Artemisinin Resistance: Why Now?
Abstract & Commentary
By. Lin H. Chen MD
Dr. Chen is Assistant Clinical Professor, Harvard Medical School, Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA.
Dr. Chen reports no financial relationships relevant to this field of study.
Synopsis: Resistance of malaria parasites to artemisinin has been documented both in vivo and in vitro in western Cambodia, probably because of artemisinin monotherapy. Artemisinin-based combination therapies may delay the development of resistance and should be used instead of monotherapy.
Source: Dondorp A, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009;361:455-67.
Dondorp and colleagues conducted two open-label, randomized trials that compared malaria treatment efficacies in western Cambodia (Pailin) and northwestern Thailand (Wang Pha). The treatments used were: 1) oral artesunate 2 mg per kg per day for 7 days; and 2) artesunate 4 mg per kg per day for 3 days followed by mefloquine 25 mg per kg total, divided into two doses. The study enrolled 40 patients in each site. The parasite clearance times were 84 hours in Pailin and 48 hours in Wan Pha. Because patients in Pailin included children, whereas Wang Pha only included patients aged 16 and older, the investigators also analyzed the subset of patients who were at least 16 years of age from both sites and still found a significant difference in parasite clearance times. Furthermore, there was no significant difference in parasite clearance times for patients younger than 16 years of age compared to patients 16 years of age or older. Fever clearance times showed no significant difference between the sites.
Early treatment failure (fever and parasitemia for more than 72 hours after initiation of therapy) occurred in 3/40 (8%) patients in Pailin vs. none in Wang Pha. Late parasitologic failure (parasites confirmed by polymerase-chain-reaction more than 7 days after therapy initiation) occurred in 6/20 (30%) patients treated with artesunate monotherapy in Pailin and 2/20 (10%) in Wang Pha. In patients treated with artesunate-mefloquine combination, late parasitologic failure occurred in 1/20 (5%) patients from each site.
The investigators evaluated artesunate pharmacokinetics, P. falciparum susceptibility, and molecular markers of resistance (mutations of the genes encoding a multidrug resistance protein PfMDR1 or sarco-endoplasmic reticulum calcium ATPase6 PfSERCA). They found that the differences in response could not be explained by these molecular markers or by age, drug pharmacokinetics, or in vitro susceptibility tests.
Commentary
Artemisinins (quinhaosu in Chinese) are compounds derived from the plant Artemisia annua (sweet wormwood), long used as an herbal remedy in China. Artemisinins have short half-lives, and their rapid actions represent an ideal property for malaria treatment, but not for malaria chemoprophylaxis. Artemisinin-based combination therapies (ACTs) were formulated to minimize the development of drug resistance that occurs with artemisinin monotherapy and have shown excellent efficacy in treating malaria, with rapid parasite clearance and fever resolution.1,2 The World Health Organization (WHO) has recommended ACTs for several years as first-line treatment of uncomplicated falciparum malaria in endemic areas.3 These ACTs include artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, and artesunate-sulfadoxine-pyrimethamine. In the United States, artemether-lumefantrine recently received FDA approval for the treatment of uncomplicated malaria, a welcome addition to the limited regimens available.4
Of note, some herbal supplements contain artemisinin, and a case of hepatitis in the United States recently was reported in association with such a supplement.5 The patient ingested an herbal supplement containing an equivalent of 7.5 mg/kg/day of artemisinin over 10 days for a "parasitic disease" (unnamed protozoan in the stool), clearly a higher dose than standard treatment for malaria.5 Because regulation of dietary supplements differs from that of pharmaceutical products, the case raises concern over poor quality control and improper usage of artemisinin-containing supplements.
Many of the components of ACTs (artesunate, amodiaquine, mefloquine, and sulfadoxine-pyrimethamine) have been used as monotherapy in the past in endemic countries, including Cambodia. Not surprisingly, artimisinin-resistant P. falciparum has emerged in southeast Asia.6
The significantly slower parasite clearance in western Cambodia and reduced P. falciparum parasite susceptibility to artesunate documented in the Dondorp study are alarming, especially since resistance to chloroquine, sulfadoxine-pyrimethamine, and mefloquine originated in this region and subsequently spread globally. Concurrently published in the New England Journal of Medicine, a study by Noedl et al also showed artemisinin resistance using histidine-rich protein 2 malaria in vitro drug susceptibility assay on parasites from 247 malaria patients from Bangladesh, western and eastern Thailand, and Cambodia.7 Parasite sensitivity to artemisinin remained high in Bangladesh, where ACTs have not been used extensively until recently, compared to decreased parasite sensitivity in eastern Thailand and Cambodia.7
Southeast Asia has struggled with counterfeit drugs, and some treatment failures in malaria patients have been attributed to poor-quality artemisinin drugs.8,9 With further evidence of artemisinin resistance shown by Dondorp et al, malaria control programs clearly need to eliminate the use of monotherapy with artemisinin derivatives.10
For now, ACTs remain reasonable treatment options for uncomplicated malaria in travelers going to malaria-endemic areas (for example, used as standby emergency treatment), but clinicians should follow further development of parasite resistance, especially in southeast Asia. Physicians treating travelers who acquired malaria in western Cambodia should consider other options, given the possibility of artemisinin resistance. Travel medicine specialists should be familiar with WHO malaria treatment guidelines regarding ACTs and assess the appropriateness of overseas diagnosis and treatment for malaria. Travelers who are treated in malaria-endemic countries with artemisinin monotherapy likely had suboptimal evaluation and treatment.
References:
- Nosten F, White NJ. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg 2007;77(6 Suppl):181-92.
- Sinclair Det al. Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev 2009;(3):CD007483.
- World Health Organization. Guidelines for the treatment of malaria. World Health Organization, Geneva, 2006.
- CDC. Guidelines for treatment of malaria in the United States, updated May 18, 2009. Available at: http://cdc.gov/malaria/pdf/treatmenttable.pdf. Downloaded August 20, 2009.
- CDC. Hepatitis temporally associated with an herbal supplement containing artemisinin — Washington, 2008. MMWR 2009;58(31):854-6.
- Noedl H, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008;359(24):2619-20.
- Noedl H, et al. Artemisinin-resistant malaria in Asia. N Engl J Med 2009;361:540-1.
- Sengaloundeth S, et al. A stratified random survey of the proportion of poor quality oral artesunate sold at medicine outlets in the Lao PDR — implications for therapeutic failure and drug resistance. Malar J 2009;8(1):172.
- Keoluangkhot V, et al. Impaired clinical response in a patient with uncomplicated falciparum malaria who received poor-quality and underdosed intramuscular artemether. Am J Trop Med Hyg 2008;78:552-5.
- Campbell CC. Malaria control — addressing challenges to ambitious goals. N Engl J Med 2009;361:522-3.
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