Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria

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Key Points

  • Malaria has devastating consequences: it strikes over 250 million people worldwide and kills approximately 1 million people each year, many of whom are children under 5 years of age.

  • Malaria can be prevented by interventions focused on breaking the cycle of transmission, either by eliminating the mosquito (through the use of insecticides) or preventing bites (through the use of insecticide-treated bed nets).

  • It can also be treated through the use of antimalarial drugs. Drug resistance, however, remains the biggest threat to current drug efficacy. The former mainstays of antimalarial chemotherapy, chloroquine and sulfadoxine–pyrimethamine, have been rendered ineffective for the treatment of Plasmodium falciparum malaria by the emergence and spread of drug-resistant parasites.

  • Almost all malaria-endemic regions have switched to artemisinin (ART)-based combination therapies (ACTs) for the first-line treatment of P. falciparum malaria.

  • ACTs combine an ART semisynthetic derivative, which has a short half-life, with a longer-lasting partner drug. This results in sustained antimalarial pressure after the plasma concentrations of the ART derivatives have fallen below therapeutic levels

  • ACTs are discussed in terms of their modes of action and pharmacokinetic properties and the proposed mechanisms of resistance to them.

  • We summarize several therapeutic strategies that might decrease the emergence of drug resistance and present a perspective on the current ACT-based efforts to reduce the burden of malaria.

Abstract

Plasmodium falciparum resistance to chloroquine and sulphadoxine–pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages. These combinations increase the rates of clinical and parasitological cures and decrease the selection pressure for the emergence of antimalarial resistance. This Review article discusses our current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance.

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Figure 1: The worldwide incidence of malaria and the rapid adoption of artemisinin-based combination therapies across sub-Saharan Africa.
Figure 2: Site of action of antimalarial drugs.
Figure 3: Recent trends in malaria cases and deaths.

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Acknowledgements

We thank I. Borghini-Fuhrer and C. Li for their critical reading of the manuscript. R.T.E. is supported in part by the Training Program in Microbiology for Infectious Diseases (T32 AI007161, Department of Microbiology & Immunology, Columbia University Health Sciences, New York, USA). Funding for this work was also provided in part by the National Institute of Allergy and Infectious Diseases (R01 AI079709). We also thank T. Harris (Graphic Arts Center, Albert Einstein College of Medicine, Bronx, New York) for her initial input into developing figure 2. Our thanks extend also to A. Guilloux (WHO, Geneva) and P. Salama and E. White Johansson (UNICEF, New York) for providing the information for figures 1 and 3.

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Correspondence to Richard T. Eastman or David A. Fidock.

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DATABASES

Entrez Genome Project

Anopheles gambiae

Plasmodium berghei

Plasmodium chabaudi

Plasmodium falciparum

Plasmodium vivax

Saccharomyces cerevisiae

Xenopus laevis

FURTHER INFORMATION

David A. Fidock's homepage

Affordable Medicines Facility – malaria

Bill and Melinda Gates Foundation

The Global Fund to Fight AIDS, Tuberculosis and Malaria

Medicines for Malaria Venture

President's Malaria Initiative

Roll Back Malaria Partnership

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Glossary

Artemisinin-based combination therapy

A combination of artemisinin or one of its derivatives with one or more antimalarials of a different chemical class.

Pharmacokinetic properties

Characteristics of a drug, including its mechanisms of absorption and distribution, the rate at which a drug action begins and the duration of the effect, the chemical changes of the agent in the body, and the effects and routes of excretion of drug metabolites.

Antimalarial resistance

The ability of a parasite strain to survive and multiply despite the administration and adsorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject. The form of the drug that is active against the parasite must be able to gain access to the parasite or to the infected red blood cell for the duration that is necessary for its normal action.

Recrudescence

The reappearance of asexual parasitaemia, after initial parasite clearance, that results from the same infection that caused the original illness.

Pharmacodynamic properties

These include: the physiological effects of a drug on the body, on microorganisms or on parasites in or on the body; the mechanisms of drug action; and the relationship between drug concentration and effect. Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug.

Gametocyte

A sexual form of the intra-erythrocytic Plasmodium parasite that matures over a 2-week period, after which it can transmit to Anopheles mosquito vectors. Following ingestion during the insect blood meal, a gametocyte transforms rapidly into a female or male gamete that can undergo sexual recombination in the mosquito midgut.

Asexual blood-stage trophozoite

An asexual form of the intra-erythrocytic Plasmodium parasite that is undergoing cell growth and nuclear division, in preparation for parasite differentiation into a mature schizont that produces individual progeny (known as merozoites). These merozoites burst from the infected cell, ready to initiate new rounds of intracellular development.

Selection pressure

Evolutionary pressure that allows certain genotypes to outcompete others. In the case of malaria, resistance to antimalarials disseminates owing to the selective survival advantage that resistant parasites have in the presence of the drug. In a given population, the greater the proportion of parasites that are exposed to antimalarials at concentrations that allow proliferation only of resistant parasites, the greater the selection pressure.

Pharmacovigilance

The pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects resulting from the short- or long-term use of medicines.

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Eastman, R., Fidock, D. Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol 7, 864–874 (2009) doi:10.1038/nrmicro2239

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