Protocol: Amphotericin B for treatment of visceral leishmaniasis; a systematic review of prospective, comparative clinical studies including dose ranging studies
Background
Description of the condition
Visceral leishmaniasis (VL), caused by the unicellular parasite Leishmaniadonovani is potentially fatal if untreated[1]. Over 90% of VL cases in the world are reported from six countries namely; Brazil, Ethiopia, Somalia, South Sudan, Sudan and India. Approximately 200 million people are at risk of the infection in these countries. Pentavalent antimonial compounds have been the first line of treatment for many decades. However these drugs have inherent toxicity and resistance to therapy is now frequently encountered specially in India[2].
Description of the intervention
Amphotericin B (AmB) is a macrolidepolyene antifungal agent that is increasingly being used as the preferred choice in areas with antimonial resistance. Amphotericin B is also not soluble in saline and has to be mixed with the detergent sodium deoxycholate. Soon after entry into plasma, the drug dissociates from the detergent and binds to circulating lipoproteins. The lipid soluble property of amphotericin has been used to develop several lipid soluble variants that also has less toxicity and hence an increased therapeutic index. These preparations are; liposomal amphotericin (L-AmB), amphotericin B lipid complex (ABLC) and amphotericin B emulsion (ABLE)[3].
With emerging resistance to pentavalent antimonials, amphotericin B is emerging as a preferred choice. However, the lipid formulations of amphotericin B is costly than the pentavalent antimonial compounds and this is a major obstacle in rolling out therapy in endemic regions. Within the last decade there have been several prospective randomized clinical trials that compare different dosing regimens and different preparations of amphotericin B for VL. It is important to collate the evidence from these studies to gauge the efficacy of the drug. There may also be a geographical bias in the resistance patterns of the Leishmania species and evidence from these studies have to be interpreted in this context.
Objectives
- To assess the efficacy of different formulations of AmB in the treatment for VL
- To determine the minimum effective dose for each formulation of AmB
- Identify any geographical bias in the efficacy of AmB
- Compare the efficacy of different AmB formulations against other drugs used in the treatment of VL
Methods
Eligibility criteria: We will includecomparative prospective clinical trials (randomized or non-randomized) in this analysis. Case series where control populations were not available will be excluded. Dose ranging studies will be included.
Participants: Adults and children diagnosed with VL by demonstration of parasites in lymph node, splenic or bone marrow aspirate
Types of interventions: Any formulation of AmB prescribed and compared with a) placebo, b) other standard drug treatment or c) a different dose of AmB
Primary outcome: Definitive cure (bone marrow, splenic or lymph node aspirate free of parasites) after at least 6 months since the completion of therapy
Secondary outcomes: Adverse events and mortality
Information sources and search strategy: We will searchPubMed, EMBASE, Scopus, Web of Science and CINAHL for relevant articles. PubMedwill be searched with the keywords ‘Leishmania*’ in any field and ‘amphotericin’ in any field without any language, time or other restrictions. EMBASE, CINAHL and web of science will be searched with the same criteria.SCOPUSwill be searched with the same in the keywords, title or abstract with no language or time limits. We will use Endnote X7 (Thomson Reuters, Carlsbad, CA 92011, USA) to filter articles. The PROSPERO registration number for this review is CRD42017067488. This review will be conducted according to the standards specified in the Cochrane handbook of systematic reviews.
Study selection and data collection:CRand PW will do the preliminary screen by reading the titles and abstracts of all articles. Depending on the abstracts, the papers will be classified as ‘yes’ (meets inclusion criteria), ‘no’ (does not meet inclusion criteria) and ‘doubtful’. Full articles will be obtained for all studies meeting the inclusion (or doubtful) criteria. Any conflicts will be resolved with consensus of all authors.
Data items: The following data items will be extracted from each eligible study; participant demographics, intervention and control groups, drug doses, locality of study, immediate and definitive cure rates, adverse events attributable to therapy, relapses during follow up and mortality statistics.
Risk of bias:We will assess the risks of bias of included studies qualitatively using the Cochrane risk of bias assessment tool[4]. We will not calculate quality scores for individual studies as it is not perceived by all as an objective measure of risk of bias[5].
Summary measures and synthesis of results:If comparative trials are available,we will combine them in a meta-analysis using Review Manager 5[4]. Dichotomous data will be compared with relative risk (RR) and 95% confidence intervals (CI) and continuous data with mean differences. A fixed effect model will be used for analysis. The heterogeneity will be assessed using the I2 statistic [6]. This examines the percentage of total variation across studies that are due to heterogeneity rather than chance.If there is high heterogeneity (I2>70%), a random effect model will be used for the analysis. Quality of evidence will be assessed with GRADEPro software.
Risk of bias across studies: We will construct funnel plots to assess publication bias if there are enough studies per comparison (less than 3 per comparison).
Missing data: The analysis will be done according to an intention-to-treat analysis. We will contact individual authors to clarify about missing data.
Subgroup analysis: None planned
References
1Sundar S, Singh A. Recent developments and future prospects in the treatment of visceral leishmaniasis. Ther Adv Infect Dis. 2016; 3: 98-109.
2Sundar S, Goyal AK, More DK, Singh MK, Murray HW. Treatment of antimony-unresponsive indian visceral leishmaniasis with ultra-short courses of amphotericin-b-lipid complex. Ann Trop Med Parasitol. 1998; 92: 755-764.
3Hamill RJ. Amphotericin b formulations: A comparative review of efficacy and toxicity. Drugs. 2013; 73: 919-934.
4The Nordic Cochrane Centre. Review manager [computer program]. 5.1 edn. Copenhagen: The Cochrane Collaboration 2011.
5Greenland S. Quality scores are useless and potentially misleading. Am J Epidemiol. 1994; 140: 300-301.
6Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ. 2003; 327: 557–560.