Delaying Evolution Of Drug Resistance In Malaria Parasite Possible

David Smith, associate director of disease ecology at UF's Emerging Pathogens Institute, said the study will guide scientists and policy makers in extending the longevity of current artemisinin-based malaria drugs combined with partner drugs. Smith is a co-author of a report on the study, scheduled to publish online this week in the Proceedings of the National Academy of Sciences and in print on Sept. 16.

Smith collaborated with lead author Maciej Boni of Resources for the Future and Princeton University, and Ramanan Laxminarayan, also with RFF, to create mathematical models assessing the strategic effectiveness and clinical outcomes of using one, two and three first-line drug therapies to treat malaria within a population over a 20-year period. Their results show that using two or three drugs simultaneously reduced the total clinical cases and number of failed treatments , and slowed the rate at which drug-resistant genes spread within the parasites that cause malaria: Plasmodium falciparum, P. vivax, P. malariae and P. ovale.

"The models indicate that we can slow the evolution of resistance to current artemisinin-based therapies if nations use them in combination with two or more partner drugs," Smith said. "Currently, most nations don't do this. They use one therapy at a time, wait for it to fail, and then switch to a different therapy."

Artemisinin-combined therapies, or ACTs, are currently not widely implemented due to operational challenges and expense, Smith said. But he said the study offers compelling evidence for global leaders to collaborate and overcome these issues.

"This is not to say that implementing multiple first-line therapies solves all of our malaria problems," Boni said. "Anti-malarial drug development needs to continue so that we have novel and highly effective anti-malarials that can be plugged into the recommended strategy of deploying multiple therapies."

In the past century, chloroquine and sulfadoxine-pyrimethamine were widely used to combat malaria, but the parasites eventually evolved resistance leading to the drugs' failure. Artemesinin drugs, derived from the herb Artemisia annua, are relatively new and the malaria parasite does not yet appear to have a resistance to it. They work by triggering chemical reactions which damage the Plasmodium parasite.

"We don't have anything in the pipeline after ACTs, and it's basically just a matter of time until drug resistance evolves and artemisinin also fails," Smith said. "So the question becomes how do we keep ACTs in our arsenal for as long as effectively possible?"

The researchers' models also show that cycling through single drugs accelerated the rate at which malaria parasites evolved drug resistance. Smith said this occurred because cycling a single drug degraded the parasite's average fitness, which made it easier for drug-resistant genes to spread throughout the parasite population.

The cycling models predicted a declining therapeutic value of a single drug within 3.54 years, versus a longer effective therapeutic value of 9.95 years when three drugs were used in equal proportions within a population. The research was funded in part by grants from the Bill and Melinda Gates Foundation, and the National Institutes of Health.

"Using multiple first-line drugs reduces the selection pressure for resistance to a single drug," Smith said. "This is one way to make the ACTs last longer and benefit more people."

Co-author Laxminarayan, a senior research fellow at RFF, said ACTs are the best treatment option for malaria, now as well as in the foreseeable future.

"Novel treatment strategies improve our ability to delay the emergence of drug resistance without the need to deny treatment," Laxminarayan said.

Wil Milhous, associate dean for research at the University of South Florida's College of Public Health, said the research is "clearly a superb breakthrough in mathematical modeling applied to malaria drug deployment." Milhous has worked to develop new drugs for malaria for more than 25 years and is unaffiliated with the study.

"We have done the math in drug development, but only in terms of the cost of goods for drug combinations to include advanced preclinical and clinical testing. These are extremely time-consuming and costly but critical to regulatory approval," Milhous said. "Now we have a highly quantitative reality check that poor implementation strategies doom drugs to failure."