IDDO is looking forward to sharing some of our recent work on malaria, COVID-19 and visceral leishmaniasis (VL) during the virtual conference hosted from Bergen, Norway.

• Dr Prabin Dahal will present his new paper Visceral Leishmaniasis in pregnancy and vertical transmission: A systematic literature review on the therapeutic orphans .
• Dr Dahal will also be presenting two posters, the first is called ‘Methodological variations in design and conduct of visceral leishmaniasis clinical trials: A systematic review’ and the second is titled ‘Haemoglobin at inclusion in visceral leishmaniasis clinical studies: A systematic review and proposal for an individual patient data meta-analysis’. Find out more about our VL work here.
• Dr Kasia Stepniewska will present a poster on her work in malaria titled, ‘Optimisation of single-dose primaquine used with artemisinin combination therapy for reduction of Plasmodium falciparum transmission: WWARN Individual Patient Data Meta-Analyses.
• And Dr Alistair McLean will present a poster on his COVID-19 research, called ‘Characteristics of COVID-19 clinical trial registration investigating priority pharmacological treatments: a complex landscape’ . Find out more about our COVID=19 work here.

View the event website for more information and follow #ECTMIH2021 updates on Twitter @ectmih2021 using the #ECTMIH2021 hashtag and visit us at @IDDOnews

The review, Visceral Leishmaniasis in pregnancy and vertical transmission: A systematic literature review on the therapeutic orphans identifies reported cases and assesses the risk-benefit balance of antileishmanial therapies to the pregnant woman and the child. It brings together scattered observations of VL in pregnant women in the clinical literature and highlights that the disease in pregnancy is under-reported and under-studied. The authors found that information was often incomplete and it was difficult to derive generalisable information on outcomes, however, the findings suggest that liposomal amphotericin B (L-AmB) should be the preferred treatment for VL during pregnancy.

In practice, pregnant and lactating women are regularly excluded from clinical studies and are considered “therapeutic orphans”. IDDO researchers have previously found that existing knowledge on drug efficacy is derived from a study population that is heavily skewed towards adult males while, substantially less is known about the optimal treatment response in female patients. This means that existing therapeutic guidelines regarding drug usage in pregnancy are guided by limited evidence generated from case reports and small case series.

A recent IDDO large-scale systematic review and meta-analysis collating all reported serious adverse events (SAE) in VL clinical studies and quantifying the incidence of mortality during the first 30 days of therapy, found that mortality following treatment was an extremely rare event and SAEs were poorly reported. However, regulatory restrictions and the limited evidence on the safety of antileishmanial chemotherapeutics during pregnancy have meant that historically, clinicians had to rely on personal experience or limited published case-reports. This led to delays in treatment or it only being given when the adjudicated risk of VL to the pregnant women outweighed the risk posed by the drug.

Better understanding of the treatment of VL in pregnancy is important because of the severe impact of VL on pregnant women in low-income settings.

A leading scientist on the epidemiology of VL in the East African region, Professor Ahmed Musa, of IEND, University of Khartoum, said: “As a chronic illness visceral leishmaniasis (VL) is usually a barrier to pregnancy or causes miscarriage early on. However, in cases where the pregnancy continues, it often results in stillbirth or the child is born with some parasites and develops VL and in the majority of cases it is fatal. The added complication of access to limited rural health facilities means that VL in pregnant women is often undiagnosed and resulting in under-reporting in regional or national health statistics and to scant literature.”

One of the paper’s authors Dr Fabiana Alves, Head of Visceral Leishmaniasis Disease at Drugs for Neglected Diseases initiative (DNDi), said: “This is the most comprehensive review of visceral leishmaniasis in pregnant women and vertical transmission of leishmaniasis to date. Despite the limitations and paucity of data, this review confirms that liposomal amphotericin B is the safest treatment option for pregnant women, and it is critical to ensure access to L-AmB as a treatment of choice for this patient population. Prospectively, a pregnancy registry to systematically record data on pregnant women treated for visceral leishmaniasis should be promoted.”

This new paper aims to assess the risk-benefit balance of antileishmanial therapies to the pregnant woman and the child and to identify the cases of vertical transmission. It is the third in a series of systematic reviews aimed at enhancing the understanding about treatments for VL.

• The first study, carried out by IDDO researchers, found that existing knowledge on drug efficacy is derived from a study population that is heavily skewed towards adult males while, substantially less is known about the optimal treatment response in female patients. Despite an ongoing trend for a decreasing proportion of males being enrolled in antileishmanial therapeutic efficacy trials over time, there are still 1.8 times as many males as females  enrolled in clinical trials.

• The second study, a large-scale systematic review and meta-analysis collating all reported serious adverse events (SAE) in VL clinical studies and quantifying the incidence of mortality during the first 30 days of therapy, found that mortality following treatment was an extremely rare event and serious adverse events following treatments were poorly reported.

VL is a neglected tropical disease caused by Leishmania sp. parasites transmitted by female sandflies. The disease is endemic in parts of South Asia, East Africa, South America and the Mediterranean region, with an estimated 50,000 to 90,000 cases in 2019. A specific concern of public health relevance is the little knowledge of the consequences of VL and its treatment on the mother and the foetus.

For this review, IDDO screened 272 publications and identified a total of 72 records (1926–2020) describing 451 VL cases in pregnant women - read the full text of Visceral Leishmaniasis in pregnancy and vertical transmission: A systematic literature review on the therapeutic orphans.

About IDDO’s VL living systematic review library of clinical studies

The Infectious Diseases Data Observatory (IDDO) VL clinical trials library has indexed 180 therapeutic efficacy studies published between 1983 through 2019. The library is a living systematic review, and the database is continually updated every six months in accordance with the Preferred Reporting Items for Systematic-Reviews and Meta-Analyses (PRISMA) guidelines. The trial library indexes publications identified from the following databases: PubMed, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, Global Index Medicus, IMEMR, IMSEAR, and LILACS.

IDDO’s Director Professor Philippe Guérin will open the event with his plenary ‘Exploring the re-use of existing data for poverty-related diseases – a scientific or an ethical imperative or both?' at 10 am (BST) on Monday, 21 June, 2021. This will be followed by other talks that day from IDDO collaborators:

• From 11am to 11.40am: Professor Mitali Chatterjee, a Professor of Pharmacology at the Institute of Postgraduate Medical Education & Research (IPGMER), Kolkata, India and chair of IDDO’s visceral leishmaniasis Scientific Advisory Committee; and Dr Prabin Dahal, a Post-doctoral researcher with IDDO, will present ‘Methodological challenges in measuring drug efficacy for the treatment of visceral leishmaniasis’.
• From 11.45am to 12.25pm: Dr Martin Walker, assistant professor at the Royal Veterinary College, University of London, and IDDO Senior Scientist, will discuss work in developing a research agenda for a sharing and reuse of clinical data on schistosomiasis and soil-transmitted helminthiases.
• From 12.45pm to 1.25pm: Dr Nathalie Strub-Wourgaft, Director of Neglected Tropical Diseases with the Drugs for Neglected Diseases initiative, DNDi, will discuss the ‘Value of a data platform for drug development and for regulatory agencies: the case of Chagas disease’.
• From 1.30pm to 2.10pm: Professor Sir Nicholas White, Professor of Tropical Medicine at the University of Oxford and also Professor at Mahidol University in Thailand and IDDO board member, will reflect on the achievements of 10 years of the WWARN global malaria clinical data platform.

The BSP meeting takes place over five-days from June 21^st to the 25^th. Thanks to the design of the virtual conference interface there will be plenty of opportunities for interaction, through live Q&A sessions, breakout discussion rooms and virtual trade stands for our exhibitors and sponsors.

The conference will include a mix of high-quality themed scientific sessions, keynote speakers and presentations, as well as interactive poster sessions giving delegates the opportunity for discussion with poster presenters.

Visceral leishmaniasis (VL) is a poverty-related infectious disease that causes up to 30,000 deaths per year, with over 600 million people at risk. The disease causes fever, weight loss and spleen and liver enlargement. If left untreated, it can cause death within two years. Existing treatments are often lengthy, painful, costly and poorly tolerated. However, despite antileishmanial drugs being associated with poor tolerability, a comprehensive library on different safety events following these therapies is lacking.

The authors conducted a comprehensive review of the clinical literature to document reports of SAEs following antileishmanial chemotherapies. The systematic review identified 157 published studies from 1980 to 2019, which included 35,376 patients across 347 different treatment arms.

Overall, mortality following antileishmanial treatment was a rare event reported in the clinical trials. Some variation in mortality rates was seen across geographic regions and patient sub-groups, for example, patients with HIV co-infection. These estimated rates of mortality can serve as a baseline against which mortality data from prospective studies can be compared.

It was found that reporting of SAEs was inconsistent in the published literature. The timing, cause and frequency of these were often poorly reported. Furthermore, just over two-thirds of the studies did not provide the standards used to assess the severity of SAEs.

Dr Sauman Singh, the lead author on the research said: “This work highlights the need for improved and standardised approach for capturing solicited and unsolicited adverse events appearing during clinical trials, which could be achieved through the adoption of uniform reporting guidelines as well as easily accessible research outcomes. Clear and transparent reporting of the methodology used in safety assessments is also essential for downstream analyses and the generation of new evidence.”

The results from this review provide baseline estimates for comparing routine data collected by national elimination programmes as well as data from new research, such as data from ongoing pharmacovigilance trials, studies about prospective drugs or research into optimal treatment regimes.

Dr Prabin Dahal, one of the study co-leads remarked: “This review has taught us that despite making excellent progress in understanding the clinical efficacy of the existing drug regimens, the research on the safety aspects remains far from ideal. In particular, the lack of uniformity in standards adopted for defining and recording adverse events and disparate practices among research groups in reporting safety data at different time-points remains a challenge for amalgamating existing evidence to the highest standards. The IDDO VL data platform provides us with a unique opportunity to overcome some of these challenges by facilitating individual participant data meta-analysis.”

IDDO is working with the VL research community in a new global collaboration to develop a set of freely-available universal standards for the collection of VL data. This collaboration, involving representatives from the VL research community, the pharmaceutical industry, drug regulators, key national and global health partners and CDISC aims to set guidelines that will benefit current and future research into the disease.

Read the research: Serious adverse events and mortality following treatment of Visceral Leishmaniasis: A systematic review and meta-analysis. PLOS Neglected Tropical Diseases. 

IDDO’s VL research theme aims to answer key research questions through data reuse from VL studies conducted around the world. The VL data platform is assembling and standardising individual patient data for researchers to apply to access for their own analyses.