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Plasmodium falciparum and artemisinin combination therapies

Artemisinin Combination Therapies are currently the frontline treatments against Plasmodium falciparum malaria. Although these treatments are working well in many parts of the world, there is serious concern that malaria parasites are once again developing widespread resistance to this vital treatment.

History of Plasmodium falciparum drug resistance

Antimalarial drug resistance first emerged in Southeast Asia and has subsequently spread to Africa through the Indian subcontinent [1]. Chloroquine (CQ) resistance emerged simultaneously and independently in South America and Southeast Asia [2]. The resistant strains of the parasites arrived at the East African coasts from Southeast Asia in the late 1970s and spread relentlessly across the continent over the next decade. Resistance to sulphadoxine pyrimethamine (SP), the immediate replacement of CQ, rapidly emerged in Southeast Asia in less than five years of usage [3].

Resistance to artemisinin combination therapies

In the same region where CQ and SP resistance emerged, resistance has now emerged against artemisinin [4]. The concurrent evolution of resistance against partner drugs alongside the reported artemisinin resistance is extremely concerning [5–7]. Multiple foci of origin of resistance have already been discovered, suggesting that resistance is emerging independently [1]. The pace of resistance has quickened and achievements made in the past decades in the global fight against malaria is now under threat of being reversed.

We are beginning to see the past repeat itself. If this drug resistance spreads further afield or arrives or emerges in Africa then millions of lives will be at risk. 

Triple artemisinin combination therapies

Triple ACTs, where additional partner drugs are added to an ACT, are currently being considered in Southeast Asia in an effort to combat the resistant parasites [8, 9]. Tracking Resistance to Artemisinin Collaboration (TRAC) II trial is currently underway and the initial results are reassuring [10]. If successfully developed and deployed, triple ACTs will have an important role to play to stall and potentially reverse the spread of these resistant parasites.

Preventing further spread and emergence

Containing antimalarial drug resistance in Southeast Asia – and preventing the spread of resistance through Asia to Africa and beyond – is a global public health priority. The WHO Global Action Plan for Artemisinin Resistance Containment (GPARC) was published in 2011, and outlines comprehensive recommendations for the containment of drug resistance.

Continuous monitoring of drug resistance in malaria-endemic countries along with research into the various contributing factors will enable health authorities and practitioners to more effectively prevent drug resistance from spreading.

A major focus of resistance containment activities is in ceasing the use of artemisinin as monotherapies. In Southeast Asia, where there is relatively low transmission of malaria, containment programmes aim to accelerate the elimination of P. falciparum parasites. Elimination of the parasites would be the ideal way to stop the spread of resistance entirely. In areas where there is high malaria transmission, decreasing the risk of a spread of resistance is possible through an increase in malaria control efforts.

References

1. Nsanzabana C, Djalle D, Guerin PJ, Menard D, González IJ. Tools for surveillance of anti-malarial drug resistance: an assessment of the current landscape. Malar J. 2018;17:1–16.

2. Payne D. Spread of chloroquine resistance in Plasmodium falciparum. Parasitol Today. 1987;3:241–6.

3. Hurwitz ES, Johnson D, Campbell CC. Resistance of Plasmodium Falciparum Malaria To Sulfadoxine-Pyrimethamine (Fansidar) in a Refugee Camp in Thailand. Lancet. 1981;317:1068–70.

4. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–67.

5. Leang R, Barrette A, Bouth DM, Menard D, Abdur R, Duong S, et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated plasmodium falciparum and plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother. 2013;57:818–26.

6. Saunders DL, Vanachayangkul P, Lon C. Dihydroartemisinin–Piperaquine Failure in Cambodia. N Engl J Med. 2014;371:484–5.

7. Phuc BQ, Rasmussen C, Duong TT, Dong LT, Loi MA, Tarning J, et al. Treatment Failure of Dihydroartemisinin/Piperaquine for Plasmodium falciparum Malaria, Vietnam. Emerg Infect Dis. 2017;23:715–7.

8. Dini S, Zaloumis S, Cao P, Price RN, Fowkes FJI, Pluijm RW Van Der, et al. Investigating the Efficacy of Triple Artemisinin-Based Combination Therapies for Treating Plasmodium falciparum Malaria Patients Using Mathematical Modeling. Antimicrob Agents Chemother. 2018;62:e01068-18.

9. White NJ. Triple artemisinin-containing combination anti-malarial treatments should be implemented now to delay the emergence of resistance. Malar J. 2019;18:1–3. doi:10.1186/s12936-019-2955-z.

10. van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis. 2019;19:952–61.