Artemisinins and Malaria: Resistance Already?
Artemisinins and Malaria: Resistance Already?
Abstract & Commentary
By Brian Blackburn, MD, Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Blackburn reports no financial relationships relevant to this field of study.
Source: Dondorp AM, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455-467.
Synopsis: Artemisinins are among the newest and most effective antimalarials available. This open-label trial conducted in Cambodia and Thailand suggests that Plasmodium falciparum exhibits decreased in vivo susceptibility to artesunate in western Cambodia, based on slower parasite clearance times and possible increased recrudescence in patients treated there compared to northwestern Thailand. Urgent containment measures may be necessary.
Artemisinins are the most rapidly acting antimalarials available, have few serious side effects, and have been used extensively with few reports of resistance until recently.1-6 They are now recommended by the World Health Organization (WHO) as a part of first-line treatment regimen for uncomplicated malaria in all malaria-endemic areas and have been an emerging cornerstone of malaria control programs globally over the past decade.1 To stave off the development of artemisinin resistance, it is recommended that these drugs be used only as part of combination regimens, so-called artemisinin-based combination therapy (ACT).1
Southeast Asia has been the initial region in which resistance has developed to many of the currently available antimalarials.7 Several recent studies have now suggested the possibility of the development of artemisinin resistance there.2-6 Dondorp et al, therefore, undertook a clinical trial in two sites, comparing artesunate (an oral artemisinin) to artesunate-mefloquine combination therapy at each site. The studies were performed in Pailin, western Cambodia, a location where artemisinins have been used for more than 30 years, and in Wang Pha, northwestern Thailand, where ACTs (artesunate plus mefloquine) have been used since 1994.
Although the studies were designed similarly in both sites, some logistical differences existed between them. For example, in Cambodia, persons with uncomplicated falciparum malaria over the age of five years were enrolled if they had a parasite density of > 10,000 parasites/mm3, whereas, in Thailand, only persons over the age of 15 years were enrolled. Exclusion criteria included pregnancy, severe disease, infection with a Plasmodium species other than falciparum, and antimalarial use within 48 hours of enrollment.
Forty patients were randomized in each location to receive (orally), in an open-label manner, either artesunate monotherapy (2 mg/kg daily for seven days) or artesunate-mefloquine combination therapy (artesunate 4 mg/kg daily for three days, followed by mefloquine 15 mg/kg on day 3 and 10 mg/kg on day 10); all patients were hospitalized for seven days.
In Cambodia, median parasite clearance time for both treatment groups combined was significantly longer (84 hours) than for the combined groups in Thailand (48 hours; p < 0.001). Although patients at the beginning of treatment had significantly higher geometric mean parasite densities in Cambodia (about 65,000/mm3) than in Thailand (about 30,000/mm3; p < 0.001), when the analysis was stratified according to the parasite density, the differences remained significant (p = 0.008) between the sites. Analysis also showed that site remained an independent predictor of response when controlled for the differential inclusion (Cambodia) vs. exclusion (Thailand) of children in the study.
Parasites were cleared significantly faster by patients in the artesunate-mefloquine arm (48 hours) than in the artesunate-monotherapy arm (54 hours; p = 0.02) in the Thailand site, but the difference was not significant in the Cambodia site. Recrudescence tended to occur more frequently in the artesunate arm (30%) than in the artesunate-mefloquine arm (5%; p = 0.09) in Cambodia, with little difference between treatment groups in Thailand. Fever clearance times did not differ between treatment groups or sites.
Plasma concentrations of artesunate and dihydroartemisinin (the active metabolite of artemisinin) were measured in study participants, and they did not differ significantly between the groups. In vitro resistance testing also was performed, and showed that P. falciparum isolates from Cambodia did exhibit significantly higher MICs to dihydroartemisinin, but there was not a significant correlation between MICs and parasite clearance times in either Cambodia or Thailand.
Commentary
This study demonstrated that parasite clearance times were significantly longer in patients with uncomplicated falciparum malaria who were treated with artesunate in western Cambodia, compared to those treated in northwestern Thailand. In addition, recrudescence appeared to be more common in patients treated with artesunate monotherapy compared to those treated with artesunate-mefloquine combination therapy in the Cambodia study site, and patients treated with artesunate monotherapy cleared parasites more slowly than patients treated with combination therapy in Thailand. These differences appear to herald the development of resistance to artesunate in western Cambodia among P. falciparum parasites and were not explained by differences in baseline parasitemia levels, patient characteristics, or plasma drug concentrations.
The development of resistance to artesunate could have disastrous consequences for malaria control and elimination efforts globally. ACTs are becoming a cornerstone of most malaria control programs, as artemisinins are well tolerated, effective, and act rapidly.1 Resistance to many earlier antimalarials also first appeared in Southeast Asia, including to chloroquine, pyrimethamine-sulfadoxine (Fansidar), and mefloquine.7 It appears that this phenomenon may now, unfortunately, be extending to artesunate. Precisely to prevent this from happening, a critical aspect of recent malaria treatment policies has been the requirement that artemisinins be used only as a part of combination therapy.1 Despite this, the use of artemisinin monotherapy has been rife in western Cambodia for decades,8 and is most likely the explanation for the findings of this study.
Although previous work has suggested the possibility of increasing resistance to artesunate in Cambodia,2-4 the current study defines the presence of this unfortunate phenomenon best. It is of particular relevance, given that it demonstrates this in vivo, and reflected by the clinically significant outcomes reported. Other recent work seems to corroborate this finding in this part of the world in vitro. Another group has now reported that higher MICs exist among P. falciparum parasites from Cambodia and eastern Thailand compared to western Thailand and Bangladesh.6
Limitations of the study include the open-label design of the trial and the difficulty in comparing the artesunate monotherapy arms to the artesunate-mefloquine arms, given the different artesunate doses used in each treatment group. In addition, comparison of the Cambodian and Thai study sites is made difficult by the inclusion of children 5-15 years old in one site (Cambodia) but not the other; attempts were made to control for this in analysis, but it would have been preferable to have had the same inclusion and exclusion criteria in each site.
Despite these limitations, the findings in this study are of great concern. While further study regarding artemisinin resistance is ongoing in southeast Asia, urgent control measures are needed to address this potentially disastrous development in malaria control.
References
- Nosten F, et al. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg. 2007;77:181-192.
- Noedl H, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359:2619-2620.
- Denis MB, et al. Efficacy of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia. Trop Med Int Health. 2006;11:1800-1807.
- Denis MB, et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health. 2006;11:1360-1366.
- Carrara VI, et al. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One. 2009;4:e4551.
- Noedl H, et al. Artemisinin-resistant malaria in Asia. N Engl J Med. 2009;361:540-1541.
- Baird JK. Effectiveness of antimalarial drugs. N Engl J Med. 2005;352:1565-1577.
- World Health Organization. Global malaria control and elimination: report of a meeting on containment of artemisinin tolerance: 19 January 2008, Geneva, Switzerland. Available at http://apps.who.int/malaria Accessed 3 Sept 2009.
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