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Meta-Analysis
. 2018 Jul 24;7(7):CD009012.
doi: 10.1002/14651858.CD009012.pub3.

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis

Ingrid Eshun-Wilson  1 , Mbah P Okwen, Marty Richardson, Tihana Bicanic
Affiliations
Meta-Analysis

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis

Ingrid Eshun-Wilson et al. Cochrane Database Syst Rev. .

Abstract

Background: There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV-positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced.

Objectives: To compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive people with concurrent cryptococcal meningitis.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies.

Selection criteria: We included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV-positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion.

Data collection and analysis: Two review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time-to-death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach.

Main results: Four trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low- and middle-income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used.Early ART initiation may increase all-cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low-certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low-certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I2 = 54%; very low-certainty evidence). We are uncertain if early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (RR 0.93, 95% CI 0.72 to 1.22; 205 participants, 2 trials; I2 statistic = 0%; very low-certainty evidence).We were unable to pool results related to rate of fungal clearance for the two trials that reported this outcome; individual trial results indicated that there was no difference in cerebrospinal fluid fungal clearance between trial arms. Similarly, we were unable to pool results on adverse events for the trials reporting on this outcome; individual trial results indicated no difference in the occurrence of grade 3 to 5 adverse events between trial arms.Three of the four included trials had an overall low or unclear risk of bias related to the primary outcome of all-cause mortality. However, we assessed one trial as at high risk of bias due to selective outcome reporting and other bias. This, in addition to the few clinical events and imprecision of effect estimates, led to downgrading of the evidence to low or very low certainty.

Authors' conclusions: The results of this review are relevant to HIV-positive adults with cryptococcal meningitis in low- and middle-income countries. These data suggest a higher risk of mortality among people who initiate ART within four weeks of cryptococcal meningitis diagnosis. However, it is unclear if this higher mortality risk is related to cryptococcal meningitis-IRIS.

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Conflict of interest statement

Ingrid Eshun‐Wilson has no known conflicts of interest. Mbah P Okwen has no known conflicts of interest. Marty Richardson has no known conflicts of interest. Tihana Bicanic has received payment of fees and a grant from Gilead and Basilea for advisory board, speaker fees, and grants outside the submitted work.

Figures

1
1
Study flow diagram.
2
2
‘Risk of bias' summary: review authors' judgements about each ‘Risk of bias' item for each included trial.
3
3
‘Risk of bias' graph: review authors' judgements about each ‘Risk of bias' item presented as percentages across all included trials.
4
4
Forest plot of comparison: 1 Early versus delayed ART, outcome: 1.1 All‐cause mortality at 6 to 12 months.
5
5
Forest plot of comparison: 1 Early versus delayed ART, outcome: 1.3 Cryptococcal meningitis relapse.
6
6
Forest plot of comparison: 1 Early versus delayed ART, outcome: 1.5 Cryptococcal IRIS.
7
7
Forest plot of comparison: 1 Early versus delayed ART, outcome: 1.6 Sensitivity analysis: cryptococcal IRIS.
8
8
Forest plot of comparison: 1 Early versus delayed ART, outcome: 1.8 Sensitivity analysis: virological suppression at 24 weeks.
1.1
1.1. Analysis
Comparison 1 Early versus delayed ART, Outcome 1 All‐cause mortality at 6 to 12 months.
1.2
1.2. Analysis
Comparison 1 Early versus delayed ART, Outcome 2 Sensitivity analysis: all‐cause mortality.
1.3
1.3. Analysis
Comparison 1 Early versus delayed ART, Outcome 3 Cryptococcal meningitis relapse.
1.4
1.4. Analysis
Comparison 1 Early versus delayed ART, Outcome 4 Mortality hazard ratio.
1.5
1.5. Analysis
Comparison 1 Early versus delayed ART, Outcome 5 Cryptococcal IRIS.
1.6
1.6. Analysis
Comparison 1 Early versus delayed ART, Outcome 6 Sensitivity analysis: cryptococcal IRIS.
1.7
1.7. Analysis
Comparison 1 Early versus delayed ART, Outcome 7 Virological suppression at 24 weeks (viral load < 400 copies/mL).
1.8
1.8. Analysis
Comparison 1 Early versus delayed ART, Outcome 8 Sensitivity analysis: virological suppression at 24 weeks.
1.9
1.9. Analysis
Comparison 1 Early versus delayed ART, Outcome 9 Subgrouping by antifungal drug: all‐cause mortality.
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Update of

References

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Makadzange 2015a {published data only}
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