In this third instalment in our series on malaria, we examine the phenomenon of resistance to anti-malarial agents.

Growing resistance to anti-malarial medications represents a major challenge to global efforts to control malaria.[1] Drug resistance is the ability of the malarial parasite species to survive and/or multiply despite the administration and absorption of a drug given in dosages equal to or higher than those usually recommended, but within the limit of tolerance. Resistance to nearly all commonly used anti-malarials, notably chloroquine and sulphadoxine-pyrimethamine, has been spreading worldwide since the late 1950s and early 1960s, respectively.[2]  Resistance is most commonly seen in Plasmodium falciparum, though sporadic cases have also been reported in vivax malaria.

The main line of defence against drug-resistant malaria has been the use of artemisinin-based compounds. Artemesinin is derived from the sweet wormwood bush, better known to Chinese herbalists as Qing Hao, a plant that has been used in East Asia as a remedy for fever for over 2000 years. During the Vietnam war, Ho Chi Minh appealed to China for traditional remedies for soldiers who had malaria. Tea made from Qing Hao leaves worked, and eventually became the basis for artemisinin-based anti-malarial drugs.

Artemesinin has a very short half-life, so is best used in combination with one of the longer-acting anti-malarial drugs. The World Health Organisation has recommended the use of artemisinin-combination therapy (ACT) in all areas where there is resistance to traditional anti-malarial treatments.[3]  However, various factors including cost considerations have meant that this policy recommendation is frequently not reflected in actual practice. Extracting artemisinin is expensive and there are often bottlenecks in supply. Recently, the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, announced a new simple and cost-effective way of synthesising artemisinin from the waste products of the plant,[4]  a discovery that has the potential to make the drug more affordable for the 225 million people affected by malaria every year.

Worryingly, there are signs that the malarial parasite may be developing resistance to artemisinin, the most potent medication currently in use against malaria.  In 2009, evidence of resistance to ACT was reported in the Thai-Cambodian border and has since appeared along the Burmese border with Thailand and China.[5,6]  The mechanism behind this underlying resistance is still unclear, but it is likely that resistance has developed due to inappropriate use of artemisinin in these regions. The drug is often used as monotherapy and terminated prematurely following the rapid disappearance of symptoms. This results in incomplete treatment and the survival of resistant parasites.  In addition, its widespread use to treat non-malarial febrile illnesses and substandard drugs sold over-the-counter are likely to be contributing factors to the development of ACT-resistance.

It is essential that new anti-malarial drugs with different modes of action are developed so alternatives are available when resistance to ACT spreads. Public-private partnerships such as the Medicines for Malaria Venture (MMV) and the Drugs for Neglected Diseases Initiative (DNDi) have been important in this regard, and several non-artemisinin-based drugs with novel modes of action against the malarial parasite are in development. However, it will be several years before these are available. Ultimately, the control of malaria will require progress in both treatment and prevention. For now, it is a case of trying to remain one step ahead of developing trends in anti-malarial resistance.

In the next instalment in this series, we examine some developments in the prevention of malaria, focusing on the role of bed nets and vector control.

References 

[1]    Kokwaro G. Ongoing challenges in the management of malaria. Malar J 2009; 8 Suppl 1:S2.

[2]    Farooq U., Mahajan R.C. Drug resistance in malaria. J Vector Borne Dis 2004; 41:45-53.

[3]    WHO. World Malaria Report: Geneva.  2010. Retrieved on 02/05/2012 from www.who.int/malaria/publications/atoz/9789241564106/en/index.html

[4]    Honigsbaum, M & Seeberger P. We can treat malaria for less. The Observer.  5-12-2012. Retrieved on 02/05/2012 from www.guardian.co.uk/technology/2012/feb/05/malaria-drug-synthesis-peter-seeberger 

[5]    Dondorp A.M., Nosten F., Yi P. et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009; 361:455-467.

[6]    Phyo A.P., Nkhoma S., Stepniewska K. et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 2012.