From the *Medical Research Council Unit, Fajara, The Gambia; and †Institute of Tropical Medicine, Antwerp, Belgium.
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: Umberto D’Alessandro, PhD, Institute of Tropical Medicine, Antwerp, Belgium. E-mail: firstname.lastname@example.org.
Antimalarial drugs have played a central role in the control of malaria, both infection and clinical disease. Artemisinin and its derivatives are undoubtedly the best available treatment for Plasmodium falciparum malaria. Since their introduction and scale up, malaria morbidity and mortality have significantly decreased in several endemic countries, to such an extent that the terms malaria “elimination” and “eradication” are back onto the global agenda.1 Nevertheless, the burden of malaria remains unacceptably high, particularly in sub-Saharan Africa where the greatest effect is in children <5 years of age. This review examines current approaches and considers challenges in the use of artemisinin-based treatments in an era of changing malaria epidemiology.
ANTIMALARIAL TREATMENT WITH ARTESUNATE DERIVATIVES
Artemisinin derivatives are at the core of current treatment against malaria because of their high potency, rapid clinical and parasitological response, efficiency against various parasite stages and low toxicity. They include a range of lipophilic—artemether and arteether available for intramuscular use although artemether capsules to be taken orally exist—and water-soluble compounds, for example, artesunate (AS) that can be given orally, by injection and as suppositories. After administration, all are converted to the active ingredient, dihydroartemisinin (DHA), which is also available as an oral preparation. Artemisinin derivatives have a very short half-life and are rapidly cleared. They were initially introduced as monotherapy for the treatment of uncomplicated malaria. However, because of the rapid relief of symptoms occurring soon after the start of the treatment, patients were less likely to complete the full treatment course. For this reason and also for preventing the emergence of drug resistance, artemisinin derivatives have been combined to another antimalarial drug, the artemisinin-based combination treatments (ACT), most of them currently available as co-formulations. The World Health Organization currently recommends 5 ACTs for the treatment of uncomplicated malaria, namely artemether-lumefantrine, AS-amodiaquine (AQ), AS-MQ, DHA-PPQ and AS with SP, the latter not available as a fixed dose combination (Table 1).2 Comparative studies on efficacy of these treatments showed only marginal differences, probably because of the characteristics of the partner drug. In 2011, 79 endemic countries were using ACTs as first-line treatment with 278 million treatment courses delivered globally.3
Treatment of young children with uncomplicated malaria may be difficult with tablets as dosage is determined according to body weight. Tablets have to be cut/crushed and mixed with food to improve their often bitter taste and hence tolerability. Crushing the tablets is an inefficient procedure, which may result in loss of drug and reduced dose ingested, increasing the risk of treatment failure. Considering these problems together with the disproportionate morbidity and mortality in children, there was sufficient justification for the development of pediatric formulations. Among the recommended ACTs, artemether-lumefantrine and AS-pyronaridine are available as dispersible tablets, while AS-AQ is available as water-soluble tablets for oral administration. These pediatric formulations have shown equivalent safety and efficacy and are better tolerated than tablets.5
AS derivatives are prescribed on a mg/kg dosage based on findings which suggest that weight is an important predictor for the pharmacokinetics of the drug in children.6 Studies in infants and very young children are, however, needed because the most marked differences in drug metabolism are likely to be observed in this group. There is also the need to determine their cost-effectiveness in support for their large-scale deployment as they are presently not readily available.
The management of severe malaria has also significantly evolved since the introduction of the artemisinin derivatives. For many decades, quinine has been the main drug for the treatment of severe falciparum malaria, although important challenges with its usage include a complex dosing regimen, the prolonged treatment course and its unfavorable adverse event profile. AS and artemether are both effective in severe malaria, although the latter did not show a significant advantage over quinine in reducing mortality. A recent trial carried out in African children with severe malaria demonstrated that compared with quinine, AS reduced mortality by 22.5%7 and is now the recommended first-line treatment in both children and adults (Table 1). AS suppositories can be used as prereferral treatment in settings such as peripheral health posts where complete parenteral treatment is not possible. However, the biggest challenge faced in resource-limited settings has been the nonavailability of these preparations in health care facilities. For example, in Uganda, rectal artemisinins were available in only 5% of the health care facilities despite the fact that this is the recommended prereferral drug.8
There is currently no intravenous AS product manufactured under good manufacturing practices and intravenous quinine is not registered in most industrialized countries. In Europe, the European Medicines Agency designates ACTs as “orphan drugs,” therefore creating incentives for pharmaceutical industry willing to invest in their development. Presently, artemether-lumefantrine (Riamet) and DHA-PPQ (Euratesim) are available for the European market.
ARTEMISININ USE AND DECLINING MALARIA TRANSMISSION
With declining transmission as observed in several endemic countries, antimalarial immunity in the general population will also decrease, with less antimalarial antibodies transferred from mothers to newborns, with increased risk of clinical malaria and the need of treatment. However, there is little information on the safety, pharmacokinetics, efficacy and adequate dosage in young infants, to the extent that many of them carry label restrictions for this age group. A few trials are currently underway in response to some of these issues.9
Artemisinin Resistance and Its Containment
Control efforts are at a crossroad characterized by declining transmission with the prospects of elimination and an increasing threat of resistance to ACTs. Artemisinin resistance10 is defined by both clinical and parasitological outcomes and classified as either suspected (delayed parasite clearance with detectable parasites on completion of treatment) or confirmed (persistence of parasites for 7 days or the presence of parasites at day 3 and recrudescence within 28/42 days).10 The recent emergence of P. falciparum resistance to artemisinins along the Thai-Cambodian border and its potential spread to other endemic regions is a major threat to malaria control efforts. This is even more dramatic when considering that no other antimalarial medicines offering the same level of efficacy and tolerability as ACTs are available. A Global Plan for Artemisinin Resistance Containment has been formulated by the World Health Organization in consultation with different partners and comprises 5 main activities, including stopping the spread of resistant parasites by reducing or interrupting transmission and improved monitoring and surveillance. Adding primaquine, a gametocytocidal drug, to ACT could help reduce the spread of resistant parasites and in the long run, interrupt transmission. However, early studies have been inconclusive,11,12 and the risk of hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency prevents its large-scale deployment. The benefits of this intervention would depend on the contribution of asymptomatic carriers to transmission, coverage rate and timing of administration of the combination.13 Information on the usability of primaquine in children is scarce, although a few trials are ongoing and may provide an answer to some of these questions.
Artemisinin derivatives have significantly changed the management of children with malaria. Their safety and efficacy are excellent and this has resulted in important reduction in malaria-related morbidity and mortality. However, the threat of resistance may compromise the successes registered so far. There is the urgent need of containing artemisinin resistance with all means available. Its spread to the continent with the highest malaria burden, sub-Saharan Africa, would be a major human disaster.
1. malERA Consultative Group on Drugs A research agenda for malaria eradication: drugs. PLoS medicine. 2011; 8:e1000402
2. Sinclair D, Zani B, Donegan S, et al. Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev. 2009; CD007483
4. World Health Organization Guidelines for the Treatment of Malaria. 2010; 2nd ed Geneva World Health Organization 194
5. Kurth F, Bélard S, Adegnika AA, et al. Do paediatric drug formulations of artemisinin combination therapies improve the treatment of children with malaria? A systematic review and meta-analysis. Lancet Infect Dis. 2010; 10:125–132
6. Stepniewska K, Taylor W, Sirima SB, et al. Population pharmacokinetics of artesunate and amodiaquine in African children. Malar J. 2009; 8:200
7. Dondorp AM, Fanello CI, Hendriksen IC, et al. AQUAMAT group Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010; 376:1647–1657
8. Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011; 10:144
9. Novartis Pharma AG A randomized, investigator-blinded, multicenter, parallel group study to compare efficacy, safety and tolerability of Coartem® dispersible tablet formulation vs. Coartem® 6-dose crushed tablet in the treatment of acute uncomplicated Plasmodium falciparum malaria in infants and children.
Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-001333-14/3rd/. Accessed February 28, 2014
11. Shekalaghe SA, Drakeley C, van den Bosch S, et al. A cluster-randomized trial of mass drug administration with a gametocytocidal drug combination to interrupt malaria transmission in a low endemic area in Tanzania. Malar J. 2011; 10:247
12. von Seidlein L, Walraven G, Milligan PJ, et al. The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Trans R Soc Trop Med Hyg. 2003; 97:217–225
13. White NJ, Qiao LG, Qi G, et al. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common. Malar J. 2012; 11:418