weeks	1	225	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.88, 1.58]
2 Early fungicidal activity Show forest plot	1	175	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.06, 0.08]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	225	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.55, 1.42]
3.2 Renal dysfunction	1	225	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.38, 1.70]
3.3 Neutropenia	1	225	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.28, 1.82]
3.4 Hypokalaemia	1	225	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.20, 1.65]
3.5 ALT abnormality	1	225	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.07, 1.66]

Comparison 11. One week of AmBd + FLU versus two weeks of AmBd + FLU

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Comparison 12. One week of AmBd + FLU versus two weeks of AmBd + 5FC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	226	Risk Ratio (M‐H, Random, 95% CI)	1.55 [1.00, 2.43]
1.2 10 weeks	1	226	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.94, 1.72]
2 Early fungicidal activity Show forest plot	1	169	Mean Difference (IV, Random, 95% CI)	0.13 [0.06, 0.20]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	226	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.48, 1.19]
3.2 Renal dysfunction	1	226	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.65, 4.05]
3.3 Neutropenia	1	226	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.25, 1.48]
3.4 Hypokalaemia	1	226	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.24, 2.26]
3.5 ALT abnormality	1	226	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.15, 7.23]

Comparison 12. One week of AmBd + FLU versus two weeks of AmBd + 5FC

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Comparison 13. One week of AmBd + FLU versus two weeks of 5FC + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	336	Risk Ratio (M‐H, Random, 95% CI)	1.78 [1.21, 2.62]
1.2 10 weeks	1	336	Risk Ratio (M‐H, Random, 95% CI)	1.39 [1.07, 1.80]
2 Early fungicidal activity Show forest plot	1	263	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.16, ‐0.04]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	336	Risk Ratio (M‐H, Random, 95% CI)	4.42 [2.25, 8.70]
3.2 Renal dysfunction	1	336	Risk Ratio (M‐H, Random, 95% CI)	2.03 [0.91, 4.53]
3.3 Neutropenia	1	336	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.27, 1.39]
3.4 Hypokalaemia	1	336	Risk Ratio (M‐H, Random, 95% CI)	3.38 [0.82, 13.88]
3.5 ALT abnormality	1	336	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.14, 3.29]

Comparison 13. One week of AmBd + FLU versus two weeks of 5FC + FLU

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Comparison 14. Two weeks of FLU versus two weeks of 5FC + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	2	98	Risk Ratio (M‐H, Random, 95% CI)	3.04 [1.31, 7.06]
1.2 10 weeks	2	98	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.96, 2.23]
2 Early fungicidal activity Show forest plot	1	37	Mean Difference (IV, Random, 95% CI)	0.17 [0.08, 0.26]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.07, 16.47]
3.2 Renal dysfunction	1	40	Risk Ratio (M‐H, Random, 95% CI)	2.21 [0.22, 22.47]
3.3 Neutropenia	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.03, 1.73]
3.4 ALT abnormality	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 14. Two weeks of FLU versus two weeks of 5FC + FLU

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Comparison 15. Two weeks of L‐AmB versus two weeks of AmBd

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 10 weeks	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.04, 4.25]
1.3 6 months	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.11, 2.94]

Comparison 15. Two weeks of L‐AmB versus two weeks of AmBd

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Comparison 16. Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	79	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.43, 7.59]
1.2 10 weeks	1	79	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.47, 2.25]
2 Early fungicidal activity Show forest plot	1	67	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.21, 0.01]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	79	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.22, 14.61]
3.2 Renal dysfunction	1	79	Risk Ratio (M‐H, Random, 95% CI)	4.10 [0.24, 71.15]
3.3 Neutropenia	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Hypokalaemia	1	79	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.01, 0.58]
3.5 ALT abnormality	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 16. Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU

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Comparison 17. Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + 5FC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	31	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.06, 13.68]
1.2 10 weeks	1	31	Risk Ratio (M‐H, Random, 95% CI)	2.81 [0.33, 24.16]
2 Early fungicidal activity Show forest plot	1	27	Mean Difference (IV, Random, 95% CI)	0.16 [0.03, 0.29]

Comparison 17. Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + 5FC

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Comparison 18. Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.03, 1.53]
1.2 10 weeks	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.13, 1.37]
2 Early fungicidal activity Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.10, 0.12]

Comparison 18. Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + FLU

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Comparison 19. Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 4.98]
1.2 10 weeks	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.24, 4.23]
2 Early fungicidal activity Show forest plot	1	29	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.18, 0.04]

Comparison 19. Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd

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Comparison 20. One week of AmBd + 5FC + FLU versus one week of AmBd + FLU

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.10, 2.43]
1.2 10 weeks	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.35, 2.10]
2 Early fungicidal activity Show forest plot	1	37	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.23, ‐0.01]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.20, 1.65]
3.2 Renal dysfunction	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.8 [0.25, 2.55]
3.3 Neutropenia	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.39, 3.99]
3.4 Hypokalaemia	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.57]

Comparison 20. One week of AmBd + 5FC + FLU versus one week of AmBd + FLU

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Comparison 21. Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 2 weeks	1	88	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.28, 1.90]
1.2 10 weeks	1	88	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.48, 1.77]
2 Early fungicidal activity Show forest plot	1	88	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.24, ‐0.06]

3 DAIDS grade 3/4 toxicities Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Anaemia	1	88	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.62, 2.11]
3.2 Renal dysfunction	1	88	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.37, 1.98]
3.3 Neutropenia	1	88	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.28, 6.60]
3.4 Hypokalaemia	1	88	Risk Ratio (M‐H, Random, 95% CI)	3.86 [0.21, 72.44]
3.5 ALT abnormality	1	88	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 21. Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC

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