Emerging resistance to popular antimalarials, called artemisinins, may be a lot more serious than researchers thought — it might have consequences for other drugs that treat the disease too, a new study shows. This is the first time multi-drug tolerance has been shown in the malaria parasite.
When malaria parasites in a lab become resistant to artemisinins, which are part of the WHO’s recommended first-line treatment for the most severe malaria parasite, they can also become tolerant to the unrelated drugs that are paired with the class, according to a study in Emerging Infectious Diseases today. Tolerance means that malaria parasites survive the treatment, but can't multiply, and is not as serious as resistance, which means parasites continue to reproduce. Current resistance tests weren't designed to detect this kind of tolerance, so scientists have no way of knowing if malaria parasites have developed it in the field.
Malaria parasites survive the treatment, but can't multiply
Malaria is caused by a parasite called Plasmodium that's transmitted through mosquito bites. In 2012, the disease caused 207 million clinical episodes and over 600,000 deaths worldwide. Patients who are diagnosed with malaria are often treated with combination therapies that pair artemisinins — drugs designed to reduce the number of Plasmodium parasites in the blood — with a "partner drug" that can eliminate remaining parasites. It's a popular approach; in 2013, countries with malaria procured a total of 392 million ACT treatment courses. Unfortunately, not everyone uses artemisinin along with other drugs, which leads to resistance. As of February, five countries had reported artemisinin resistance, including Cambodia, Thailand, and Vietnam.
Patients who are infected with resistant parasites tend to recover, but that's only if they're treated with an effective partner drug. That's why today's study is so worrisome; it hints that artemisinin resistance might help parasites survive the drugs that are meant to prevent resistance from spreading. In the study, researchers treated malaria parasites in a lab with artemisinin for five years. The resulting offspring, all of which were resistant to artemisinin, were then treated with 10 different unrelated antimalarial drugs — many of which are used in combination therapies.
Tolerant parasites go dormant, reducing their metabolism until they stop growing
The researchers discovered that the extended artemisinin treatment caused the parasites to develop tolerance to most of the drugs — including quinine, chloroquine, and mefloquine. Tolerant parasites survive the treatment by going dormant, reducing their metabolism until they stop growing and waiting for "better times," says Françoise Benoit-Vical, director of France's National Institute of Health and Medical Research and a co-author of the study. "Once the drug is withdrawn, they start developing again."
Multi-drug tolerance has never been found in malaria parasites before, Benoit-Vical says. Because these tests were performed in controlled lab conditions using specific drug concentrations, it's possible that parasites in the field haven't and won't develop the tolerance described in the study. But current field tests can’t detect this type of tolerance, so scientists don't know if that's the case. That means that new dedicated tests will have to be developed — and they will have to implemented soon.
"A major threat to antimalarial drug policy."
"We strongly recommend that it should be urgently tested in the field," Benoit-Vical says. "If this 'multidrug tolerance' is confirmed in the field that represents a major threat to antimalarial drug policy."
Artemisinin is the cornerstone of current combination therapies against the most severe malaria parasite, P. falciparum. However, poor patient adherence to prescribed drugs, bad treatment practices, and the widespread availability of the drug — a drug that patients sometimes take alone — has resulted in resistance. That's why the WHO has called for the removal of oral artemisinin-based treatments that aren't used in combination with other drugs. But scientists don't understand the basis of artemisinin resistance or how why it leads to tolerance, says Benoit-Vical; it might not be enough to push for the wider use of combination therapies. Only atovaquone, which kills malaria parasites differently, wasn’t affected by tolerance. Unfortunately, that drug also prompts resistance quickly when it's used in areas where ACT resistance has already developed.
Whether multi-drug tolerance can occur outside the lab remains to be seen. Scientists also don’t know whether multi-drug tolerance can occur when patients use ACT, instead of artemisinin alone, Benoit-Vical says. "This is precisely why this should be monitored in the field."