What do Emperor Charles V, Thomas Jefferson, and King Tut all have in common? Each historical figure is thought to have suffered from malaria at some point during his life.
Plasmodium, malaria’s causative organism, is known as much for its effects on great civilizations and their leaders as for its present world-wide disease burden. Yearly, it is responsible for over 200 million cases of malaria and over 600 thousand malaria-related deaths.
In this week’s NEJM, two groups of researchers report important findings in the battle against malaria: one provides cause for concern, and the other, a potential hope.
For the last decade, artemisinin-combination therapy (ACT) has been the recommended first-line therapy for treatment of Plasmodium falciparum malaria. However, resistance to artemisinin was identified in certain endemic areas as early as 2006. This week’s article from the Tracking Resistance to Artemisinin Collaboration (TRAC) revealed concerning developments in the prevalence and geographic spread of artemisinin resistance.
TRAC enrolled patients with acute uncomplicated falciparum malaria and fever at 15 sites across Africa and Asia. In an open-label randomized format, patients were treated with either 2mg/kg or 4mg/kg of artesunate, an artemisinin derivative, followed by a full standard 3-day course of an ACT regimen. Parasite clearance rates were calculated for all participants. While no significant difference in clearance rates were observed between treatment groups, rising rates of artemisinin resistance were documented in Eastern Myanmar, Western Cambodia and Thailand, and Southern Vietnam, and emerging resistance was documented in Myanmar, Southern Laos, and Northeastern Cambodia.
In this concerning context, the development of new antimalarial agents should generate significant excitement. The second of the two publications reports on KAE609, a first-in-class novel antiparasitic that acts via inhibition of a plasmodium plasma-membrane sodium-ATPase. In a phase II, open-label study, 21 patients with Plasmodium vivax or Plasmodium falciparum mono-infections were enrolled at three locations in Thailand. Participants were given KAE609 (30mg/day) for 3 days, followed by a course of standard antimalarial therapy beginning on day five. Blood samples were collected at regular intervals to allow for safety monitoring and calculation of parasite clearance times, defined as the interval from starting treatment to the first blood smear negative for parasites.
Following KAE609 administration, median time to parasite clearance was 12 hours. There was no evidence of treatment failure. Two serious adverse events (fever) were reported, but no reported adverse events led to treatment discontinuation.
In the face of rising prevalence and geographic spread of artemisinin resistance, what should those involved in malaria prevention and treatment do? Firstly, all is not lost for ACT. While TRAC authors found increasing prevalence and geographic spread of artemisinin resistance, this was only isolated to Southeast Asia and was not yet present in the Indian and African areas they surveyed. Additionally, they found that resistant strains responded to prolonged artemisinin courses (6 days versus the standard 3 days). Secondly, as exciting as the KAE609 findings are, the current data are limited and the drug is not yet ready for the limelight. The large randomized control studies required to assess safety and efficacy for KAE609 and other novel drugs will take time. In the meantime, interventions should focus on refining existing strategies. The World Health Organization recently recommended that a single dose of primaquine be administered with ACT to limit the spread of artemisinin resistance. In order to continue to achieve this goal, the organization will need to consider further innovations in the area of treatment (e.g. improving primaquine compliance, extending ACT dosing) and vector control.
As NEJM Deputy Editor Dr. Lindsey Baden notes, “Plasmodium falciparum continues to evolve and evade our therapeutic options. The potential loss of the artemisinin class is likely to have a substantial impact on current malaria control efforts. Hopefully the safety and activity of KAE609 can be shown in larger trials as novel therapies are needed.”
For more on this topic, see the accompanying editorial from Brian Greenwood at the London School of Hygiene and Tropical Medicine, and Perspective article on the origins of antimalarial-drug resistance, including an audio interview with Randall Packard from Johns Hopkins School of Medicine.