Researchers pin down genes responsible for drug-resistant malaria

05 April 2012By John Timmer
ArsTechnica.com

What's a SNP?

SNP stands for single nucleotide polymophism. A nucleotide is a single base—A, C, T, or G—and polymorphism means "many forms" (single, we hope, is self explanatory). So, an SNP is just a single base at a defined position within the genome that will exist in many forms within a population. So, I might have an A there on one of my chromosomes, but a C on the other one; another person might have a C/G combination. Because these are located at specific places in the genome, the SNP will be inherited in the same way that everything else is.

Because of the vagaries of our genetic past, such as founder effects, migrations, and genetic bottlenecks, SNPs can be used to provide some hint of a person's family background, indicating what area of the globe a person's ancestors came from. New mutations, including those that cause diseases, will often arise near a known SNP. They can be used to track inheritance of the disease. Since malaria resistance is the result of a new mutation, it can be tracked using SNPs in the same way.

Over the last few decades, malarial parasites have evolved resistance to most of the drugs that we've thrown at them. This development leaves us with just one effective treatment: artemisinin. Artemisinin is currently delivered as part of a combination therapy (ACT) with other drugs that are intended to take out any resistant parasites. But recent developments in Southeast Asia have suggested that time may be running out for ACTs, as they're taking much longer to clear parasites.

Understanding artemisinin resistance is complicated by the fact that we're not entirely sure how the drug works. We also lack any understanding of the biochemical basis for resistance. All of that makes devising a test for resistant malaria a big challenge. Now, researchers have taken the first step toward nailing things down by identifying a chunk of the parasite's genome that accounts for a significant percentage of the resistance.

CAMBODIA: Malaria cases rise sharply

The number of cases remains dramatically lower than 12 years ago

BANGKOK, 27 April 2010 (IRIN) - The number of malaria cases recorded in Cambodia has increased significantly, say health officials, citing several reasons, including better detection and reporting.

According to the National Center for Parasitology, Entomology and Malaria Control, there was a 41 percent increase in cases last year.

The country - which has become an epicentre for malaria - recorded 83,217 malaria-infected persons in 2009, from 58,887 the previous year, after a steep drop in the number of cases over the past several years.

The mosquito-borne disease killed 279 people in 2009 from 209 in 2008, Chea Nguon, the centre’s deputy director, told IRIN from Phnom Penh.

Multiple factors

Nguon cited several factors for the spike, including an earlier-than-usual rainy season, a late distribution of insecticide-impregnated bed nets, and internal migration to malaria-affected areas. He said there was also a natural cyclical rise in the number of cases every two to three years.

In addition, the increase reflected a rise in the number of people with access to healthcare, he said.

Since 2004, the government has trained malaria workers in 1,300 villages to detect and treat malaria, so a greater number of patients are being properly diagnosed and recorded than in previous years.

“Cambodia is establishing more and more village malaria workers, who are detecting more malaria that wasn’t detected previously,” said Steven Bjorge, technical officer for the World Health Organization (WHO) in Cambodia.

“The populations most affected are people who work in the forest,” Bjorge said. Those include soldiers and their families, plantation workers, and even workers at a hydroelectric plant in the west of the country. Villagers hunting and gathering in the forests were also at risk, he said.

Many malaria patients in areas with poor access to public health facilities attend private clinics, which do not report cases to the government.

Nguon said the number of cases still might be higher than recorded, and as the government trained more village malaria workers, the figures may rise because of better reporting.

Drug resistance

Cambodia in recent years has become one of the world’s malaria focal points after authorities detected along the country’s western border with Thailand a strain of the disease resistant to Artemisinin, one of the most effective drugs used to treat malaria.

WHO has set up a special Artemisinin-resistant malaria containment project in the area.

“As in the past, the Thai-Cambodian border is home to the emerging drug resistance. The two countries and several partners, donors, as well as WHO, are working relentlessly to eliminate this dreadful parasite from this hot spot,” said Jai P. Narain, director of communicable diseases for the WHO Southeast Asia regional office.

Nguon noted that the number of cases in 2009 was still dramatically lower than 12 years ago, when there were 170,387 infected persons and 865 deaths.

“Compared to Vietnam or Thailand, the [numbers of] cases are still high,” he said. “We hope to eliminate malaria by 2025, and we are committed to that goal, but it’s still in the process.”

The government and NGOs are continuing to train village malaria workers and to collect data on malaria patients who sought medical assistance from private clinics.

Cambodia hopes to contain drug-resistant malaria strain

Sat, 24 Apr 2010
By Robert Carmichael
DPA

Phnom Penh - Next week, teams of health workers will head to 10 of Cambodia's most malaria-infected villages near the western town of Pailin, in a region notorious for its mystifying ability to produce resistant strains of the disease.

The purpose of their visit is unique in the country's programme to combat malaria.

Health workers will take blood samples from every villager, lab test for the falciparum malaria parasite, and then provide treatment within days to anyone with the parasite whether or not they are showing malaria symptoms.

This pre-emptive action is one of many the government and donors have taken in a year-old programme to combat a potential catastrophe: The spread of a falciparum strain that has shown resistance to the world's most important malaria treatment - ACT, which combines artemisinin with other drugs to attack the parasite.

Dr Steven Bjorge, a malaria specialist at the World Health Organization's office in Phnom Penh, said scientific tests have proven that a deadly strain resistant to chloroquine, for example, developed in western Cambodia before migrating to Africa.

"And so the fear is that again the drug-resistant parasite, for example from western Cambodia, will move to Africa, and Africa is a malaria problem many magnitudes worse than anything in South-East Asia," Bjorge said.

The objective of next week's effort, which follows World Malaria Day on April 25, is to reduce the number of malaria carriers. Should that prove successful, it will be rolled out across the country as part of a wider containment programme, he said.

"And that's going to then reduce the number of parasites that are generally in the population, and then probably reduce transmission," Bjorge said.

Dr Duong Socheat heads the government's National Centre for Malaria Control. When news broke two years ago of the increasing resistance to ACT, health professionals and the government met to map out an urgent course of action.

"The experts were very concerned - how to contain, how to stop the spread of artemisinin-resistance to other areas?" he said. "So before it spread, we had to take some action."

The resultant containment plan divides Cambodia into three zones.

Zone 1, comprising around 5 per cent of Cambodia, is centred in the west around Pailin and is the main initial focus. Zone 2, a buffer zone, expands beyond the first zone and accounts for about half of the country. Zone 3 comprises the rest of Cambodia.

The ongoing plan combines prevention, education and treatment.

Duong Socheat said one aspect has been to provide training to private health practitioners, drug manufacturers and importers to ensure they understand the importance of not using one drug to treat the disease - so-called monotherapy.

Another is a government crackdown on counterfeit drugs being sold in markets and pharmacies.

"This is a real achievement that people are following our guidelines," he said. "Before you could see plenty of counterfeit drugs in the market, but now there are very few."

Other steps include providing bed nets to prevent people being bitten by mosquitoes. WHO figures show Zone 1 now has an average of 1.79 people per bed net.

Another vital step was training at least one volunteer in every Zone 1 village how to use a free kit to provide testing for any villager with fever. In a country where people are often charged for theoretically free health services, a free testing service is key.

Duong Socheat said indications show the situation has stabilized in Zone 1, which last year reported zero deaths from malaria. The number of infections was stable too. All 270 deaths from the disease in Cambodia last year took place in Zones 2 and 3.

WHO's Bjorge said he is "very, very cautiously optimistic" the containment programme is working.

"We feel that in Zone 1 we are having some success. It's still early in the game and so we are trying to gather the data and evaluate it, but we think that we are having some impact," he said.

Assuming the data shows success, the next step is to expand the containment programme over the next five years to cover Zones 2 and 3, using money provided under the Global Fund, which targets HIV/Aids, tuberculosis and malaria.

Duong Socheat said the government wants zero malaria deaths in Cambodia by 2020. The containment programme is bound to help.

He said the most difficult task will be to ensure migrant workers who crisscross Cambodia looking for work do not bring back the resistant form to their home provinces. The more the government can help to improve the economy, the easier that task will be.

"It's very important. When the economy improves, gross domestic product increases and it's easier for poor people to protect themselves," he said.

Fears for new malaria drug resistance

The drug resistance was first detected in Pailin province in western Cambodia

Thursday, 28 May 2009
By Jill McGivering
BBC News, Cambodia

In a small community in Western Cambodia, scientists are puzzling over why malaria parasites seem to be developing a resistance to drugs - and fearing the consequences.

Ten days ago, Chhem Bunchhin, a teacher in Battambang Province, became ill with chills, fever, headache and vomiting.

At a nearby health centre he was treated with drugs considered a "silver bullet" in the battle against falciparum malaria.

This treatment with artesunate drugs was part of a clinical study being carried out by the US Armed Forces Research Institute of Medical Science (AFRIMS).

In the past, artesunates have always cleared malaria parasites from the blood in two or three days. But after four days of monitored treatment, Chhem Bunchhin was still testing positive for parasites.

Dr Delia Bethell, an investigator working on the clinical trials, said he wasn't alone. Out of about 90 patients included in the study so far, roughly a third to half were still positive for malaria parasites after three days, some even after four or five days.

"It appears that the artesunate is working more slowly than previously," she said.

"It appears that the parasite probably is developing some kind of tolerance or is somehow less sensitive to the effects of the drug. But nobody knows why that might be."

These early results need to be more thoroughly investigated, she said.

The concern is that this could be the start of emerging resistance to the artemesinin family of drugs. If full-blown resistance did develop, it would be extremely dire.

"This is by far the most effective drug we have," explained Dr Bethell.

"And there are no new drugs coming through the system in the next few years."

Scientists are particularly concerned because the last two generations of anti-malarial drugs were undermined by resistance.

And in those earlier cases, resistance also started in Western Cambodia, and in a similar way.

No-one is sure why this area seems to have become a nursery for anti-malaria drug resistance.

One factor could be the inappropriate use of drugs, related to a lack of medical supervision.

The public health system is weak. Government clinics often run out of drugs or may be closed when patients want access to them.

Instead, many patients visit private pharmacies to buy anti-malarial drugs there.

Coloured tablets

I visited one small drugs stall in Pailin's general market, sandwiched between a clothes outlet and a general grocery store.

All pharmacies are supposed to be licensed. But the stallholder told me he didn't have a licence. He'd applied for one, he said, but the paperwork had never been processed.

Many others running pharmacies, he said, were in the same position.

I watched him and his wife make up their own packets of drugs on the glass-topped counter, shaking a variety of coloured tablets into unlabelled plastic bags.

In many such private pharmacies, the customers choose what they want, deciding partly by price.

The quality of the advice they get varies enormously. If, as a result, they end up taking the wrong drugs in the wrong combinations, this too can fuel drug resistance.

The availability of many counterfeit drugs on the market only compounds the problem.

Professor Nick Day, director of the Mahidol-Oxford Tropical Medicine Research Unit, is also running clinical trials in the region.

He and his team have also found that artesunate-type drugs are starting to become less effective.

This resistance must be contained urgently, because its spread would be a global health disaster, he said.

Resistance to previous malaria drugs caused major loss of life in Africa, he said.

"If the same thing happens again, the spread of a resistant parasite from Asia to Africa, then that will have devastating consequences for malaria control."

In a clearing in the jungle, about one and a half hours drive from Pailin along rough dirt roads, I watched health workers distribute mosquito nets to about 200 villagers.

It's one of a series of measures being rushed through to stop the spread of resistant parasites.

If they're not contained, history may repeat itself - and the fear is that many millions of people worldwide will lose their protection against this deadly disease.