Popular drug was withdrawn from treatment regimens because of drug resistance

Researchers at the University of Maryland School of Medicine’s Center for Vaccine Development and the University of Malawi have found that a once popular anti-malaria medication used in Malawi has regained its effectiveness at treating the disease that continues to be the leading killer of the world’s poorest children. Chloroquine was removed from government health facilities in Malawi in 1993 after it proved ineffective at treating malaria in more than 50 percent of documented cases. But a new study appearing in the November 9, 2006, edition of the New England Journal of Medicine shows that the drug is once again useful for both preventing and treating malaria. 

“Malaria is a mosquito-borne parasite that kills more than 5,000 people every day, 90 percent of whom are children in Africa under the age of five,” says Miriam K. Laufer, M.D., an assistant professor of pediatrics at the University of Maryland School of Medicine and a researcher at the Center for Vaccine Development who helped lead the study.

“Chloroquine resistance first emerged in Southeast Asia and South America in the late 1950s, and had made its way to the African continent by the late 1970s when the resistance contributed to increased malaria transmissions and death,” adds Dr. Laufer. “Since the drug failed to treat malaria, the Malawian government replaced it in 1993 with another medication, sulfadoxine-pyrimethamine. For 12 years, chloroquine was not used in Malawi. Now, our study shows that the malaria parasite has once again become susceptible to chloroquine, and the medication could potentially be used in combination with other therapies to treat the disease effectively in the future.”

According to Dr. Laufer, chloroquine has many desirable attributes as an anti-malarial drug. It is inexpensive, rapid-acting and long-acting, and safe for all age groups and pregnant women. It is an excellent drug for preventing malaria in travelers and may be an ideal candidate for intermittent preventive treatment, a control strategy in which pregnant women and infants are periodically treated for malaria at routine health visits.  

For the study, Dr. Laufer and colleagues enrolled 210 children between six months and 12 years of age with symptoms of malaria at the Ndirande District Health Centre in Blantyre, Malawi. The children were randomly assigned to one of two study groups: those who received chloroquine and those who received the standard treatment with sulfadoxine-pyrimethamine. The children were closely monitored for 28 days after administration of the medication.
 
“We found that chloroquine was effective at treating the malaria in 99 percent of the children we studied, while sulfadoxine-pyrimethamine was effective only 21 percent of the time,” says Dr. Laufer. “Infection and fever cleared more quickly in chloroquine recipients than in those who received the standard treatment.”

Additionally, blood samples obtained by the study team showed that the genetic mutation that causes chloroquine resistance, which disappeared after the medication was withdrawn from use in Malawi, was completely absent in the parasites which caused malaria infections in the children in the study.

“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 Christopher V. Plowe, M.D., M.P.H., a professor of medicine at the University of Maryland School of Medicine and the principal investigator on the study. “Many African nations continue to use chloroquine even after officially switching to newer drugs to treat malaria. For that reason, chloroquine can’t be successfully used again until it is withdrawn throughout Africa as effectively as it was in Malawi. We envision that chloroquine could one day return to sub-Saharan Africa as an effective treatment for malaria when it is used in combination with other therapies.”

The research team expected chloroquine to perform well because genetic studies had shown that parasites carrying the choloroquine resistance mutation had gradually disappeared from the area during the 10 years after the medication was withdrawn in Malawi. “We were still amazed at how quickly these children got better on cholorquine in this clinical study,” says Dr. Plowe.

Similar efforts to bring back other drugs by withdrawing them after microbes have become resistant have not had this dramatic success, the researchers say, but “that’s likely because nobody pulled a drug out of a whole country so completely before, the way that Malawi did,” notes Dr. Plowe. “It would be worthwhile to explore the possibility of rotating drugs for malaria as well as other infections that have become resistant to important drugs.”

Future studies planned by the University of Maryland School of Medicine’s Center for Vaccine Development will test chloroquine in conjunction with other drugs to see which combinations are best at preventing resistance to chloroquine from remerging. 

Funding for this study was provided by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.