Malaria’s defiant act

DRUG-resistant malaria is on the prowl. The parasite that causes malaria is already resistant to previous mainstays of treatment, chloroquine and sulfadoxine-pyrimethamine. Now, the disease, which kills more than one person every minute, is increasingly becoming resistant to the wonder drug artemisinin. This resistance is spreading in Southeast Asia and could hit India and Bangladesh anytime, say researchers who carried out a study on the Thailand-Myanmar border. They suggest the only way out is to control the spread of the vector, mosquitoes in this case, to prevent the drug-resistant pathogen from spreading.

Malaria is mainly caused by two types of parasites—Plasmodium vivax and Plasmodium falciparum. Though P vivax affects more people, it is P falciparum that causes nine out of 10 malarial deaths. Artemisinin is used to treat malaria caused by P falciparum. Combination therapies containing artemisinin, a drug derived from Chinese plant, Artemisia annua, has helped reduce deaths due to malaria by around 30 per cent since it was introduced in the early 1990s.

In a new study, the researchers confirmed the presence of artemisinin resistant strains of the parasite on the border between Thailand and Myanmar, 800 km from western Cambodia where resistance has been known since 2005. Resistance to chloroquine and sulfadoxine-pyrimethamine was also first observed in western Cambodia and then it spread across Southeast Asia and Africa.

Tracking the spread

Resistance to artemisinin does not necessarily cause artemisinin treatment to fail completely, but it does slow the clearance of the malaria-causing parasite from the patients’ blood.

The team at Shoklo Malaria Research Unit in Thailand had been tracking malaria on the Thailand-Myanmar border since 1986 as it was the biggest cause of death and disease in the area. Since 1995, the team has been regularly following patients with high parasite counts because such people are most likely to succumb to the disease, explains François Henri Nosten, the lead researcher.

They measured the rate at which parasites were cleared from the blood of 3,000 patients treated with artemisinin. Researchers found increasing numbers of patients showed slow clearance between 2001 and 2010. The number of patients showing slow clearance rate rose from 0.6 per cent to 20 per cent over nine years. The time it took the drug to reduce the number of parasites in the blood by half rose from 2.6 hours to 3.7 hours. This means patients who were responding within two days are now taking up to four or five days to recover. They compared the clearance rate among the Thailand-Myanmar people with 119 Cambodians. They found that the clearance rate in Cambodia was 42 per cent between 2007 and 2010.

“The development would certainly compromise the idea of eliminating malaria and will probably translate into a resurgence of malaria in many places,” says Nosten. If resistance is indeed spreading, then being next to Myanmar, India and Bangladesh are the most vulnerable, he adds. The study was published in the April 5 issue of Lancet.

But what’s causing the resistance? “Artemisinin is recommended for use in combination with other antimalarials, because use of a cocktail of drugs should limit the ability of parasites to evolve resistance,” says Tim J C Anderson, one of the researchers of the study from Texas Biomedical Research Institute in the US. India too uses multi-drug therapy in areas where P falciparum is endemic.

However, in western Cambodia and some Southeast Asian countries artemisinin is widely used as monotherapy. “We suspect use of monotherapy has contributed to the spread of resistance,” Anderson adds. The team also found that people carrying the same parasite genotypes have similar clearance rates, which demonstrates that clearance rate is the genetic trait of a parasite, he notes.

Why the resistance?

This worked as a clue for researchers who then studied the genome of the malarial parasite to locate the region that might be leading to the resistance. Ian Cheeseman, a geneticist at the Texas Institute and his colleagues compared Cambodian, Thai and Laotian P falciparum populations that had different clearance rates after artemisinin treatment. By mapping single-letter DNA differences among 91 parasites with varied patterns of resistance, the team found evidence of recent strong selection—as would be caused by the evolutionary pressure to evolve drug resistance—in 33 regions of the P falciparum genome.

They found that variations in two adjacent areas on chromosome 13 of the genome were strongly associated with drug resistance. The researchers say this region accounts for one-third of the variation in clearance rates. The finding can help devise new ways to treat malaria. The study was published in the April 5 issue of Science.

Anderson says, “The study is useful as we urgently need a molecular marker for resistance. It will allow us to rapidly screen blood from malaria patients and determine whether they contain resistance.” The study can also help explain how parasites become resistant. “Then we can make modifications to the drug to restore effectiveness,” he adds.

The way out

There is a ray of hope. Researchers, headed by Nobel laureate Sidney Altman, have created a compound that prevents malaria parasite P falciparum from growing. The new drug penetrates red blood cells and targets molecular machinery of the parasite. “We inhibit the expression of gyrase gene of P falciparum which makes a protein absolutely essential for DNA replication,” says Altman. The study was published in the April 2 issue of PNAS.

But as concern grows over drug resistance, Nosten says, the best way to manage is to eliminate malaria before the resistance emerges. Vinod P Sharma, founder director of the National Institute of Malaria Research in Delhi explains. “In areas with endemic malaria, if the programme is effective, transmission can be controlled by preventive vector control, surveillance and early case detection and prompt treatment.”
 

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