Malaria

Spring 2007
NIAID Discovery News 

Once Effective Anti-Malaria Drug Shows Promise Again in Africa

A woman in Africa feeds her infant a chloroquine tablet, an antimalarial drug used to treat and prevent malaria; staged photo. (Credit: 1999 Luke Mwanza/CCP, Courtesy of Photoshare)

For nearly 40 years in the mid-20th century, chloroquine was used effectively by itself to prevent and treat malaria infection throughout the world. It was an ideal drug: inexpensive, quick-acting, long-lasting, well-tolerated, and safe for pregnant women and people from all age groups.

Yet by the late 1950s, Plasmodium falciparum, the species of malaria parasite responsible for most deaths, began to demonstrate resistance to the drug. This resistance first emerged in South America and Southeast Asia and reached Africa by the end of the 1970s, moving steadily across the continent through the 1980s. As the parasite’s resistance to the drug’s effects grew, so too did the incidence of malaria illness and death in Africa.

In 1993, when the drug became less than 50 percent effective, Malawi became the first country in Africa to remove chloroquine from use in its government health facilities. Health officials there replaced it with the drug combination of sulfadoxine and pyrimethamine.

A Resurgence of Effectiveness

As Malawi officials adopted the alternative malaria treatment, researchers at the University of Maryland School of Medicine’s Center for Vaccine Development found an encouraging sign: The molecular marker indicating chloroquine resistance among the P. falciparum parasites declined from 1992 to 2000 in Blantyre, the largest city in Malawi. By 2001, the marker was undetectable, suggesting that chloroquine might again be effective in treating malaria in the country.

To test this theory, the researchers performed small, open-label studies in Malawi, which found that low-level, asymptomatic P. falciparum malaria infections cleared after treatment with chloroquine alone. Armed with these encouraging findings, the research team, led by principal investigator Christopher V. Plowe, M.D., M.P.H., a professor of medicine at the University of Maryland, and co-investigator Miriam K. Laufer, M.D., an assistant professor of pediatrics at the university, decided to perform a clinical trial pitting chloroquine against sulfadoxine-pyrimethamine.

In 2005, the research team enrolled 210 children between six months and 12 years of age with symptoms of malaria and mild-to-moderate malaria parasite levels in their blood (2,000 to 2,000,000 parasites per cubic millimeter) at the Ndirande District Health Center in Blantyre. The children were randomly assigned to one of two study groups: those given chloroquine or those given sulfadoxine-pyrimethamine. Both groups were closely monitored for 28 days after receiving the medication.

“We found that chloroquine was effective at treating the malaria in 99 percent of the children studied, while sulfadoxine-pyrimethamine was effective only 21 percent of the time,” says Dr. Laufer. Further, infection and fever cleared more quickly in the children who received chloroquine than in those children who received the standard drug.

“The outcomes couldn’t have been any clearer,” according to Dr. Laufer. “The goal was to make the parasites disappear quickly and keep them away for at least four weeks, and that happened here. We couldn’t believe how fast these kids got better.”

The research team also found further evidence that the genetic mutation that causes chloroquine resistance has disappeared in Malawi. Blood samples taken from the study participants showed that the parasites that caused the children’s malaria infections were free of the genetic marker for chloroquine resistance.

A Future, Combination Therapy

Although the results from the study, which was funded by the National Institute of Allergy and Infectious Diseases, are extremely encouraging, the researchers warn against reintroducing chloroquine as a malaria treatment in Africa until other nations on the continent completely discontinue the drug’s use as Malawi did more than a decade ago.

Chloroquine-resistant malaria is still common in the countries surrounding Malawi, including Mozambique and Zambia, and would very likely make a rapid return, imported by people or mosquitoes from neighboring countries, if the drug were to be reintroduced too soon as a routine malaria treatment, notes Dr. Laufer.

The researchers do envision a day when chloroquine will return to Africa as an effective malaria treatment, but one that will only be used in combination with other drugs following evidence that malaria, like other infectious agents, is less likely to develop resistance when attacked by more than one drug at once.

Barriers to New Treatments

In southern Africa, the malaria parasite species responsible for most malaria-related deaths is largely resistant to the anti-malaria drug chloroquine. In Malawi, however, researchers recently found evidence suggesting the drug may be effective again at treating malaria, and that the genetic mutation that causes chloroquine resistance has disappeared in the country. (Credit: National Institute of Allergy and Infectious Diseases).

Today, the World Health Organization recommends artemisinin-based combination treatments as the first-line therapy for fighting P. falciparum malaria in areas where it is endemic. Artemisinins are effective, work quickly, have very few side effects and when combined with an unrelated drug with a different mechanism of action, minimizes the potential for drug resistance. Unfortunately, these drugs are also considerably more expensive than single-agent treatments, making them unaffordable or unavailable to many of the poor African countries most affected by malaria.

This inability to afford or acquire the newer anti-malaria treatments is why some countries in Africa continue to stock chloroquine in their pharmacies and use it despite the fact that it has lost much of its effectiveness.

To be able to reintroduce chloroquine in Africa as one of several effective measures against malaria would provide a tremendous benefit given the drug’s many positive features, including its low cost. “Chloroquine was the most important malaria drug of the 20th century, and the loss of the drug to resistance was a public health catastrophe for Africa,” says Dr. Plowe.

Today, malaria is widespread in more than 90 tropical and subtropical countries, resulting in an estimated 300 to 500 million clinical cases of malaria and one million deaths annually in Africa alone. The majority of malaria cases and deaths occur in children in Africa under the age of five.

The University of Maryland School of Medicine’s Center for Vaccine Development is planning future clinical studies designed to test chloroquine in conjunction with other drugs to see which combinations are best at preventing chloroquine resistance from re-emerging.

— Kathy Stover

Reference

Laufer, M. K. et al. Return of chloroquine antimalarial efficacy in Malawi. New England Journal of Medicine 355:1959-66 (2006).

This article was featured in the spring 2007 issue of NIAID Discovery News.

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