Visceral leishmaniasis (VL), also known as Kala-Azar, is a neglected disease caused by protozoan parasites of the genus Leishmania. The disease is endemic in parts of the Indian subcontinent, East Africa, South America and the Mediterranean region, with an estimated 50,000 to 90,000 cases occurring in 2019 [1].
If untreated, the disease is generally fatal within 2 years [2]. Historically, pentavalent antimony (PA) had been the mainstay drug for VL treatment in the South Asia [3, 4]. Due to the emergence and evolution of drug-resistant parasites and the poor safety profile of PA at higher doses [5–7], single-dose Liposomal Amphotericin B (L-AmB) has been recommended as the first-line therapy in the Indian subcontinent since 2010 [8]. PA remains the first-line therapy in East Africa – mainly as a combination regimen with paromomycin as drug resistance has not been reported and single dose L-AmB was found to have lower efficacy in this region [9, 10]. Such heterogeneity in therapeutic responses has been thought to arise due to regional differences in parasite sensitivity/susceptibility, differences in underlying patient population, and genetic variability in parasite populations, although to date the exact reasons remain unclear [11]. A consolidation of evidence from existing therapeutic studies can provide further insights into host, parasite and determinants of drug resistance or treatment failure. Some major challenges towards such evidence consolidation include: VL studies are generally small and sparse with a median sample size of 32 (range: 1 – 3,126) patients per treatment arm (See S1 Data in [12]), VL control programmes are severely underfunded [13], and the drug supply is substantially lower than the estimated case burden of VL in several endemic countires [13], and little is known on the therapeutic efficacy of the exisiting drug reimens in pregnant patients [14]. It is therefore important to establish a robust and reliable repository of historical studies that can allow pooling data across available clinical trials to maximise the research potential and consequently the impact.
The infectious diseases data observatory (IDDO) VL library of clinical studies is an open-access resource that provides a systematically assembled inventory of published therapeutic studies [15]. The IDDO VL library was first initated in 2016 by searching the published literature from 1980 until 2016. After revising the search strategies adopted in 2019, the library has been been updated bi-annually and the current approach taken to maintain the IDDO library of clinical studies follows a living systematic review methodology. A living systematic methodology is a periodic and incremental addition to a systematic review which saves resources and time that would be required to plan and conduct a new systematic review from scratch, minimising duplication and inefficiency [16]. Constantly identifying and adding information from new studies to the existing pool thus ensures that any subsequent meta-analysis is based on a robust database. This easily and freely accessible repository allows the selection of studies for inclusion in meta-analyses based on factors such as drug class, geography, and a number of host and parasite characteristics.
After the completion of the search update, the complied database of eligible studies is made publicly available to the global research community through the VL-surveyor on the IDDO website – which serves as a global “knowledge commons”[16]. Such an inventory can provide a unique resource to the VL research community for a better understanding of historical data on drug safety and efficacy, for planning aggregate data meta-analysis, to assess the potential volume of data available for subsequent data re-use, to assess the feasibility of carrying out individual participant data meta-analysis (IPD-MA) on a specific research topic, and help designing better prospective clinical trials.
This prospective protocol describes the living systematic review methodology used by IDDO to achieve the overarching aim of maintaining the VL library of clinical studies. The research objectives are:
1) The primary objective of this systematic review is to index all the clinical studies describing the efficacy of antileishmanial therapies and summarise the landscape of the clinical studies
2)The secondary objective is to extract the number of patients who develop the following clinical outcomes following treatment of VL within the study follow-up period in the studies identified by the review: a) relapse, b) initial cure, c) Lost to follow-up, d) Post-Kala Azar Dermal Leishmaniasis (PKDL).