Artemisinin-resistant malaria surfaces in India

Medical researchers have reported the first Indian cases¹ of malaria resistant to the top line anti-malarial drug artemisinin. The finding assumes significance as India sits in the middle of the world's malaria corridor — cutting from Southeast Asia to Africa — already threatened by such drug resistance.

In what joins the dots for artemisinin resistance — a stumbling block in the global fight against the mosquito-borne disease — the researchers have identified 20 malaria patients in the eastern Indian state of West Bengal resistant to the standard combination drug therapy of artesunate–sulfadoxine–pyrimethamine.

While anaylsing data from 362 patients infected with the malaria-causing Plasmodium falciparum , researchers from Vidyasagar University, Midnapore, Calcutta School of Tropical Medicine, Kolkata and National Centre for Cell Science, Pune found that blood samples of 20 of these patients continued to harbour malarial parasites even after three days of artemisinin-based combination treatment.

However, they successfully treated the drug-resistant patients with a more effective combination therapy of artemether-lumefantrine. The researchers say this therapy worked due to two factors: the high efficacy of lumefantrine and higher number of required artemisinin doses, which was six in this case (artesunate is generally used for three doses).

The World Health Organisation recommends five different combination therapies. These combination therapies have one fast acting compound of artemisinin, such as artesunate or artemether, along with a slow acting drug that can wipe off residual parasites in the bloodstream over a longer period. WHO is now considering the use of artesunate-pyronaridine, a new therapy ratified by the European Medicines Agency (EMA), in areas where other combination therapies are failing.

The researchers, led by Somenath Roy, professor of human physiology at the Vidyasagar University, concluded that artemisinin cleared the majority of parasite within five hours but the remaining parasite was cleared by longer acting drugs. "Here longer acting drugs sulfadoxine-pyrimethamine were unable to clear the parasite biomass, which leads to partial artemisinin resistance as well late treatment failure,” said co-author, Sabyasachi Das, presently a physiology lecturer in the Faculty of Medicine at Lincoln University College, Malaysia.

The researchers also report some previously unseen mutations in the kelch13 gene, which is important in the molecular epidemiology of decreased artemisinin effectiveness.

"The study statistically and experimentally identifies the emergence of probable partial artemisinin resistance in the malaria parasite Plasmodium falciparum in eastern India for the first time," Roy told Nature India .

The researchers undertook two separate studies — first, in the lower Ganges delta of Bengal, where they found five out of 136 patients resistant to artemisinin-based therapy; and second, in the Purulia, Bankura, Midnapore, and Kolkata districts of West Bengal, which threw up 15 resistant cases out of 226. The second study has been accepted by the journal Clinical Infectious Diseases and is awaiting publication.

"The strong possibility of emergence of artemisinin resistance in India might have very serious adverse effects on the country's malaria control and treatment," Roy said.

Illusive superbugs

Decreasing effectiveness of artemisinin-based antimalarial agents was first documented in malaria patients in Southeast Asia and has been particularly menacing in the Greater Mekong subregion comprising Cambodia, China, Lao PDR, Myanmar, Thailand and Vietnam.

Notably, at least four of the 20 drug-resistant patients identified in West Bengal had traveled to Southeast Asia at some point.

"If these clinical threats spread from Southeast Asia to India, or further to Africa, it puts over a billion inhabitants in some malaria endemic regions at higher risk for disease and death," says Pradipsinh Rathod, a University of Washington chemistry professor and South Asia director of the International Center of Excellence for Malaria Research.

Rathod and colleagues had also ramped up surveillance efforts in 2017 to look for artemisinin-resistant strains in the region under a US National Institute of Health project, partnering with the National Institute of Malaria Research in New Delhi.

Rathod expressed concern over the West Bengal patients showing longer ring-stage parasite survival in the lab. "This is particularly concerning since it is known to co-relate most tightly with delayed clearances. Such traits can eventually lead to outright drug failures," he told Nature India . The new molecular changes reported in kelch13 gene are also of interest, though the causal role of these mutations in artemisinin resistance is yet to be established, he said.

India had an estimated 13 million cases of malaria in 2015 and more than 90 per cent of its 1.3 billion people live in areas with a risk of malaria transmission. The study, Rathod said, should inspire closer examination of artemisinin effectiveness in other parts of India.

Roy said identification of artemisinin resistant isolates and failure of artemisinin-based combination therapies call for a review of the malaria treatment protocol, surveillance, and containment strategies in India. "This is needed for limiting the resistance to the last line of treatment and also to understand the proper genetic lineage of resistant parasite."