When the Best Malaria Drug Starts Losing Power

Good things don’t last very long they say. Artemisinin, the plant-derived compound that has today become the best drug for malaria has started losing its effectiveness. Two new reports published today in Science and The Lancet show that the most deadly species of malaria parasite (Plasmodium falciparum) is becoming resistant to artemisinin-based drugs and the first evidence has come from the Thailand-Myanmar border.

The concern is rising that this could now spread to India and then to Africa, as has happened in the past with other malarial drugs. When the first-line treatment of a disease that kills close to 0.7 million people (655,000 in 2010, over one per minute, to be precise according to the World Malaria Report) shows cracks, then the full force of the global biomedical community is needed.

Artemisinin derivatives have the advantage over other anti-malarial drugs such as chloroquinine and mefloquine in acting more rapidly and having fewer side-effects. Until recently, no resistance was noticed anywhere. But a 10-year study, between 2001-2010, in the region by researchers at Shoklo Malaria Research Unit shows that the average time taken to reduce the number of parasites in the blood by half (known as parasite clearance half life) increased from 2.6 hours in 2001 to 3.7 hours in 2010. It’s a clear sign that the drug is becoming less effective.

These finings are backed by another report in Science by the same group of researchers and shows change in the genetic makeup of the parasites. This study narrows the search to a region of the parasite genome containing around 10 genes. Researchers say they haven’t found the precise changes involved, but they are “getting close.”

“This study emphasizes the importance of staying ahead of malaria,” says Prabhat Jha, Director, Centre for Global Health Research at the University of Toronto. He was  not involved in these two studies. Some of the resistance in East Asia is because of sub-standard drugs, or solo therapies (meaning artemisinin is used alone, without other anti-parasites) which are more likely to increase resistance, he says.

This is a strong argument for all governments supporting the Affordable Medicine Facility for malaria which uses novel economic subsidies to crowd out bad manufactures, and which should thus reduce the spread of resistance.  “The AmFM board is meeting this fall, and without question its funding should be renewed,” says Jha.

India needs to be extra cautious: One third of all the people who are at risk of malaria live here.

So how is the spread of the present resistance related to the past?

Professor Francois Nosten, director of the Shoklo  Unit says resistance to chloroquine and to sulfadoxine-pyrimethamine emerged in South East Asia (Cambodia) and spread westward through Thailand, Myanmar, Bangladesh, India, all the way to Africa. “Resistance to artemisinin may be different,” he tells Forbes India. “What we report is that it is present on the Thai Myanmar border but we do not know whether it has spread from Cambodia or emerged spontaneously. Either scenario is worrisome because ACTs [artemisinin combination therapies] are now used worldwide.”

As always, the case in India is complicated. Almost half of the malaria infection here is caused by another species, Palmodium vivax. In such  instance, what do we make of this resistance?

The relevance to vivax is indirect, says Nosten. This parasite is also developing resistance to chloroquine (now in Myanmar and Thailand) and there are calls to use ACTs to treat both falciparum and vivax, he adds.

Jha’s study in 2010, also published in The Lancet, found that there “could be about 200,000 malaria deaths in India in 2005, of which 120,000 were in adults”.  Similar findings have emerged from African death studies that malaria does not just kill kids but also adults.

(In Jha’s study, death figures are 13 times of what the WHO had estimated and 200 times of what India’s own National Vector Borne Disease Control Programme has recorded. The big leap in Jha’s study is the sampling of the rural areas; WHO estimates rely on just hospital settings. In the true Indian tradition, a committee was formed soon after Jha's study was published. It intended to resolve the issue – How many people actually die of malaria in India? More than a year later, the committee is yet to give its report.)

The strategy, according to Jha, particularly for Orissa (where his group estimated about 50,000 malaria deaths) is to expand artemisinin combination therapies, including for adults.  “This would have the benefit of treating early, before more resistance forms take place (such as happened with chloroquine resistance in India).”

The international community is rattled by these findings. “This new study suggests that containing the spread of resistance is going to be even more challenging and difficult than we had first feared,’ says Nick White, chair of the Worldwide Antimalarial Resistance Network.

UPDATE at 1.30 pm: 

Prof G Padmanabhan, DBT’s Distinguished Professor and former director of IISc in Bangalore has been experimenting with a combination of artemisinin and curcumin. He thinks that “ART-Curcumin combination will make a difference in considerably delaying spread of resistance,” but ultimately we need a new pharmacophore to replace ART and that is only at the research stage. “I do not expect a new effective molecule as a drug to replace ACT within the next three to five years, even if the international leads fructify.”

“Falciparum malaria is the main issue in India and I am not sure decisions based on appropriate treatment are taken in time. The country has to ensure effective use of ART-based combination and make it affordable.”

The problem in Thai-Cambodia border ( and developing countries in general) is the use of spurious and sub-optimal doses of the drug, a sure prescription for resistance development. He is not sure if any body has studied this in India.

The thoughts and opinions shared here are of the author.