Promising Antimalarial Drug Proves Ineffective at Saving Children’s Lives

Photo: Matthis Kleeb/Swiss TPH
Photo: Matthis Kleeb/Swiss TPH

A large-scale study by the Swiss Tropical and Public Health Institute (Swiss TPH) and partners has found that rectal artesunate (RAS) has no beneficial effect on the survival of young children with severe malaria when used as an emergency treatment in resource-constrained settings. The study, which took place under real-world conditions in three African countries, concludes that the use of RAS is unlikely to reduce malaria deaths unless underlying health system weaknesses are addressed. The results could have implications on current WHO guidelines. A viewpoint about these findings was published today in The Lancet Infectious Diseases.

Rectal artesunate (RAS), a promising antimalarial drug, proves ineffective at saving the lives of young children suffering from severe malaria, according to the results of a new study conducted by the Swiss Tropical and Public Health Institute (Swiss TPH) and partners. A viewpoint about these findings was published today in The Lancet Infectious Diseases.

The study, which investigated a large-scale roll-out of RAS in the DR Congo, Nigeria and Uganda, found that when used as an emergency treatment under real-world conditions, RAS did not improve the odds of survival for young children with severe malaria.

-Our findings point to a very inconvenient but important issue,- said Manuel Hetzel, Professor of Epidemiology at Swiss TPH and first author of the publication. -We found that the overall management of severe malaria cases is so poor, that adding a single product does not seem to make a positive difference. Our focus must be on investment in improving existing health systems instead of relying on individual interventions.-

The observational study, which included 6,200 severely ill children under the age of 5 years, found that in some instances, the children who received RAS were more likely to die than those who did not. -RAS was previously shown to have a beneficial effect if it is followed by adequate post-referral care at a hospital, which raised hopes in the malaria community,- added Hetzel. -But more often than not, children do not finish the entire treatment due to lack of transportation to hospitals, cost of transport and treatment, or poor quality of care at hospitals.-

Pre-referral treatment with RAS is the administration of a single suppository by a community health worker or in a remote health facility as an emergency treatment, in order to bridge the time until a child is admitted to a hospital where comprehensive post-referral care is available. Post-referral care for severe malaria includes treatment with an injectable antimalarial, followed by a full oral course of artemisinin-based combination therapy (ACT), plus antibiotics and measures to manage potential complications.

Current recommendation by the WHO

The current WHO guidance on using RAS as pre-referral treatment is based on a randomised controlled trial that took place between 2000 and 2006 in Ghana, Tanzania and Bangladesh. The trial offered limited guidance on introducing RAS at scale. -Under real-life conditions, many factors influence whether an individual is appropriately treated and cured, which is why interventions that work well in a controlled trial may not always fulfil their potential in real life.- said Phyllis Awor, co-investigator of the study at the Makerere University School of Public Health in Uganda.

Based on the results of this new study, the WHO issued an Information Note in October 2021 recommending that countries either delay scale-up until further guidance on the safe implementation of RAS is made available, or urgently review the conditions under which it is currently being used. At present, the current WHO guidelines on RAS are under review by a team of WHO-appointed experts.

-The real-world evidence generated in our study should be taken into consideration before pushing for a large-scale roll-out of pre-referral RAS in systems that do not have a functioning continuum of care,- said Hetzel. -Without a comprehensive approach that acknowledges the complex realities faced by caregivers and health workers in remote, underserved areas, children will continue to die from malaria, and promising interventions such as RAS will fail to meet their full potential.-

About the study

The Community Access to Rectal Artesunate for Malaria (CARAMAL) project was an observational study that accompanied the introduction of pre-referral RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda between 2018 and 2021. It is the first study of its kind to look at the introduction of quality-assured RAS in existing community-level healthcare systems at a large scale. The project was implemented by the Clinton Health Access Initiative (CHAI), UNICEF and Swiss TPH, with funding from Unitaid. Swiss TPH was responsible for the evidence generation jointly with the University of Kinshasa School of Public Health in the DRC, Akena Associates in Nigeria and the Makerere University School of Public Health in Uganda. The study was published on 11 October 2022 in BMC Medicine.


Hetzel MW et al. Pre-referral rectal artesunate: no cure for unhealthy systems. Lancet Infectious Diseases 2022; published online Dec 19.­1473-3099(­22)00762-9