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

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)...

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Autores principales: Eshun‐Wilson, Ingrid, Okwen, Mbah P, Richardson, Marty, Bicanic, Tihana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513637/
https://www.ncbi.nlm.nih.gov/pubmed/30039850
http://dx.doi.org/10.1002/14651858.CD009012.pub3
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author Eshun‐Wilson, Ingrid
Okwen, Mbah P
Richardson, Marty
Bicanic, Tihana
author_facet Eshun‐Wilson, Ingrid
Okwen, Mbah P
Richardson, Marty
Bicanic, Tihana
author_sort Eshun‐Wilson, Ingrid
collection PubMed
description 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International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017.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; I(2) = 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; I(2) 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. 11 April 2019 Up to date All studies incorporated from most recent search All eligible published studies found in the last search (7 Aug, 2017) were included
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spelling pubmed-65136372019-05-21 Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis Eshun‐Wilson, Ingrid Okwen, Mbah P Richardson, Marty Bicanic, Tihana Cochrane Database Syst Rev 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; I(2) = 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; I(2) 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. 11 April 2019 Up to date All studies incorporated from most recent search All eligible published studies found in the last search (7 Aug, 2017) were included John Wiley & Sons, Ltd 2018-07-24 /pmc/articles/PMC6513637/ /pubmed/30039850 http://dx.doi.org/10.1002/14651858.CD009012.pub3 Text en Copyright © 2018 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the Creative Commons Attribution‐Non‐Commercial (https://creativecommons.org/licenses/by-nc/4.0/) Licence, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Eshun‐Wilson, Ingrid
Okwen, Mbah P
Richardson, Marty
Bicanic, Tihana
Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis
title Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis
title_full Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis
title_fullStr Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis
title_full_unstemmed Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis
title_short Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis
title_sort early versus delayed antiretroviral treatment in hiv‐positive people with cryptococcal meningitis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513637/
https://www.ncbi.nlm.nih.gov/pubmed/30039850
http://dx.doi.org/10.1002/14651858.CD009012.pub3
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