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Resistance to frontline antimalarial artesunate might have contributed to fatal malaria case in GMS

8 February 2018

Resistance to the commonly used antimalarial treatment artesunate might have contributed to the death of a patient suffering from severe malaria on the Thailand-Myanmar border, a recently published article reveals.

Published in Malaria Journal, the article documented two cases of artesunate failing to cure a 30-year-old farmer and an 18-year-old man who were diagnosed with Plasmodium falciparum malaria in late 2015 and early 2017, respectively. When injections of artesunate, the drug of choice for treatment, recommended by the World Health Organization (WHO), failed to clear the parasite from their bloodstreams, doctors administered quinine to both patients, but only the younger patient survived.

The treatment failures arrive at a time of growing resistance to artemisinin combination therapies (ACTs), the frontline treatments for uncomplicated falciparum malaria, in the GMS. Artemisinin-resistant malaria first emerged in the Mekong region along the Thailand–Cambodia border 10 years ago and has spread to other parts of Southeast Asia. Last year scientists identified a multi-drug resistant strain of P. falciparum which has caused high rates of treatment failures in Cambodia.

Injectable artesunate is derived from artemisinin and is recommended by the WHO for the treatment of severe malaria due to its ability to reduce the biomass of malaria parasites rapidly.

However, after being treated with artesunate, the number of malaria parasites in the two patients increased rather than decreased. The physicians therefore provided them with an injectable treatment of quinine as a complement.

With the combination of quinine and artesunate, the younger patient gradually recovered after 11 days’ treatment, but the farmer died within one day after being hospitalised.

“We found mutations C580Y and P441L, associated with artemisinin resistance, on the parasites extracted from the patients’ blood, and the time it took to clear the parasites was exceptionally prolonged,” said, Dr Aung Pyae Phyo, co-author of the paper, and researcher at the Mahidol Oxford Tropical Medicine Research Unit (MORU)’s Shoklo Malaria Research Unit (SMRU) in Mae Sot, Thailand.

It is nevertheless difficult to attribute the farmer’s death solely to artemisinin resistance. Patients with severe malaria infected with drug sensitive P. falciparum may develop life-threatening complications such as organ dysfunction, respiratory distress, and severe anaemia, despite treatment. What was remarkable in these two cases is the very slow response to treatment. Furthermore, the younger man had advanced HIV infection.

”The younger patient was severely immunocompromised, which could have contributed to his poor response to the drug,” said Dr Elizabeth Ashley, a clinical researcher at MORU. ”But these cases warn us to be vigilant for compromised efficacy of artesunate injection to treat malaria in Southeast Asia in the current era of established artemisinin resistance.”

Scientists are concerned that growing artemisinin resistance might reverse the recent gains in malaria control in Southeast Asia. Despite the fact that the death rate from malaria in this area dropped dramatically after 2010, this decline stalled between 2015 and 2016. Furthermore, if drug-resistant strains spread to Africa, millions of lives could be at risk, they say.

“These two cases warn us that antimalarial resistance might be even more severe than we expected,” said Professor Francois Nosten, the director of SMRU, who recommended changes to treatment regimens for severe cases. “Considering the extension of artemisinin resistance in the region, a combination of artesunate and quinine should be considered for patients treated with severe malaria. Rapid elimination of P. falciparum from this region is the highest priority.”

 

Selected resources:

Guidelines for the treatment of malaria. Third edition

Dorndorp A, Nosten F, Stepniewska K, et al. (2005). "Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial". Lancet. 366 (9487): 717–25. doi:10.1016/S0140-6736(05)67176-0. PMID 16125588.  

WHO. Tropical Medicine and International Health, 19 (Suppl. 1), 7–131 SEVERE MALARIA. doi:10.1111/tmi.12313  

Severe Malaria Observatory