By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: A prospective nationwide study in France found that intravenous artesunate use was rapidly adopted by clinicians and was safe and highly effective in the treatment of severe malaria due to Plasmodium falciparum.
SOURCE: Roussel C, Ndour PA, Kendjo E, et al; FRench Artesunate Working Group. Intravenous artesunate for the treatment of severe imported malaria: Implementation, efficacy, and safety in 1391 patients. Clin Infect Dis 2021;73:1795-1804.
Rousel and colleagues evaluated the results of a national French program designed to facilitate the deployment of artesunate for the treatment of imported severe malaria due to Plasmodium falciparum. They prospectively collected data on 1,391 patients from 110 centers from 2011-2017, the first years of the program. During that time, the proportion of patients treated with artesunate increased from 9.9% between 2011 and 2013 and went on to increase to 71.4% in 2017, while the use of intravenous quinine correspondingly decreased. Of note is that one-fourth of patients instead received first-line oral therapy during the period of study, but with a switch from atovaquone-proguanil to artemisinin-based combinations.
Parasitological failure was observed in 27 of the 318 patients with blood smears on days 3, 7, and 28. This included 13 with slow clearance (i.e., taking > 7 days), seven with clearance followed by early resurgence before day 8, and seven with late resurgence occurring between days 8 and 28. No k13 (Kelch 13 propeller) nonsynonymous mutations were detected in the seven cases in which pretreatment blood samples were available.
Forty-one (4.1%) of 1,011 patients followed for 28 days died, most (80%) within four days after diagnosis. Compared to the total group, mortality was higher in those with an initial parasitemia > 10%, as well as in patients older than 50 years of age and those of European origin, while it was lower in those of African origin. The outcome in pregnant women and in human immunodeficiency virus (HIV)-infected patients was similar to that of the entire cohort. While an initial parasitemia > 10% was associated with higher mortality, there was no mortality difference between those with levels < 4% and those with 4% to 10%.
The drug generally was well tolerated, although the only pregnant patient treated during her first trimester experienced a hemorrhagic miscarriage. Hematological adverse effects were reported in 43.3%, although their relation to treatment as opposed to the illness itself is uncertain. The exception is post-artesunate-delayed-hemolysis (PADH), which occurred in 42.8% of patients specifically followed to detect it. As previously reported, this occurred more frequently in those of European as compared to African origin — 57.9% vs. 29.2%.
COMMENTARY
This French nationwide prospective study demonstrates the safety and efficacy of intravenous (IV) artesunate in the treatment of severe P. falciparum malaria. The U.S. Centers for Disease Control and Prevention (CDC) recommends that intravenous artesunate is the treatment of choice for patients with confirmed severe malaria as defined by the presence of at least one of the following: parasite density > 5%, impaired consciousness, seizures, circulatory collapse/shock, pulmonary edema or acute respiratory distress syndrome, acidosis, acute kidney injury, bleeding or disseminated intravascular coagulation, jaundice, or hemoglobin < 7 g/dL.1,2 Intravenous artesunate also is recommended for patients unable to take oral medications.
Despite the overall safety of artesunate, PADH occurred in 42.8% of patients monitored for its occurrence in this study. Fortunately, most often this is a relatively benign event. Nonetheless, the CDC states: “All persons treated for severe malaria with IV artesunate should be monitored weekly for up to four weeks after treatment initiation for evidence of hemolytic anemia.”1,2 PADH also has occurred after oral treatment with artemether-lumefantrine.
REFERENCES
- Centers for Disease Control and Prevention. Treatment of malaria: Guidelines for clinicians (United States). https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html
- Centers for Disease Control and Prevention. Intravenous artesunate for treatment of severe malaria in the United States. https://www.cdc.gov/malaria/diagnosis_treatment/artesunate.html
A prospective nationwide study in France found intravenous artesunate use was rapidly adopted by clinicians and was safe and highly effective in the treatment of severe malaria due to Plasmodium falciparum.
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