Artemisinin resistance dents the anti-malaria armour

Anopheles stephensi is a primary mosquito vector of malaria in urban India. - Photo  CDC - Dr. William Collins

Anopheles stephensi is a primary vector of malaria in urban India. – Photo: Dr. William Collins/CDC

The emergence of resistance to the artemisinin drug, a potent anti-malarial medicine, now threatens to affect the big gains achieved in recent years in reducing the global burden of malaria — an estimated 1.2 billion fewer malaria cases and 6.2 million fewer malaria deaths globally between 2001 and 2015. This resistance, to artemisinin, becomes all the more dangerous as it has been the “backbone of combination therapy” for more than 10 years and will continue to be used to treat malaria caused by Plasmodium falciparum — a protozoan parasite and one of the species of Plasmodium that causes malaria in humans; it is transmitted by the female Anopheles mosquito. The use of artemisinin came into the picture at a critical time when resistance to commonly used chloroquine was making malaria treatment highly inefficient.

It was only in December 2013 that researchers could conclusively prove that resistance to this powerful drug was due to mutations seen in the malaria parasite. Mutations in specific regions of the parasite’s kelch gene on chromosome 13 (K-13) was found to confer resistance to artemisinin.

On the flip side, with K-13 mutations serving as a marker for artemisinin resistance, the spread of artemisinin resistance across the world could be mapped. A study published on June 23, 2016 in The New England Journal of Medicine has done precisely this and the results are quite positive. The K-13 mutations are still restricted to Southeast Asia and China with “no immediate threat to artemisinin efficacy in most countries where malaria is endemic”. “The prevalence of K-13 mutations in Southeast Asia and China is high: from 30-60 per cent to close to 100 per cent,” says Dr. Didier Menard, the first author of the paper from the Institut Pasteur in Cambodia, Phnom Penh, Cambodia.

A link with human movement

While no sample was collected from India, those from Bangladesh did not show K-13 mutations. “I think that resistance is (still) confined to Southeast Asia because we are at the beginning of the story. Emergence of artemisinin-resistant parasite is quite recent. Secondly, the containment strategy deployed has possibly been effective in limiting the spread. But the risk [of the resistant parasites spreading to other countries] is high due to intensive human population movement,” says Dr. Menard.

It is particularly important that the highly malaria-endemic region of Africa is free of artemisinin-resistant malaria. Otherwise it would lead to a global health crisis. Nearly 88 per cent of the malaria cases and deaths in 2015 had occurred in the World Health Organisation (WHO) African region, the 2015 World Malaria Report says.

Even in Asia, a majority of the K-13 mutations are distributed within two regions — Cambodia, Vietnam and Laos as one region and western Thailand, Myanmar and China as the other.

Combination therapies

The WHO insists that artemisinin must not be used as oral monotherapy as it promotes the development of drug resistance. Instead, it recommends artemisinin-based combination therapies (ACT) as first-line treatment for acute uncomplicated Plasmodium falciparum malaria. The combination therapies are effective as the mechanism of action of the two active ingredients is different.

Aung Pyae Phyo and Prof Francois Nosten (1)-Optimized

Thailand had to change the combination drug used due to artemisinin resistance, says Dr. Aung Pyae Phyo (left) from Shoklo Malaria Research Unit, Thailand.

While resistance to artemisinin generally leads to a delay in clearing the parasites from the body and not treatment failure, high treatment failures have been seen in Cambodia, Lao PDR and Vietnam despite the use of combination drugs. This arises due to resistance emerging in drugs that are used in combination with artemisinin.

A recent study in the journal Clinical Infectious Diseases says that along the Thai-Myanmar border, artemisinin resistance is leading to failure of the mefloquine (a partner drug used in combination therapy) drug and, in turn, the failure of the drug combination (mefloquine-artesunate) that was introduced in 1994. In fact, the study says that K-13 mutations in artemisinin and multiple copies of a particular multidrug resistant gene (Pfmdr-1) in mefloquine have a multiplicative than additive effect on risk of treatment failure. As a result, while patients are not being cured, the malaria parasite continues to spread further.

Now, another study shows that P.vivax parasite has developed resistance to mefloquine drug, though the drug is used primarily to treat malaria caused by P. falciparum.

As early as 1992, the cure rate of even a high dose of mefloquine drug when used alone (monotherapy) had dropped to 50 per cent but was rescued by the use of artemisinin as a combination therapy (mefloquine-artesunate). “But when K-13 mutation emerged, the artemisinin component couldn’t compensate for the already feeble mefloquine component and the whole combination failed,” says Dr. Aung Pyae Phyo, the first author of the Clinical Infectious Diseases paper from Shoklo Malaria Research Unit, Thailand.

The only recourse left for Thailand was to change the combination drugs used. “We switched our first-line antimalarial to another combination therapy (Dihydroartemisinin-Piperaquine), which relies mostly on piperaquine component. We don’t have piperaquine resistance in this area yet,” Dr. Phyo says.

But changing to a different combination drug is only a short-term solution. Western Cambodia, for instance, has started seeing high piperaquine resistance.

“We don’t have many options except eliminating the resistant malaria before the resistance progresses to a higher degree,” Dr. Phyo says.

Published in The Hindu on June 26, 2016

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