Intravenous Artesunate for the Treatment of Severe Imported Malaria: Implementation, Efficacy, and Safety in 1391 Patients

Abstract

Background

Intravenous artesunate is the World Health Organization–recommended first-line treatment for severe malaria worldwide, but it is still not fully licensed in Europe. Observational studies documenting its safety and efficacy in imported malaria are thus essential.

Methods

We prospectively collected clinical and epidemiological features of 1391 artesunate-treated patients among 110 participant centers during the first 7 years (2011–2017) of a national program implemented by the French Drug Agency.

Results

Artesunate became the most frequent treatment for severe malaria in France, rising from 9.9% in 2011 to 71.4% in 2017. Mortality was estimated at 4.1%. Treatment failure was recorded in 27 patients, but mutations in the Kelch-13 gene were not observed. Main reported adverse events (AEs) were anemia (136 cases), cardiac events (24, including 20 episodes of conduction disorders and/or arrhythmia), and liver enzyme elevation (23). Mortality and AEs were similar in the general population and in people with human immunodeficiency virus, who were overweight, or were pregnant, but the only pregnant woman treated in the first trimester experimented a hemorrhagic miscarriage. The incidence of post-artesunate–delayed hemolysis (PADH) was 42.8% when specifically assessed in a 98-patient subgroup, but was not associated with fatal outcomes or sequelae. PADH was twice as frequent in patients of European compared with African origin.

Conclusions

Artesunate was rapidly deployed and displayed a robust clinical benefit in patients with severe imported malaria, despite a high frequency of mild to moderate PADH. Further explorations in the context of importation should assess outcomes during the first trimester of pregnancy and collect rare but potentially severe cardiac AEs.

severe malaria, artesunate, post-artesunate–delayed hemolysis, safety

Intravenous (IV) artesunate is the World Health Organization (WHO)-recommended first-line treatment for severe malaria worldwide. Compared with IV quinine, IV artesunate reduces lethality in Asian adults and in African children by 35% and 22.5%, respectively [1, 2]. Artesunate was designated as an orphan drug by the European Medicines Agency in 2007 (EU/3/07/430). Artesunate meeting good manufacturing practice (GMP) standards is currently not available in Europe, and it is not approved by drug agencies in most nonendemic countries. It is therefore not available for emergency use except through specific distribution programs [3]. In this situation, patients needing artesunate may not have immediate access to it [4, 5]. Artesunate was developed by Guilin Pharmaceuticals. In 2010, the company’s parenteral formulation was prequalified by WHO. In June 2019, the American Society of Tropical Medicine & Hygiene raised concerns that the public distribution program could delay the provision of artesunate and result in adverse outcomes for patients, and advocated for a fast approval of artesunate in the United States [6]. In May 2020, the US Food and Drug Administration approved GMP IV artesunate manufactured by Amivas (US) LLC for the treatment of severe imported malaria.

In France, IV artesunate had been recommended by a national experts panel in 2007 [7], but the distribution of this off-licensed drug was not organized, leaving IV quinine as the only effectively available option. In 2009, an independent panel of academic experts challenged the national drug agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé) and, in May 2011, IV artesunate (ACE Pharmaceuticals BV, The Netherlands) became available in a temporary use approval program for severe imported malaria [3]. A specific distribution program compatible with the emergency treatment of severe malaria was implemented through the prepositioning of artesunate at hospital pharmacies throughout France. The Agence Nationale de Sécurité du Médicament et des Produits de Santé performed a post hoc validation of the use of artesunate. This specific program implied that clinicians, biologists, and pharmacists involved in the use of artesunate would provide treatment start up, treatment end, and post-follow-up efficacy and safety data. This enabled the French program to precisely oversee the implementation of this new treatment.

We assessed the outcome of the program for nationwide artesunate deployment for severe imported malaria, as well as the efficacy and safety of this treatment in both the general patient population and in specific patient subgroups.

METHODS

Study Population

We analyzed a cohort of patients treated with IV artesunate for malaria in France between 25 May 2011 and 31 December 2017. Observations from the first 123 treated patients have been reported previously and were included in this analysis [8]. Data were prospectively collected in the Malaria National Reference Center (MNRC) database shared by a network of 110 sites in France. Additional data were prospectively collected from medical charts and specific distribution program forms [3] completed by the attending physicians at the beginning and end of treatment and at the end of patient follow-up (Figure S1). All patients who received IV artesunate at an MNRC network site during the study period were included. Data were retrieved from the MNRC database (Voozanoo, Epiconcept) on 3 July 2018.

Adverse events (AEs) were obtained from the MNRC database and the national pharmacovigilance system as described elsewhere [8]. Postmarketing surveillance was done by 31 nationally distributed pharmacovigilance centers. Additional information on safety was retrieved by the expert group from medical charts and direct contact with pharmacists, physicians, and biologists in charge of the patients. No assumption on the imputability of artesunate in AEs was made at the time of analysis.

Case Definitions

Definitions used for severe/uncomplicated malaria [7], parasitological failure (PF), and anemia when reported as an AE are provided in Text S1 and Text S2. Main outcomes of acute malaria were defined as death or survival at day 28, median length of stay (LOS) in the intensive care unit (ICU) and in the hospital. Definitions used for “geographic origin” are provided in Text S1.

Treatment regimens are indicated in Text S2.

Post-artesunate–Delayed Hemolysis

Post-artesunate–delayed hemolysis (PADH) was specifically assessed in a 98-patient subgroup, based on hematological and biochemical parameters (hemoglobin, hematocrit, lactic acid dehydrogenase, bilirubin, and reticulocytes) before and after treatment (until day 28 posttreatment) as described in Text S2 [8]. The PADH incidence subgroup comprised all cohort patients with complete day 0 to day 28 biological and clinical follow-up and day 0 frozen serum in the MNRC (Table S1). Their laboratory and clinical data were reviewed by experts who confirmed group allocation based on published criteria [9, 10].

Detection of Kelch 13-Propeller Domain Mutations

We retrieved pretreatment frozen whole blood samples from the MNRC for patients presenting it and looked for the Kelch 13-propeller domain mutations (Text S2).

Statistical Analysis

Outliers and implausible or missing information were checked. Implausible values were recorded as missing when no other information could be found. Quantitative variables were expressed as medians (interquartile range) or means (standard deviation) as appropriate. Qualitative variables were expressed as percentages. Differences among groups were analyzed with the Fisher’s exact test for categorical variables, and the Mann-Whitney test for 2 or the Kruskal-Wallis test for more than 2 continuous variables. Stata 13 Statistical Software (Stata Corp LP, College Station, TX) was used for all analyses. All reported P values are 2-sided. The adjusted chi-square test was used to compare the characteristics of the PADH incidence subgroup and the whole cohort.

Ethical Considerations

The study was authorized by the French National Commission for Data Protection and Liberties (declaration number 1223103) and approved by the Ethics Committee for Biomedical Research (Text S2).

RESULTS

Replacement of IV Quinine by IV Artesunate to Treat Severe Imported Malaria in France

During the transition period (2011–2017), the number of severe imported malaria cases declared to the MNRC and the proportion of severe malaria among all reported malaria cases increased from 2011 to 2014 and then stabilized between 2014 and 2017 (Figure 1A). Severe malaria-specific lethality decreased from 6.2% in 2012 to 3.4% in 2017 (Figure 1B).

Figure 1.

Medical context, kinetics, and completeness of artesunate implementation in France (May 2011–December 2017). A, Annual incidence of malaria (gray bars) and proportion of severe malaria cases (red line). B, Lethality of malaria (black line) and specific lethality of severe malaria (red line). C, Proportion of patients with severe malaria treated with IV artesunate (red line), IV quinine (blue line), or oral therapy (black line). D, Proportion of patients with severe malaria cases treated orally with atovaquone-Proguanil (AP; green line), artemisinin-based combination therapies (ACT; red line), or other drugs (blue line). Abbreviation: IV, intravenous.

The proportion of severe malaria patients treated with artesunate rapidly increased between May 2011 and December 2014 from 9.9% to 61.9%, whereas that of patients treated with IV quinine decreased from 72.5% to 19.2%. A nearly complete transition was thus observed within 3 years. From January 2015 to December 2017, the proportion of artesunate-treated patients continued to slowly increase, reaching 71.4% in 2017 (Figure 1C). Interestingly, almost 25% of severe malaria patients were treated with first-line oral therapy, a proportion that remained stable during the study period, but with a marked switch from atovaquone-proguanil to artemisinin-based combinations (Figure 1D).

Description of the Cohort

During the study period, 1391 malaria patients, of whom 98.5% (n = 1370) had severe Plasmodium falciparum malaria according to French definitions, were treated with IV artesunate. A total of 145 patients (10.4%) met the French but not the WHO 2015 criteria for severe malaria. Children (<15 years) and seniors (>65 years) accounted for 9.2% and 8.9% of the cohort, respectively. Fifteen pregnant women were treated, including 1 in the first, 6 in the second, and 6 in the third trimesters (missing information for 2). There were 98 (7.9%) immunocompromised patients, of whom 67 (5.4%) had HIV. A total of 74.6% of the patients lived in nonendemic areas, 56.7% were born in endemic countries, and 67.7% declared an African origin (Table 1). Patient characteristics were similar to those of severe imported malaria patients reported by the GeoSentinel analysis in 2017 [11].

Table 1.

Population Characteristics of Artesunate-Treated Patients (France: May 2011–December 2017)

	N (% of Available Data)
Geographic origin (n = 1224)
African	829 (67.7)
European	362 (29.6)
Asian	11 (0.9)
Other	22 (1.8)
Location of birth (n = 1174)
Endemic area	666 (56.7)
Nonendemic area	508 (43.3)
Location of residencea (n = 1056)
Endemic area	268 (25.4)
Nonendemic area	788 (74.6)
Immunodepression (n = 1240)
Yes	98 (7.9)
Human immunodeficiency virus	67 (5.4)
Cancer	10 (0.8)
Corticosteroid therapy	6 (0.5)
Hematological malignancy	5 (0.4)
Organ transplant	3 (0.2)
Other	5 (0.4)
Unknown	2 (0.2)
Pregnancy (n = 1293)
Yes	15 (1.7)
Sex (n = 1389)
Female	473 (34.1)
Male	916 (65.9)
Age category (n = 1391), y
0–2	23 (1.7)
2–5	28 (2.0)
5–15	77 (5.5)
16–30	273 (19.6)
31–49	477 (34.3)
50–65	389 (28.0)
>65	124 (8.9)
Weight categories (n = 914), kg
>100	40 (4.4)
<50	109 (11.9)

^a> 6 months in the past 12 months.

Clinical Efficacy

PF occurred in 27 of the 318 cohort patients who had complete parasitological follow-up (ie, blood smear available at days 3, 7, and 28). Among the PF patients, 13 had slow parasite clearance (>7 days), 7 had early resurgence (before day 8), and 7 had late resurgence (between days 8 and 28). One PF patient died from cardiogenic shock and ventricular fibrillation. No PF risk factors were found in univariate analysis (Table S2), and PF risk did not increase during the study period (not shown). Pretreatment frozen whole blood samples were available for 7 of the 27 PF patients. No k13 nonsynonymous mutants were found in the 7 tested isolates.

Forty-one patients died during the study period and 970 were recorded as cured; day 28 outcome was missing for 380 patients (27.3%). Overall mortality was 4.1% (41/1011) when considering only patients with explicitly reported day 28 death or survival data. The majority (80%) of deaths occurred within the first 4 days after diagnosis (Figure S2). Median hospital and ICU LOS were 6 (4–8) and 2 (1–4) days, respectively (Table 2). Blood transfusion was reported in 130 patients (9.3%).

Table 2.

Clinical Presentation, Treatment Characteristics and Main Outcomes in Artesunate-Treated Patients (France: May 2017–December 2017)

	N (% of Available Data)
Prescription of artesunate (n = 1391)
First-line intention	1135 (81.6)
Second-line intention	256 (18.4)
Treatment received before artesunate when given in second intention (n = 1388)
Quinine (IV or PO)	146 (57.7)
Atovaquone + proguanil	54 (21.3)
Artemether + lumefantrine	23 (9.1)
Dihydroartemisinin + piperaquine	22 (8.7)
Mefloquine	5 (2.0)
Chloroquine	1 (0.4)
Other	2 (0.8)
Severity (n = 1391)
Uncomplicated malaria without vomiting	13 (0.9)
Uncomplicated malaria with vomiting	8 (0.6)
Severe malaria	1370 (98.5)
Plasmodium species (n = 1391)
P. falciparum alone or co-infectiona	1381 (99.3)
Otherb	10 (0.7)
Place malaria acquired (n = 1344)
West Africa	800 (59.5)
East and Central Africa	521 (38.8)
South America	5 (0.4)
Asia	6 (0.4)
Other	12 (0.9)
Chemoprophylaxis during travel (n = 1247)
Yes	271 (21.7)
Atovaquone + proguanil	76 (28.0)
Mefloquine	42 (15.5)
Doxycycline	101 (37.3)
Chloroquine	26 (9.6)
Proguanil	15 (5.5)
Other	11 (4.1)
Reason for stay in malaria-endemic zone (n = 1037)
VFR	535 (51.6)
Tourism	78 (7.5)
Tourism from endemic zone	117 (11.3)
Business in endemic zone	140 (13.5)
Expatriate	66 (6.4)
Military	29 (2.8)
Humanitarian	38 (3.7)
Seafarers	5 (0.5)
Other	29 (2.8)
Length of stay (n = 1138), wk
<4	403 (35.4)
4–12	456 (40.1)
>12	279 (24.5)
Evolution (n = 1011)
Died	41 (4.1)
Sequelae (n = 574)
Sequelae	48 (8.4)
Severity criteria (clinical) (n = 1391)
Impaired consciousness	475 (34.7)
Coma (Glasgow score < 11)	62 (4.5)
Repeated generalized seizures	12 (0.9)
Circulatory collapse	167 (12.2)
Spontaneous bleeding	44 (3.2)
Respiratory distress	70 (5.1)
Macroscopic hemoglobinuria	136 (9.9)
Clinical jaundice	417 (30.4)
Severity criteria (biological) (n = 1391)
Hyperparasitemia > 4%	820 (59.9)
Hemoglobin < 5 g/dL, hematocrit < 15%	12 (0.9)
Hemoglobin < 7 g/dL, hematocrit < 20%	54 (3.9)
Creatinine > 265 µmol/L or elevated for age	215 (15.7)
Hypoglycemia (< 2.2 mmol/L)	23 (1.7)
Total bilirubin > 50 µmol/L	446 (32.6)
Hyperlactatemia > 5 mmol/l	404 (29.5)
Acidosis (pH < 7.35 or sodium bicarbonate < 15 mmol/L)	101 (7.4)
Severity criteria specific to imported malaria (n = 1391)	145 (10.4%)
Isolated hyperparasitemia (4%–10%)	131 (9.4)
Isolated hemoglobinuria	8 (0.6%)
Isolated clinical jaundice	6 (0.4%)
	Median (Q1-Q3)
Initial parasitemia (%) (n = 1258)	5.2 (1.5–9.6)
Temperature at day 0 (°C) (n = 1217)	39 (38–39.7)
Initial dose of artesunate first intention (mg) (n = 882)	180 (150–200)
Time between onset of symptoms and diagnosis (d) (n = 1263)	4 (2–6)
Length of stay in intensive care unit (d) (n = 866)	2 (1–4)
Length of stay in hospital (d) (n = 901)	6 (4–8)

Abbreviations: IV, intravenous; PO, by mouth; VFR, visiting friends and relatives.

^aPlasmodium ovale (6), P. vivax (10), P. malariae (11), Plasmodium spp (1).

^bPlasmodium ovale (4), P. vivax (2), P. malariae (1).

Compared with the general population of artesunate-treated patients, mortality was higher in patients with initial parasitemia >10%, patients aged >50 years and patients of European origin, and lower in patients <15 years old (1.0%) or of African origin. HIV-positive patients had an increase in total LOS but not an increase in mortality. Pregnant women had outcomes similar to the general population (Table 3). Initial parasitemia was significantly higher in patients of European origin but similar among the other subgroups (Table S3). Of note, no outcome differences were observed between the patients with initial parasitemia <4% and those with initial parasitemia from 4% to 10% (Table 3). At the end of follow-up, sequelae were reported in 48 patients (8.4% of 574 patients with available information, Table S4).

Table 3.

Main Outcomes in Different Subgroups

	No. of Subjects in Each Group	Mortality			Total Length of Stay (d)			ICU Length of Stay (d)
		N Deaths / N Patients With Reported Outcome	Estimated Frequencies	Statistical Significance	Median	(Q1–Q3)	Statistical Significance	Median	(Q1–Q3)	Statistical Significance
Total	1391	41/1011	4.1%		6	(4–8)		2	(1–4)
Geographic origin
Africa	829	13/615	2.1%	P < .000	5	(4–7)	P = .0001	2	(1–3)	P = .0001
Europe	362	20/289	6.9%	P = .007	7	(5–9)		3	(1.5–4)
Age, y
<2	23	0/17	0%	P = .003	5	(4–6)	P = .0023	1	(0–3)	P = .0125
2–5	28	1/19	5.3%		4.5	(3.5–6)		3	(1–4)
6–15	77	0/60	0%		5	(4–8)		2	(1–3)
16–30	273	6/194	3.1%		5	(4–7)		2	(1–3)
31–49	477	6/336	1.8%		6	(4–7)		2	(1–3)
≥50	513	28/385	7.3%		6	(4–8)		3	(1–4)
Pregnancya	15	0/5	0%	P = 1.000	7	(5.5–10)	P = .2010	2	(1–4)	P = .8564
Weight categories, kg
< 50	109	2/91	2.2%	P = 1.000	6	(4–7.5)	0.1323	2	(1–4)	P = .0089
50–100	765	19/590	3.2%		6	(4–8)		2	(1–4)
> 100	40	1/33	3.0%		7	(5–9)		3	(3–5)
HIV+ b	67	1/41	1.8%	P = .724	7	(5–10)	P = .0102	2	(1–3)	P = .7096
Parasitemia
< 4	511	12/394	3.0%	P < .000	6	(4–8)	P = .0028	2	(1–3)	P = .0001
4–10	466	7/350	2.0%		5	(4–7)		2	(1–3)
> 10	281	19/206	9.2%		7	(4.5–9.5)		3	(2–4)

P values < .05 are in bold.

Abbreviations: HIV, human immunodeficiency virus; ICU, intensive care unit; Q, quartile.

^aComparisons were made versus patients without notified pregnancy.

^bComparisons were made versus patient without notified HIV-positive status.

Safety

Information on AEs (absence or presence) was available for 568 artesunate-treated patients. A total of 360 AEs were reported for 241 patients (42.4%). Seventy-six patients with declared AEs had received another antimalarial treatment (including IV quinine in 45 patients) before artesunate. Death was reported as an AE in 9 patients (Figure 2 and Table S5).

Figure 2.

Adverse events declared in patients treated with artesunate. Abbreviations: AI, autoimmune; DIVC, disseminated intravascular coagulation; MOF, multiorgan failure; NOS, not otherwise specified. *See Table S3 for further details.

Hematological AEs were reported in 156 cases (43.3%). Anemia and/or hemolysis were reported in 23.9% (136/568) of patients with available AE data and were significantly more frequent in initial parasitemia >10% and patients of European origin when compared with patients of African origin (Table 4). No deaths or sequelae were reported related to hematological AE.

Table 4.

Main Adverse Events in Different Subgroups

	No. Subjects in Each Group	No. Subjects With Available Data on AE	Anemia and/or Hemolysis			Cardiovascular AEs			Renal Failure
			N	Estimated Frequencies	Statistical Significance	N	Estimated Frequencies	Statistical Significance	N	Estimated Frequencies	Statistical Significance
Total	1391	568	136	23.9%		24	4.2%		15	2.6%
Geographic origin
Africa	829	333	58	17.4%	P < .000	6	1.8%	P = .002	6	1.8%	P = .018
Europe	362	162	60	37.0%	P < .000	12	7.4%	P = .011	10	6.2%	P = .030
Age, y
<2	23	8	1	12.5%	P = .680	0	0.0%	P = .575	0	0.0%	P = .946
2–5	28	14	1	7.1%		1	7.1%		0	0.0%
6–15	77	39	8	20.5%		2	5.1%		1	2.6%
16–30	273	111	24	21.6%		3	2.7%		4	3.6%
31–49	477	200	51	25.5%		5	2.5%		5	2.5%
≥50	513	196	49	25.0%		9	4.6%		8	4.1%
Pregnancya	15	8	3	37.5%	P = .399	0	0.0%	P = 1.000	0	0.0%	P = 1.000
Weight categories, kg
< 50	109	54	12	22.2%	P = .137	3	5.6%	P = .520	2	3.7%	P = 1.000
50–100	765	365	91	24.9%		13	3.6%		13	3.6%
> 100	40	19	1	5.3%		0	0.0%		0	0.0%
HIV+ b	67	22	4	18.2%	P = .798	0	0.0%	P = 1.000	0	0.0%	P = 1.000
Parasitemia
< 4	511	199	28	14.1%	P < .000	9	4.5%	P = .807	4	2.0%	P = .021
4–10	466	191	45	23.6%		6	3.1%		2	1.0%
> 10	281	129	51	39.5%		5	3.9%		8	6.2%

P values < .05 are in boldface.

Abbreviations: AEs, adverse events; HIV, human immunodeficiency virus.

^aComparisons were made versus patients without notified pregnancy.

^bComparisons were made versus patient without notified HIV-positive status.

^cAccording to univariate analysis.

Because PADH can be mild and go unnoticed, its incidence is probably underestimated. This remains true even when AEs are recorded prospectively, as in this study. We defined a PADH incidence subgroup to precisely estimate the incidence of this AE in travelers treated with artesunate. The PADH incidence subgroup was similar to the entire cohort on most population characteristics, clinical presentation, treatment characteristics, and main outcomes. Exceptions were place of residence, sex ratio, mortality, and initial parasitemia (Table S1). When systematically assessed, the incidence of PADH was much higher (42.8% of patients, n = 42). Furthermore, its higher frequency in patients of European (57.9%) versus African (29.2%) origin was confirmed (P = .014) (Figure S3).

In pregnant women, 1 first trimester hemorrhagic miscarriage was reported. No other pregnancy-related complications were noted apart from benign contractions without cervical dilation. Other AEs included digestive (n = 56, including 19 nausea and/or vomiting cases and 22 elevated liver enzyme cases), neurological (n = 40), cardiocirculatory (n = 24, including 6 QT prolongation cases, Table S6), renal (n = 18, including 15 renal failure cases), metabolic (n = 16 including 5 hypoglycemia cases), cutaneous (n = 14), and splenic (n = 2) manifestations. Four cases of multiorgan failure were declared as AEs (Figure 2 and Table S5). Renal failure was more frequently reported when initial parasitemia was >10%. Renal and cardiac events were more frequently reported in patients of European origin. The incidences of hypoglycemia and liver enzyme elevation were similar in the general and subgroup populations (Table S7). No increase in AE incidence was noted in children, or over-/underweight, HIV-positive, or pregnant patients (Table 4).

DISCUSSION

Randomized trials in endemic areas have demonstrated the superiority of artesunate over quinine [1, 2]. Artesunate induces rapid parasite clearance [12], and its activity on young blood stages reduces the sequestration of parasitized red blood cells in small vessels, a process that triggers many manifestations of severe malaria. These are strong arguments to adopt IV artesunate as the first-line option in severe imported malaria, as recommended by WHO in 2010 and 2015 [13, 14]. Yet, its deployment in nonendemic countries has been slow. The absence of randomized trials comparing artesunate with a reference drug in this nonendemic context and doubts regarding safety of non-GMP formulations have favored the status quo (ie, maintaining IV quinine or quinidine as the first-line treatment). Finally, the delayed availability of artesunate has led many clinicians to keep on using immediately available quinine, or quinidine, or even oral drugs instead of switching to artesunate [4, 5].

In this context, observational studies are the only available option to assess the clinical benefit and safety of artesunate in travelers. Our epidemiological and clinical report on the implementation and performance of pre-GMP artesunate in severe malaria is the largest so far performed in a non-malaria–endemic country.

The nationwide deployment of IV artesunate in France was swift. An initial reluctance from some prescribing physicians did not affect the pace at which artesunate was adopted as the first-line treatment for severe malaria in France. Compared with references, few anti-infectives have shown benefits on all-cause mortality over the past several decades, and this was an important argument for artesunate adoption despite the absence of randomized trials in the specific context of imported malaria. Indeed, because of ethical and logistical constraints, such trials are impossible. That constraint had been perpended by national agencies when debating IV artesunate deployment and was furthermore well grasped by the medical community.

The clinical benefit of IV artesunate met or exceeded that of conventional antimalarials used in severe malaria. Patient age, weight, HIV status, or pregnancy did not alter that benefit. We observed a mortality rate of 4.1%, close to the 3.9% and 5% rates reported with IV quinine in travelers [15, 16]. When compared with quinine in travelers [15, 17–20], IV artesunate did not appear to reduce mortality, but the difference in favor of artesunate fell short of statistical significance. Mortality rates for patients treated with quinine is relatively low (5%) in most nonendemic countries, in part because of availability and quality of intensive care [16]. Demonstrating a statistically significant superiority for artesunate in terms of mortality in this context would require the inclusion of tens of thousands of patients in a randomized trial. Reduced ICU LOS in artesunate compared with quinine-treated patients was demonstrated in the context of importation [15, 19]. The median ICU LOS in our study (2 [1–4]) was consistent with previous data [21].

No cases of confirmed parasite resistance to artemisinin were reported and resistance-associated k13 mutations were not found in the isolates tested. This is likely because very few of the patients in our cohort returned from areas where parasite resistance to artemisinin is prevalent.

The safety of artesunate in travelers was good in observational studies, despite a high incidence of delayed hemolytic episodes (PADH) [21]. Here, we confirmed those observations. Reported AEs were estimated as potentially drug related by physicians in charge, but because of the observational design of our study, causality of artesunate in their occurrence cannot be definitively established. Anemia and/or hemolysis were by far the most frequently-reported AEs (37.6% of total). Among those, typical PADH episodes were reported in 32 patients (5.6% of patients with reported AEs). However, PADH is underestimated because it generally occurs after discharge and thus may go unnoticed or unreported. We confirmed that in our specific assessment of incidence in the PADH incidence subgroup, where a thorough workup was performed. There, typical PADH occurred in 42.8% of patients, confirming the high frequency of these episodes. As stated by WHO in 2013, PADH does not undermine artesunate’s superiority over quinine [22]. However, the observation of severe cases [21, 23], although relatively rare, warrants a systematic assessment of the risk of PADH in IV artesunate. The development of a predictive dipstick test performed 2–4 days after treatment initiation has simplified this assessment [10]. We confirm here that PADH is more frequent in hyperparasitemic patients and show that its incidence is twice as high in patients of European origin. This observation conforms with what is known about the main PADH mechanism (synchronous hemolysis of pitted cells as a trigger of the phenomenon) [9] and with the observation that artemisinin-induced pitting rates are lower in immune versus nonimmune patients [24].

Neurological manifestations, elevated liver enzymes, and nausea and/or vomiting were also frequently reported, as mentioned by the manufacturer (SPC Guillin) and previous reports [21]. Although considered uncommon [25], we observed cardiovascular manifestations in 24 patients, including 20 episodes of conduction disorders and/or arrhythmia. The causal role of artesunate cannot be definitely established in those episodes because severe malaria itself and preexisting conditions or concomitant medication (including IV quinine) can all be associated with cardiovascular events. Two cases of sinusal bradycardia and 2 episodes of QT prolongation occurred in the absence of shock in patients with no cardiovascular history and who did not receive quinine. The incidence of cardiac AEs was lower than those previously reported with IV quinine or quinidine [25]. Nevertheless, the possibility of rare artemisinin-mediated cardiac effects should not be ruled out at this stage. Other artemisinin derivatives (artemether, arteether) have been associated with QT prolongation in animal studies [26], but to date, no significant effect has been shown in humans [25, 27]. Electrocardiography should be performed before and during treatment, particularly in patients with preexisting cardiovascular disease, and proactive reporting of cardiac AE should be implemented.

In our study, information was collected by a task force of public sector entities with limited, predominantly academic, specific funding. Thus, our proportion of missing data may be higher than that of conventional prospective trials and a degree of minor AEs underreporting is likely. However, the density of the MNRC network, the involvement of the national pharmacovigilance system and the cross-referencing of information sources make it unlikely that a major event went unnoticed.

In conclusion, artesunate can be rapidly implemented on a nationwide scale. Distribution was streamlined by prepositioning artesunate in hospital pharmacies. The simpler use of artesunate compared with quinine, the lower incidence of AE, including hypoglycemia (<1% in our cohort), and the high cure rates in clinical trials in endemic areas and observational cohorts in travelers [8, 17–20, 28, 29] supported its swift, countrywide adoption. We confirmed its robust clinical benefit in a cohort of 1391 malaria patients and in several clinically important subgroups. Taken together, our results advocate for the use of IV artesunate as the first-line treatment for severe imported malaria, as per WHO recommendations. Hematological events—for which a simple dipstick-based predictive process exists—were by far the most frequent AEs, but not associated with fatal outcomes or sequelae. Clinicians and patients should be aware of the high frequency of PADH following treatment, particularly in patients of European origin. Similar implementation experiences are ongoing and could be envisioned in other countries affected by severe imported malaria.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. C. R., S. J., and P. B. designed and performed research, contributed vital analytical tools, performed statistical analyses, analyzed data, and wrote the paper. P. A. N., E. K., S. L., B. H., and B. L. V. performed research, contributed to data collection and analysis, and wrote the paper. M. T. and R. P. designed research, analyzed data, and wrote the paper. A. T., O. M., C. C., H. D., and D. C. performed research and contributed to data collection. F. G., J. Y. S., F. B., S. H., N. A., A. A., O. B., M. D., and E. C. performed research and wrote the paper.

Acknowledgments. The authors thank all patients, staff, clinicians, and biologists at all of the French Malaria National Reference Center corresponding sites and thank Dahlia Khnafo, Camelia Savulescu, and Lore Merdrignac (Epiconcept, Paris, France) for their technical assistance.

Financial support. This work was supported by INSERM and MNRC during the entire study period. Authors all belong to one or both entities and thus both were involved in study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the paper for publication. WRAIR and Guilin pharmaceutical provided financial support and financed C. R. from September 2013 to April 2014 and A. T. and C. C. from March 2017 to April 2019, respectively, but did not play any role at any time in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication. Bill & Melinda Gates Foundation provided financial support (#OPP1123683, C15/0872a01) but did not play any role at any time in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication. C. R. was supported by a fellowship from the Laboratory of Excellence GR-Ex. The labex GR-Ex, Reference ANR-11-LABX-0051 is funded by the program “Investissements d’Avenir” of the French National Research Agency, Reference ANR-11-IDEX-0005-02.) B. H. was supported by a fellowship from Région Ile de France (DIM Malinf).

Potential conflicts of interest. C. R. received financial support from WRAIR from September 2013 to April 2014. A. T. received financial support from Guilin Pharmaceutics from February 2017 to April 2019. C. C. received financial support from Guilin Pharmaceutics from March 2017 to September 2018. M. D., O. B., and S. J. provided expertise for/received personal fees from AlfaSigma France from 2013 to 2021. O. B. participated in a study on Eurartesim conducted by AlfaSigma. A. N., S. J., and P. B. received financial support from Guilin Laboratories; P. B. provided expertise for Fast-Track Drugs & Biologics LLC and Sigma-Tau Pharmaceuticals from 2013 to 2016, and provided expertise to Sanofi Aventis Research & Development from 2013 to 2015. P. A. N. reports grants from Guilin Pharmaceutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Author notes

Senior authors S. J. and P. B. contributed equally to this work.

List of FRench Artesunate Working Group is displayed in the Supplementary materials.