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Last Doubts Resolved: Artesunate Is Superior to Quinine for the Treatment of Severe Falciparum Malaria
Abstract & Commentary
By Brian G. Blackburn, MD
Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine
Dr. Blackburn reports no financial relationship to this field of study; this article originally appeared in the May issue of Infectious Disease Alert.
Synopsis: African children with severe falciparum malaria were randomized to receive either intravenous artesunate or intravenous quinine. Those who received artesunate died significantly less frequently than those who received quinine. These data, taken together with previous trials, strongly suggest that intravenous artesunate should replace intravenous quinine as the treatment of choice for severe falciparum malaria worldwide.
Source: Dondorp AM, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial. Lancet 2010;376:1647-1657.
Despite the recent gains achieved by multidisciplinary control programs, malaria still kills nearly 1 million people and causes almost 300 million symptomatic illnesses globally per year, with most of this burden borne by sub-Saharan Africa. Severe malaria, usually caused by Plasmodium falciparum, is defined in part by respiratory distress, renal failure, altered mental status/seizures, metabolic acidosis/hypoglycemia, and hyperparasitemia. The mortality rate of severe malaria, even with appropriate treatment, is as high as 15%-20% in some series, and the disease is nearly universally fatal if untreated.
The standard treatment worldwide for severe malaria has been intravenous quinine for many years (given the unavailability of intravenous quinine in the United States, quinidine is used instead, a drug with similar efficacy but more toxicity). Although effective, the mortality rate of severe malaria treated with quinine remains high, and quinine/quinidine are toxic, sometimes causing infusion-related hypotension, cinchonism, blindness, deafness, and hypoglycemia; quinidine adds to these adverse effects an even higher risk of arrhythmias than seen with quinine.
Artemisinins, the most rapidly acting antimalarials available, are potent and well-tolerated, providing a theoretical advantage for this drug class over the quinine derivatives. A major clinical trial performed recently in Southeast Asia showed that the mortality rate in patients with severe falciparum malaria was 22% in patients treated with intravenous quinine, and 15% in those treated with intravenous artesunate.1 Because few children were included in this trial, the generalizability of these results to children with severe malaria was questioned.1 In addition, the applicability of these results to malaria acquired in Africa also was unclear. The authors therefore undertook a clinical trial comparing the intravenous formulations of quinine and artesunate in children with severe falciparum malaria in Africa.
More than 5,400 children (age < 15 years) with severe falciparum malaria from nine different sub-Saharan African countries were enrolled in the trial. The median age of enrolled patients was about 3 years. The trial was an open-label, randomized comparison of the standard dosing regimens of intravenous artesunate and intravenous quinine. At trial entry, 30% of patients had severe anemia, about one-third had coma, one-third had seizures, and more than 40% had severe acidosis, with no difference between the study groups. About 6% of those tested (125 of 2,095) were HIV-positive; the case-fatality rate was high (28%) in HIV-infected patients, with no significant mortality difference between treatment groups. The primary outcome measure of the trial was in-hospital mortality.
Overall, 8.5% of patients who received artesunate died, compared with 10.9% of patients who received quinine (P = 0.0022), a relative mortality reduction of 22.5%. Significantly fewer patients in the artesunate-treated group developed worsening neurological status, coma, or seizures than in the quinine-treated group after trial entry, although the frequency of long-term neurological sequelae did not differ between groups. No serious treatment-related adverse effects were seen, and significantly fewer patients in the artesunate-treated group developed hypoglycemia than in the quinine-treated group after enrollment. The authors also performed a meta-analysis of all severe malaria trials that have compared survival between parenteral artesunate and parenteral quinine. The overall odds ratio for death was 0.69 (P < 0.00001) in favor of artesunate, with no significant heterogeneity between results generated in Africa and Asia.
This large, well-designed trial showed that artesunate significantly reduces mortality among African children with severe falciparum malaria. Despite the findings of the earlier SEAQUAMAT trial in Southeast Asia, which demonstrated a 35% mortality reduction in patients treated with IV artesunate compared to those treated with IV quinine, some questions about the applicability of these results to children or to patients with malaria acquired in Africa were raised.1 This was in part because of perceived differences in the epidemiology, pathology, and susceptibility of malaria parasites to quinine in Africa, and differences in the natural history of the disease in children as compared to adults. These concerns were not substantiated, based on both the current AQUAMAT trial, and the meta-analysis the authors performed of trials that have compared artesunate to quinine for severe malaria.
It now appears that for all regions and patient populations, artesunate should be the drug of choice for treating severe malaria, given that it is more rapidly acting, better tolerated, and more effective than quinine (and "by extension," quinidine). Unfortunately, access to the drug remains problematic, and currently no Good Manufacturing Process (GMP) formulation of artesunate is commercially available. Because it is not FDA-approved in the United States, artesunate is only available from the Centers for Disease Control and Prevention (CDC) through an investigational new drug (IND) protocol for severe malaria in patients who meet certain criteria.2 Although the drug is available on an emergency basis through CDC, delay to administration is inevitable with this mechanism, and rapid therapy clearly matters for severe malaria. Given that there is little doubt that this is the superior drug for a disease with a high mortality rate, artesunate should be approved for widespread use in the United States immediately, and wider supplies of this vital drug ensured worldwide.