title: Systematic review and mixed treatment comparison meta-analysis of randomized clinical trials of primary oral antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients.
abstract: BACKGROUND
  Antifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant (alloHCT) recipients, but the optimum prophylactic agent is unknown. We used mixed treatment comparison (MTC) meta-analysis to compare clinical trials examining the use of oral antifungals for prophylaxis in alloHCT recipients, with the goal of informing medical decision-making.
  
  
  METHODS
  Randomized controlled trials (RCTs) of fluconazole, itraconazole, posaconazole, and voriconazole for primary antifungal prophylaxis were identified through a systematic literature review. Outcomes of interest (incidence of IFI/invasive aspergillosis/invasive candidiasis, all-cause mortality, and use of other antifungals) were extracted from eligible RCTs and incorporated into a Bayesian hierarchical random-effects MTC.
  
  
  RESULTS
  Five eligible RCTs, randomizing 2147 patients in total, were included. Relative to fluconazole, prophylaxis with itraconazole (odds ratio [OR]: 0.52; interquartile range [IQR]: 0.35-0.76), posaconazole (OR: 0.56; IQR: 0.32-0.99), and voriconazole (OR: 0.46; IQR: 0.28-0.73) reduced incidence of overall proven/probable IFI. Posaconazole (OR: 0.31; IQR: 0.17-0.58) and voriconazole (OR: 0.33; IQR: 0.17-0.58) prophylaxis reduced proven/probable invasive aspergillosis more than itraconazole (OR: 0.68; IQR: 0.42-1.12). All-cause mortality was similar across all mould-active agents.
  
  
  CONCLUSIONS
  As expected, mould-active azoles prevented IFIs, particularly invasive aspergillosis, more effectively than fluconazole in alloHCT recipients. The paucity of comparative efficacy data suggests that other factors such as long-term tolerability, availability of intravenous formulations, local IFI epidemiology, and drug costs may need to form the basis for selection among the mould-active azoles.
authors.affiliation: CancerCare Manitoba, 675 McDermot Ave, Winnipeg, MB, Canada. EJBow@cancercare.mb.ca.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bow
authors.affiliation: University of Wisconsin and Visiting Scientist at Evidera, Madison, Wisconsin, USA. dvanness@wisc.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vanness
authors.affiliation: Royal Melbourne Hospital, Melbourne, Australia. Monica.Slavin@mh.org.au.
authors.forename: Monica
authors.initials: M
authors.lastname: Slavin
authors.affiliation: Assistance Publique-Hopitaux de Paris, Hôpital Henri Mondor and Université Paris-Est-Créteil, Creteil, France. carlcord@club-internet.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cordonnier
authors.affiliation: Department I of Internal Medicine, Clinical Trials Centre Cologne, ZKS Köln, BMBF 01KN1106, Center for Integrated Oncology CIO KölnBonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. Oliver.Cornely@zks-koeln.de.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: University Hospitals Bristol NHS Foundation Trust, Bristol, UK. david.marks@uhbristol.nhs.uk.
authors.forename: David I
authors.initials: DI
authors.lastname: Marks
authors.affiliation: King's College Hospital, London, UK. antonio.pagliuca@kcl.ac.uk.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pagliuca
authors.affiliation: Hospital Clínico, INCLIVA Foundation, University of Valencia, Valencia, Spain. solano_car@gva.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solano
authors.affiliation: Evidera, Bethesda, Maryland, USA. lael.bilzor@verizon.net.
authors.forename: Lael
authors.initials: L
authors.lastname: Cragin
authors.affiliation: Evidera, Bethesda, Maryland, USA. mendoza.alissa@gmail.com.
authors.forename: Alissa J
authors.initials: AJ
authors.lastname: Shaul
authors.affiliation: Evidera, Bethesda, Maryland, USA. Sonja.Sorensen@evidera.com.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sorensen
authors.affiliation: Pfizer, Collegeville, Pennsylvania, USA. richard.chambers@pfizer.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Chambers
authors.affiliation: Pfizer, Paris, France. Michal.Kantecki@Pfizer.com.
authors.forename: Michal
authors.initials: M
authors.lastname: Kantecki
authors.affiliation: Pfizer, Paris, France. douvedel@yahoo.fr.
authors.forename: David
authors.initials: D
authors.lastname: Weinstein
authors.affiliation: HTS Pharma Consulting, New York, New York, USA. HTSchlamm@att.net.
authors.forename: Haran
authors.initials: H
authors.lastname: Schlamm
mesh_terms: D006801:Humans; D000935:Antifungal Agents / Q000627:therapeutic use; D001499:Bayes Theorem; D018380:Hematopoietic Stem Cell Transplantation; D009181:Mycoses / Q000188:drug therapy / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic; D066027:Transplant Recipients
chemical_list: D000935:Antifungal Agents