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Amphotericin B for Treatment of Visceral Leishmaniasis: Systematic Review and Meta-Analysis of Prospective Comparative Clinical Studies Including Dose-Ranging Studies

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Amphotericin B for Treatment of Visceral Leishmaniasis: Systematic Review and Meta-Analysis of Prospective Comparative Clinical Studies Including Dose-Ranging Studies Clinical Microbiology and Infection 24 (2018) 591e598 Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com Systematic review Amphotericin B for treatment of visceral leishmaniasis: systematic review and meta-analysis of prospective comparative clinical studies including dose-ranging studies * C. Rodrigo 1, , P. Weeratunga 2, S.D. Fernando 3, S. Rajapakse 2 1) Department of Pathology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia 2) Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka 3) Department of Parasitology, Faculty of Medicine, University of Colombo, Sri Lanka article info abstract Article history: Objectives: To evaluate the evidence for use of different formulations of amphotericin B (AmB), minimum Received 4 September 2017 effective dose for each formulation and its comparative efficacy against other drugs in achieving Received in revised form definitive cure of visceral leishmaniasis. 2 November 2017 Methods: This systematic review and meta-analysis included following data sources: PubMed, Embase, Accepted 5 November 2017 Scopus, Web of Science and CINAHL. Controlled prospective clinical trials (randomized or non- Available online 11 November 2017 randomized, including dose-ranging studies) conducted between 1996 and 2017 with at least one Editor: L Leibovici treatment group receiving AmB were included (published data only). The primary outcome was defin- itive cure at 6 months. Adverse events and mortality were assessed as secondary outcomes. The Keywords: PROSPERO registration number for this review is CRD42017067488. Amphotericin B Results: Thirty-one studies (26 from India) that enrolled 6903 patients into 84 study groups met the Clinical trials selection criteria. In India, liposomal AmB was not inferior to AmB deoxycholate (relative risk 1.00, 95% Liposomal amphotericin confidence interval (CI) 0.96e1.03, two randomized controlled trials (RCTs), 514 participants, high- Systematic review quality evidence), and a single dose of the earlier formulation as low as 3.75 mg/kg achieved a cure Visceral leishmaniasis rate of over 89% (95% CI 70.6e97.2). AmB deoxycholate was as effective as miltefosine (relative risk 0.99, 95% CI 0.95e1.03, two trials, 523 participants, high-quality evidence) and may be better than paromo- mycin (relative risk 1.04, 95% CI 1.02e1.07, one trial, 667 participants, low-quality evidence) in achieving definitive cure. Conclusions: AmB is an efficacious drug in the Indian subcontinent. Further evidence is needed from prospective clinical trials in other endemic geographical regions. C. Rodrigo, Clin Microbiol Infect 2018;24:591 © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Introduction for many decades. However, these drugs have inherent toxicity, and on top of that, parasitic resistance is now frequently encountered in Visceral leishmaniasis (VL), which is caused by the unicellular India [2]. Amphotericin B (AmB) is a macrolide polyene antifungal parasite Leishmania donovani, is potentially fatal if untreated [1]. agent that has become the preferred choice in areas with antimo- Over 90% of VL cases in the world are reported from six coun- nial resistance. triesdBrazil, Ethiopia, Somalia, South Sudan, Sudan and Indiad AmB is not soluble in saline and has to be mixed with a deter- with approximately 200 million residents at risk of the infection. gent, sodium deoxycholate. Soon after entry into plasma, the drug Pentavalent antimonial compounds were the first line of therapy dissociates from the detergent and binds to circulating lipoproteins [3]. The lipid-soluble property of AmB has been used to develop several lipid-soluble variants that have less toxicity and a better * Corresponding author. C. Rodrigo, Room 207, Level 2W, Wallace Wurth Building, therapeutic index. These preparations are liposomal AmB (L-AmB), School of Medical Sciences, UNSW, NSW, Sydney, 2052, Australia. AmB lipid complex (ABLC) and AmB emulsion (ABLE) [3]. However, E-mail address: [email protected] (C. Rodrigo). https://doi.org/10.1016/j.cmi.2017.11.008 1198-743X/© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. 592 C. Rodrigo et al. / Clinical Microbiology and Infection 24 (2018) 591e598 it must be noted that any of these formulations are not homoge- that included any formulation of AmB by itself or in combination nous entities and the efficacies may vary depending on the with another drug in any one of the trial arms. Case series, obser- manufacturer. vational studies and retrospective analyses were excluded. Given AmB's increasing importance as a preferred therapeutic option over the last two decades, the objectives of this systematic Information sources and search strategy review and meta-analysis were to evaluate the evidence for use of different formulations of AmB, to discover the minimum effective PubMed, Embase, Scopus, Web of Science and CINAHL were dose for each formulation and to assess its comparative efficacy searched for relevant articles with the keywords ‘leishmania*’ in against other drugs in achieving definitive cure of VL. any field and ‘amphotericin’ in any field without any language re- strictions. Articles published over the last 20 years (1 January Methods 1996e20 May 2017) in all languages were included. Only published data were considered. We used Endnote X7 software (Thomson Protocol and registration Reuters, Carlsbad, CA, USA) to filter articles. The flow diagram for article selection is shown in Fig. 1. The PROSPERO registration number for this review is CRD42017067488. The review protocol is available online in Study selection Supplementary File S1. Two authors (CR and PW) performed the search and coded the Eligibility criteria studies according to the inclusion criteria. After reading all ab- stracts, key articles were identified by consensus. Full articles were We performed a systematic review and meta-analysis of all obtained for all studies meeting the inclusion criteria (including published prospective clinical trials (randomized or non- articles of undetermined status) for further assessment. Bibliogra- randomized, including dose-ranging studies) on treatment of VL phies of selected articles were also searched to identify relevant studies. The final list of included studies had the concurrence of all authors. Data collection and data items The data items extracted from each study included participant demographics, intervention and control groups, drug doses, locality and dates of study, immediate and definitive cure rates, adverse events, relapses during follow-up and mortality statistics. The pri- mary outcome in the analysis was definitive cure, defined as pa- tients being free of parasites as demonstrated by splenic, lymph node or bone marrow aspiration at least 6 months after completion of therapy. Adverse events and mortality were analysed as sec- ondary outcomes. All studies were assessed according to an intention-to-treat model. Risk of bias Risks of bias were assessed by the Cochrane risk of bias assessment tool [4]. Summary measures and synthesis of results Comparable trials with regard to the intervention and the out- comes were combined in a meta-analysis using Review Manager 5 software [4]. Dichotomous data were compared by relative risk (RR) and 95% confidence intervals (CI). Heterogeneity was assessed with the I2 statistic and visual inspection of forest plots [5]. Heteroge- neity was also minimized by combining studies that only assessed comparable interventions and outcomes in the meta-analysis. A fixed-effect model was used for the analysis, which was converted to a random-effect model if a high level of heterogeneity was encountered (I2 statistic >70%) [5]. Quality of evidence was assessed by GRADEPro software (McMaster University, Hamilton, Canada). Funnel plots to assess publication bias could not be created because there were only a few studies per comparison. This research was not funded. Results Thirty-one studies that enrolled 6903 patients in 84 study Fig. 1. PRISMA flowchart of study selection process. groups met the inclusion criteria (Fig. 1). All studies except five C. Rodrigo et al. / Clinical Microbiology and Infection 24 (2018) 591e598 593 [6e10] were conducted in India, and two studies included HIV- coinfected patients [7,8]. All trials excluded pregnant and breast- feeding women. The findings of these studies are discussed in the following sections according to the main themes of comparisons. The risk of bias in each of the studies is highlighted in Fig. 2. All trials diagnosed VL by identifying parasites in splenic, lymph node or bone marrow aspirates, and all confirmed immediate and definitive cure after the completion of treatment and at 6 months (unless stated otherwise), respectively, by the same method. Any new parasitaemia observed between immediate cure and definitive cure was considered a relapse. A summary of dosing regimens, comparisons, and percentages of immediate and definitive cure (±95% confidence intervals), including the absolute numbers of patients, are provided in Tables 1e7. Characteristics of all included studies are provided online in Supplementary File 2. Comparison of different formulations of AmB Regarding the comparison of different formulations of AmB, four prospective studies (all performed in Bihar, India) including one nonrandomized
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