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Review
, 7 (7), CD005647

Treatment for HIV-associated Cryptococcal Meningitis

Affiliations
Review

Treatment for HIV-associated Cryptococcal Meningitis

Mark W Tenforde et al. Cochrane Database Syst Rev.

Abstract

Background: Cryptococcal meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV-related deaths worldwide. The best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis is unclear, particularly in resource-limited settings where management of drug-related toxicities associated with more potent antifungal drugs is a challenge.

Objectives: To evaluate the best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis; to compare side effect profiles of different therapies.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South-East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018.

Selection criteria: We included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV-associated cryptococcal meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction.

Data collection and analysis: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random-effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10-week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta-analysis using multivariate meta-regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two-week and 10-week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node-splitting approach, and global inconsistency using design-by-treatment interaction modelling. For the network meta-analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10-week mortality.

Main results: We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. All studies were carried out in adults, and all but two studies were conducted in resource-limited settings, including 11 of 12 studies with 10-week mortality data.In the direct pairwise comparisons evaluating 10-week mortality, one study from four sub-Saharan African countries contributed data to several key comparisons. At 10 weeks these data showed that those on the regimen of one-week amphotericin B deoxycholate (AmBd) and flucytosine (5FC) followed by fluconazole (FLU) on days 8 to 14 had lower mortality when compared to (i) two weeks of AmBd and 5FC (RR 0.62, 95% CI 0.42 to 0.93; 228 participants, 1 study), (ii) two weeks of AmBd and FLU (RR 0.58, 95% CI 0.39 to 0.86; 227 participants, 1 study), (iii) one week of AmBd with two weeks of FLU (RR 0.49, 95% CI 0.34 to 0.72; 224 participants, 1 study), and (iv) two weeks of 5FC and FLU (RR 0.68, 95% CI 0.47 to 0.99; 338 participants, 1 study). The evidence for each of these comparisons was of moderate certainty. For other outcomes, this shortened one-week AmBd and 5FC regimen had similar fungal clearance (MD 0.05 log10 CFU/mL/day, 95% CI -0.02 to 0.12; 186 participants, 1 study) as well as lower risk of grade three or four anaemia (RR 0.31, 95% CI 0.16 to 0.60; 228 participants, 1 study) compared to the two-week regimen of AmBd and 5FC.For 10-week mortality, the comparison of two weeks of 5FC and FLU with two weeks of AmBd and 5FC (RR 0.92, 95% CI 0.69 to 1.23; 340 participants, 1 study) or two weeks of AmBd and FLU (RR 0.85, 95% CI 0.64 to 1.13; 339 participants, 1 study) did not show a difference in mortality, with moderate-certainty evidence for both comparisons.When two weeks of combination AmBd and 5FC was compared with AmBd alone, pooled data showed lower mortality at 10 weeks (RR 0.66, 95% CI 0.46 to 0.95; 231 participants, 2 studies, moderate-certainty evidence).When two weeks of AmBd and FLU was compared to AmBd alone, there was no difference in 10-week mortality in pooled data (RR 0.94, 95% CI 0.55 to 1.62; 371 participants, 3 studies, low-certainty evidence).One week of AmBd and 5FC followed by FLU on days 8 to 14 was the best induction therapy regimen after comparison with 11 other regimens for 10-week mortality in the network meta-analysis, with an overall SUCRA ranking of 88%.

Authors' conclusions: In resource-limited settings, one-week AmBd- and 5FC-based therapy is probably superior to other regimens for treatment of HIV-associated cryptococcal meningitis. An all-oral regimen of two weeks 5FC and FLU may be an alternative in settings where AmBd is unavailable or intravenous therapy cannot be safely administered. We found no mortality benefit of combination two weeks AmBd and FLU compared to AmBd alone. Given the absence of data from studies in children, and limited data from high-income countries, our findings provide limited guidance for treatment in these patients and settings.

Conflict of interest statement

Mark W Tenforde declares no relevant conflicts of interest. Adrienne E Shapiro has received salary compensation from the University of Washington, as a trainee postdoctoral fellow in Infectious Diseases. A portion of the salary derives from an NIH T32 training grant. Benjamin Rouse declares no relevant conflicts of interest. Joseph N Jarvis has been an investigator in several clinical trials of therapies for HIV‐associated cryptococcal meningitis. He has previously received grant support through his institution from Gilead Sciences Europe (investigator initiated award for the Ambition Phase II Trial) Tianjing Li declares no relevant conflicts of interest. Ingrid Eshun‐Wilson declares no relevant conflicts of interest. Nathan Ford declares no relevant conflicts of interest.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
‘Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figure 3
Figure 3
‘Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figure 4
Figure 4
Forest plot of comparison: 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, outcome: 7.1 Mortality.
Figure 5
Figure 5
Forest plot of comparison: 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, outcome: 7.2 Early fungicidal activity.
Figure 6
Figure 6
Forest plot of comparison: 8 Two weeks of AmBd + FLU versus two weeks of AmBd, outcome: 8.1 Mortality.
Figure 7
Figure 7
Forest plot of comparison: 8 Two weeks of AmBd + FLU versus two weeks of AmBd, outcome: 8.2 Early fungicidal activity.
Figure 8
Figure 8
Forest plot of comparison: 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, outcome: 9.1 Mortality.
Figure 9
Figure 9
Forest plot of comparison: 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, outcome: 9.2 Early fungicidal activity.
Figure 10
Figure 10
Network plot for 10‐week mortality.
Figure 11
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.
Figure 12
Figure 12
Ten‐week mortality risk for each treatment combination compared to reference of two weeks of AmBd and FLU.
Figure 13
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%).
Figure 14
Figure 14
Modified GRADE for network meta‐analysis
Analysis 1.1
Analysis 1.1
Comparison 1 One week of AmBd + 5FC versus two weeks of AmBd + 5FC, Outcome 1 Mortality.
Analysis 1.2
Analysis 1.2
Comparison 1 One week of AmBd + 5FC versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.
Analysis 1.3
Analysis 1.3
Comparison 1 One week of AmBd + 5FC versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 2.1
Analysis 2.1
Comparison 2 One week of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 1 Mortality.
Analysis 2.2
Analysis 2.2
Comparison 2 One week of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 2.3
Analysis 2.3
Comparison 2 One week of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 3.1
Analysis 3.1
Comparison 3 One week of AmBd + 5FC versus one week of AmBd + FLU, Outcome 1 Mortality.
Analysis 3.2
Analysis 3.2
Comparison 3 One week of AmBd + 5FC versus one week of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 3.3
Analysis 3.3
Comparison 3 One week of AmBd + 5FC versus one week of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 4.1
Analysis 4.1
Comparison 4 One week of AmBd + 5FC versus two weeks of 5FC + FLU, Outcome 1 Mortality.
Analysis 4.2
Analysis 4.2
Comparison 4 One week of AmBd + 5FC versus two weeks of 5FC + FLU, Outcome 2 Early fungicidal activity.
Analysis 4.3
Analysis 4.3
Comparison 4 One week of AmBd + 5FC versus two weeks of 5FC + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 5.1
Analysis 5.1
Comparison 5 Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 1 Mortality.
Analysis 5.2
Analysis 5.2
Comparison 5 Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.
Analysis 5.3
Analysis 5.3
Comparison 5 Two weeks of 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 6.1
Analysis 6.1
Comparison 6 Two weeks of 5FC + FLU versus two weeks of AmBd + FLU, Outcome 1 Mortality.
Analysis 6.2
Analysis 6.2
Comparison 6 Two weeks of 5FC + FLU versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 6.3
Analysis 6.3
Comparison 6 Two weeks of 5FC + FLU versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 7.1
Analysis 7.1
Comparison 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, Outcome 1 Mortality.
Analysis 7.2
Analysis 7.2
Comparison 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, Outcome 2 Early fungicidal activity.
Analysis 7.3
Analysis 7.3
Comparison 7 Two weeks of AmBd + 5FC versus two weeks of AmBd, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 8.1
Analysis 8.1
Comparison 8 Two weeks of AmBd + FLU versus two weeks of AmBd, Outcome 1 Mortality.
Analysis 8.2
Analysis 8.2
Comparison 8 Two weeks of AmBd + FLU versus two weeks of AmBd, Outcome 2 Early fungicidal activity.
Analysis 8.3
Analysis 8.3
Comparison 8 Two weeks of AmBd + FLU versus two weeks of AmBd, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 9.1
Analysis 9.1
Comparison 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 1 Mortality.
Analysis 9.2
Analysis 9.2
Comparison 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 9.3
Analysis 9.3
Comparison 9 Two weeks of AmBd + 5FC versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 10.1
Analysis 10.1
Comparison 10 Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU, Outcome 1 Mortality.
Analysis 10.2
Analysis 10.2
Comparison 10 Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 10.3
Analysis 10.3
Comparison 10 Two weeks of AmBd + FLU + steroids versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 11.1
Analysis 11.1
Comparison 11 One week of AmBd + FLU versus two weeks of AmBd + FLU, Outcome 1 Mortality.
Analysis 11.2
Analysis 11.2
Comparison 11 One week of AmBd + FLU versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 11.3
Analysis 11.3
Comparison 11 One week of AmBd + FLU versus two weeks of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 12.1
Analysis 12.1
Comparison 12 One week of AmBd + FLU versus two weeks of AmBd + 5FC, Outcome 1 Mortality.
Analysis 12.2
Analysis 12.2
Comparison 12 One week of AmBd + FLU versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.
Analysis 12.3
Analysis 12.3
Comparison 12 One week of AmBd + FLU versus two weeks of AmBd + 5FC, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 13.1
Analysis 13.1
Comparison 13 One week of AmBd + FLU versus two weeks of 5FC + FLU, Outcome 1 Mortality.
Analysis 13.2
Analysis 13.2
Comparison 13 One week of AmBd + FLU versus two weeks of 5FC + FLU, Outcome 2 Early fungicidal activity.
Analysis 13.3
Analysis 13.3
Comparison 13 One week of AmBd + FLU versus two weeks of 5FC + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 14.1
Analysis 14.1
Comparison 14 Two weeks of FLU versus two weeks of 5FC + FLU, Outcome 1 Mortality.
Analysis 14.2
Analysis 14.2
Comparison 14 Two weeks of FLU versus two weeks of 5FC + FLU, Outcome 2 Early fungicidal activity.
Analysis 14.3
Analysis 14.3
Comparison 14 Two weeks of FLU versus two weeks of 5FC + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 15.1
Analysis 15.1
Comparison 15 Two weeks of L‐AmB versus two weeks of AmBd, Outcome 1 Mortality.
Analysis 16.1
Analysis 16.1
Comparison 16 Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU, Outcome 1 Mortality.
Analysis 16.2
Analysis 16.2
Comparison 16 Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU, Outcome 2 Early fungicidal activity.
Analysis 16.3
Analysis 16.3
Comparison 16 Short‐course L‐AmB + FLU versus two weeks of L‐AmB + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 17.1
Analysis 17.1
Comparison 17 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 1 Mortality.
Analysis 17.2
Analysis 17.2
Comparison 17 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.
Analysis 18.1
Analysis 18.1
Comparison 18 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + FLU, Outcome 1 Mortality.
Analysis 18.2
Analysis 18.2
Comparison 18 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 19.1
Analysis 19.1
Comparison 19 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd, Outcome 1 Mortality.
Analysis 19.2
Analysis 19.2
Comparison 19 Two weeks of AmBd + 5FC + FLU versus two weeks of AmBd, Outcome 2 Early fungicidal activity.
Analysis 20.1
Analysis 20.1
Comparison 20 One week of AmBd + 5FC + FLU versus one week of AmBd + FLU, Outcome 1 Mortality.
Analysis 20.2
Analysis 20.2
Comparison 20 One week of AmBd + 5FC + FLU versus one week of AmBd + FLU, Outcome 2 Early fungicidal activity.
Analysis 20.3
Analysis 20.3
Comparison 20 One week of AmBd + 5FC + FLU versus one week of AmBd + FLU, Outcome 3 DAIDS grade 3/4 toxicities.
Analysis 21.1
Analysis 21.1
Comparison 21 Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC, Outcome 1 Mortality.
Analysis 21.2
Analysis 21.2
Comparison 21 Two weeks of AmBd + 5FC + IFNg versus two weeks of AmBd + 5FC, Outcome 2 Early fungicidal activity.
Analysis 21.3
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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References

References to studies included in this review

    1. Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, et al. Adjunctive dexamethasone in HIV‐associated cryptococcal meningitis. New England Journal of Medicine 2016;374(6):542‐54. - PMC - PubMed
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    1. Jarvis JN, Meintjes G, Rebe K, Williams GN, Bicanic T, Williams A, et al. Adjunctive interferon‐γ immunotherapy for the treatment of HIV‐associated cryptococcal meningitis: a randomized controlled trial. AIDS 2012;26(9):1105‐13. - PMC - PubMed

References to studies excluded from this review

    1. Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse A, et al. High‐dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV‐infected patients: a randomized trial. Clinical Infectious Diseases 2008;47(1):123‐30. - PubMed
    1. Bisson GP, Molefi M, Bellamy S, Thakur R, Steenhoff A, Tamuhla N, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clinical Infectious Diseases 2013;56(8):1165‐73. - PubMed
    1. Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. New England Journal of Medicine 2014;370(26):2487‐98. - PMC - PubMed
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References to ongoing studies

    1. ISRCTN72509687. High dose AMBISOME on a fluconazole backbone for cryptococcal meningitis induction therapy in sub‐Saharan Africa. www.isrctn.com/ISRCTN72509687 (first received 23 June 2017). - PMC - PubMed
    1. NCT00885703. High‐dose fluconazole for the treatment of cryptococcal meningitis in HIV‐infected individuals (HiFLAC) [A phase I/II dose‐finding study of high‐dose fluconazole treatment in AIDS‐associated cryptococcal meningitis]. clinicaltrials.gov/ct2/show/NCT00885703 (first received 22 April 2009).
    1. NCT01802385. Adjunctive sertraline for the treatment of HIV‐associated cryptococcal meningitis (ASTRO‐CM). clinicaltrials.gov/ct2/show/NCT01802385 (first received 1 March 2013).

Additional references

    1. Anderegg N, Kirk O on behalf of IeDEA‐Global Adults and COHERE. Immunodeficiency at the start of combination antiretroviral therapy in low‐, middle‐ and high‐income countries. 9th International AIDS Society Conference on HIV Science; 2017 July 23‐26; Paris, France. 2017.
    1. Bahr NC, Rolfes MA, Musubire A, Nabeta H, Williams DA, Rhein J, et al. Standardized electrolyte supplementation and fluid management improves survival during amphotericin therapy for cryptococcal meningitis in resource‐limited settings. Open Forum Infectious Diseases 2014;1(2):ofu070. - PMC - PubMed
    1. Bicanic T, Harrison T, Niepieklo A, Dyakopu N, Meintjes G. Symptomatic relapse of HIV‐associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clinical Infectious Diseases 2006;43(8):1069‐73. - PubMed
    1. Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral‐naive or antiretroviral‐experienced patients treated with amphotericin B or fluconazole. Clinical Infectious Diseases 2007;45(1):76‐80. - PubMed
    1. Bicanic T, Brouwer AE, Meintjes G, Rebe K, Limmathurotsakul D, Chierakul W, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS 2009;23(6):701‐6. - PubMed

References to other published versions of this review

    1. Sloan D, Dlamini S, Paul N, Dedicoat M. Treatment of acute cryptococcal meningitis in HIV‐infected adults in resource‐limited settings. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD005647] - DOI - PubMed
    1. Sloan D, Dlamini S, Paul N, Dedicoat M. Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource‐limited settings. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/14651858.CD005647.pub2] - DOI - PubMed

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